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1. Immune digital twins for complex human pathologies: applications, limitations, and challenges

Author: Niarakis, Anna, Laubenbacher, Reinhard, An, Gary, Ilan, Yaron, Fisher, Jasmin, Flobak, Åsmund, Reiche, Kristin, Rodríguez Martínez, María, Geris, Liesbet, Ladeira, Luiz, Veschini, Lorenzo, Blinov, Michael L., Messina, Francesco, Fonseca, Luis L., Ferreira, Sandra, Montagud, Arnau, Noël, Vincent, Marku, Malvina, Tsirvouli, Eirini, Torres, Marcella M., Harris, Leonard A., Sego, T. J., Cockrell, Chase, Shick, Amanda E., Balci, Hasan, Salazar, Albin, Rian, Kinza, Hemedan, Ahmed Abdelmonem, Esteban-Medina, Marina, Staumont, Bernard, Hernandez-Vargas, Esteban, Martis B, Shiny, Madrid-Valiente, Alejandro, Karampelesis, Panagiotis, Sordo Vieira, Luis, Harlapur, Pradyumna, Kulesza, Alexander, Nikaein, Niloofar, Garira, Winston, Malik Sheriff, Rahuman S., Thakar, Juilee, Tran, Van Du T., Carbonell-Caballero, Jose, Safaei, Soroush, Valencia, Alfonso, Zinovyev, Andrei, and Glazier, James A.
Published: 2024
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2. The mechanistic functional landscape of retinitis pigmentosa: a machine learning-driven approach to therapeutic target discovery

Author: Esteban-Medina, Marina, Loucera, Carlos, Rian, Kinza, Velasco, Sheyla, Olivares-González, Lorena, Rodrigo, Regina, Dopazo, Joaquin, and Peña-Chilet, Maria
Published: 2024
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3. Real-world evidence with a retrospective cohort of 15,968 COVID-19 hospitalized patients suggests 21 new effective treatments

Author: Loucera, Carlos, Carmona, Rosario, Esteban-Medina, Marina, Bostelmann, Gerrit, Muñoyerro-Muñiz, Dolores, Villegas, Román, Peña-Chilet, María, and Dopazo, Joaquín
Published: 2023
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4. drexml: A command line tool and Python package for drug repurposing

Author: Esteban-Medina, Marina, primary, de la Oliva Roque, Víctor Manuel, additional, Herráiz-Gil, Sara, additional, Peña-Chilet, María, additional, Dopazo, Joaquín, additional, and Loucera, Carlos, additional
Published: 2024
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5. drexml: A command line tool and Python package for drug repurposing

Author: Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Fundación BBVA, Esteban-Medina, Marina [0000-0003-2632-9587], Herráiz-Gil, Sara [0000-0003-0682-5225], Dopazo, Joaquín [0000-0003-3318-120X], Loucera, Carlos [0000-0001-9598-6965], Esteban-Medina, Marina, Oliva Roque, Víctor Manuel de la, Herráiz-Gil, Sara, Peña-Chilet, María, Dopazo, Joaquín, Loucera, Carlos, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Fundación BBVA, Esteban-Medina, Marina [0000-0003-2632-9587], Herráiz-Gil, Sara [0000-0003-0682-5225], Dopazo, Joaquín [0000-0003-3318-120X], Loucera, Carlos [0000-0001-9598-6965], Esteban-Medina, Marina, Oliva Roque, Víctor Manuel de la, Herráiz-Gil, Sara, Peña-Chilet, María, Dopazo, Joaquín, and Loucera, Carlos
Abstract: We introduce drexml, a command line tool and Python package for rational data-driven drug repurposing. The package employs machine learning and mechanistic signal transduction modeling to identify drug targets capable of regulating a particular disease. In addition, it employs explainability tools to contextualize potential drug targets within the functional landscape of the disease. The methodology is validated in Fanconi Anemia and Familial Melanoma, two distinct rare diseases where there is a pressing need for solutions. In the Fanconi Anemia case, the model successfully predicts previously validated repurposed drugs, while in the Familial Melanoma case, it identifies a promising set of drugs for further investigation.
Published: 2024

6. Additional file 1 of The mechanistic functional landscape of retinitis pigmentosa: a machine learning-driven approach to therapeutic target discovery

Author: Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Junta de Andalucía, Instituto de Salud Carlos III, Generalitat Valenciana, Esteban-Medina, Marina [0000-0003-2632-9587], Loucera, Carlos [0000-0001-9598-6965], Dopazo, Joaquín [0000-0003-3318-120X], Peña-Chilet, María [0000-0002-6445-9617], Esteban-Medina, Marina, Loucera, Carlos, Rian, Kinza, Velasco, Sheyla, Olivares-González, Lorena, Rodrigo, Regina, Dopazo, Joaquín, Peña-Chilet, María, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Junta de Andalucía, Instituto de Salud Carlos III, Generalitat Valenciana, Esteban-Medina, Marina [0000-0003-2632-9587], Loucera, Carlos [0000-0001-9598-6965], Dopazo, Joaquín [0000-0003-3318-120X], Peña-Chilet, María [0000-0002-6445-9617], Esteban-Medina, Marina, Loucera, Carlos, Rian, Kinza, Velasco, Sheyla, Olivares-González, Lorena, Rodrigo, Regina, Dopazo, Joaquín, and Peña-Chilet, María
Published: 2024

7. loucerac/drexml: v1.1.1

Author: Loucera, Carlos [0000-0001-9598-6965], Esteban-Medina, Marina [0000-0003-2632-9587], Loucera, Carlos, Esteban-Medina, Marina, Oliva Roque, Víctor Manuel de la, Herráiz-Gil, Sara, Loucera, Carlos [0000-0001-9598-6965], Esteban-Medina, Marina [0000-0003-2632-9587], Loucera, Carlos, Esteban-Medina, Marina, Oliva Roque, Víctor Manuel de la, and Herráiz-Gil, Sara
Published: 2024

8. Genome-scale mechanistic modeling of signaling pathways made easy: A bioconductor/cytoscape/web server framework for the analysis of omic data

Author: Rian, Kinza, Hidalgo, Marta R., Çubuk, Cankut, Falco, Matias M., Loucera, Carlos, Esteban-Medina, Marina, Alamo-Alvarez, Inmaculada, Peña-Chilet, María, and Dopazo, Joaquín
Published: 2021
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9. Drug-target identification in COVID-19 disease mechanisms using computational systems biology approaches

Author: Niarakis, Anna, Ostaszewski, Marek, Mazein, Alexander, Kuperstein, Inna, Kutmon, Martina, Gillespie, Marc E., Funahashi, Akira, Acencio, Marcio Luis, Hemedan, Ahmed, Aichem, Michael, Klein, Karsten, Czauderna, Tobias, Burtscher, Felicia, Yamada, Takahiro G., Hiki, Yusuke, Hiroi, Noriko F., Hu, Finterly, Pham, Nhung, Ehrhart, Friederike, Willighagen, Egon L., Valdeolivas, Alberto, Dugourd, Aurelien, Messina, Francesco, Esteban-Medina, Marina, Peña-Chilet, Maria, Rian, Kinza, Soliman, Sylvain, Aghamiri, Sara Sadat, Puniya, Bhanwar Lal, Naldi, Aurélien, Helikar, Tomáš, Singh, Vidisha, Fernández, Marco Fariñas, Bermudez, Viviam, Tsirvouli, Eirini, Montagud, Arnau, Noël, Vincent, Ponce-de-Leon, Miguel, Maier, Dieter, Bauch, Angela, Gyori, Benjamin M., Bachman, John A., Luna, Augustin, Piñero, Janet, Furlong, Laura I., Balaur, Irina, Rougny, Adrien, Jarosz, Yohan, Overall, Rupert, Phair, Robert, Perfetto, Livia, Matthews, Lisa, Rex, Devasahayam Arokia Balaya, Orlic-Milacic, Marija, Gomez, Luis Cristobal Monraz, De Meulder, Bertrand, Ravel, Jean Marie, Jassal, Bijay, Satagopam, Venkata, Wu, Guanming, Golebiewski, Martin, Gawron, Piotr, Calzone, Laurence, Beckmann, Jacques S., Evelo, Chris T., D’Eustachio, Peter, Schreiber, Falk, Saez-Rodriguez, Julio, Dopazo, Joaquin, Kuiper, Martin, Valencia, Alfonso, Wolkenhauer, Olaf, Kitano, Hiroaki, Barillot, Emmanuel, Auffray, Charles, Balling, Rudi, Schneider, Reinhard, Niarakis, Anna, Ostaszewski, Marek, Mazein, Alexander, Kuperstein, Inna, Kutmon, Martina, Gillespie, Marc E., Funahashi, Akira, Acencio, Marcio Luis, Hemedan, Ahmed, Aichem, Michael, Klein, Karsten, Czauderna, Tobias, Burtscher, Felicia, Yamada, Takahiro G., Hiki, Yusuke, Hiroi, Noriko F., Hu, Finterly, Pham, Nhung, Ehrhart, Friederike, Willighagen, Egon L., Valdeolivas, Alberto, Dugourd, Aurelien, Messina, Francesco, Esteban-Medina, Marina, Peña-Chilet, Maria, Rian, Kinza, Soliman, Sylvain, Aghamiri, Sara Sadat, Puniya, Bhanwar Lal, Naldi, Aurélien, Helikar, Tomáš, Singh, Vidisha, Fernández, Marco Fariñas, Bermudez, Viviam, Tsirvouli, Eirini, Montagud, Arnau, Noël, Vincent, Ponce-de-Leon, Miguel, Maier, Dieter, Bauch, Angela, Gyori, Benjamin M., Bachman, John A., Luna, Augustin, Piñero, Janet, Furlong, Laura I., Balaur, Irina, Rougny, Adrien, Jarosz, Yohan, Overall, Rupert, Phair, Robert, Perfetto, Livia, Matthews, Lisa, Rex, Devasahayam Arokia Balaya, Orlic-Milacic, Marija, Gomez, Luis Cristobal Monraz, De Meulder, Bertrand, Ravel, Jean Marie, Jassal, Bijay, Satagopam, Venkata, Wu, Guanming, Golebiewski, Martin, Gawron, Piotr, Calzone, Laurence, Beckmann, Jacques S., Evelo, Chris T., D’Eustachio, Peter, Schreiber, Falk, Saez-Rodriguez, Julio, Dopazo, Joaquin, Kuiper, Martin, Valencia, Alfonso, Wolkenhauer, Olaf, Kitano, Hiroaki, Barillot, Emmanuel, Auffray, Charles, Balling, Rudi, and Schneider, Reinhard
Abstract: Introduction: The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing. Methods: Extensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors. Results: Results revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19. Discussion: The key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies., Peer Reviewed
Published: 2024

10. Nutraceutical supplementation in inherited retinal dystrophies

Author: Velasco, Sheyla, primary, Olivares‐González, Lorena, additional, Morales, Silvia, additional, Valencia, Daira, additional, Esteban‐Medina, Marina, additional, Loucera, Carlos, additional, Salom, David, additional, García, Emilio González, additional, del Castillo, Jose Miguel Soriano, additional, and Rodrigo, Regina, additional
Published: 2024
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11. Erratum To: COVID‐19 Disease Map, a computational knowledge repository of virus‐host interaction mechanisms

Author: Ostaszewski, Marek, Niarakis, Anna, Mazein, Alexander, Kuperstein, Inna, Phair, Robert, Orta‐Resendiz, Aurelio, Singh, Vidisha, Aghamiri, Sara Sadat, Acencio, Marcio Luis, Glaab, Enrico, Ruepp, Andreas, Fobo, Gisela, Montrone, Corinna, Brauner, Barbara, Frishman, Goar, Monraz Gómez, Luis Cristóbal, Somers, Julia, Hoch, Matti, Kumar Gupta, Shailendra, Scheel, Julia, Borlinghaus, Hanna, Czauderna, Tobias, Schreiber, Falk, Montagud, Arnau, Ponce de Leon, Miguel, Funahashi, Akira, Hiki, Yusuke, Hiroi, Noriko, Yamada, Takahiro G, Dräger, Andreas, Renz, Alina, Naveez, Muhammad, Bocskei, Zsolt, Messina, Francesco, Börnigen, Daniela, Fergusson, Liam, Conti, Marta, Rameil, Marius, Nakonecnij, Vanessa, Vanhoefer, Jakob, Schmiester, Leonard, Wang, Muying, Ackerman, Emily E, Shoemaker, Jason E, Zucker, Jeremy, Oxford, Kristie, Teuton, Jeremy, Kocakaya, Ebru, Summak, Gökçe Yağmur, Hanspers, Kristina, Kutmon, Martina, Coort, Susan, Eijssen, Lars, Ehrhart, Friederike, Rex, D A B, Slenter, Denise, Martens, Marvin, Pham, Nhung, Haw, Robin, Jassal, Bijay, Matthews, Lisa, Orlic‐Milacic, Marija, Senff‐Ribeiro, Andrea, Rothfels, Karen, Shamovsky, Veronica, Stephan, Ralf, Sevilla, Cristoffer, Varusai, Thawfeek, Ravel, Jean‐Marie, Fraser, Rupsha, Ortseifen, Vera, Marchesi, Silvia, Gawron, Piotr, Smula, Ewa, Heirendt, Laurent, Satagopam, Venkata, Wu, Guanming, Riutta, Anders, Golebiewski, Martin, Owen, Stuart, Goble, Carole, Hu, Xiaoming, Overall, Rupert W, Maier, Dieter, Bauch, Angela, Gyori, Benjamin M, Bachman, John A, Vega, Carlos, Grouès, Valentin, Vazquez, Miguel, Porras, Pablo, Licata, Luana, Iannuccelli, Marta, Sacco, Francesca, Nesterova, Anastasia, Yuryev, Anton, de Waard, Anita, Turei, Denes, Luna, Augustin, Babur, Ozgun, Soliman, Sylvain, Valdeolivas, Alberto, Esteban‐Medina, Marina, Peña‐Chilet, Maria, Rian, Kinza, Helikar, Tomáš, Puniya, Bhanwar Lal, Modos, Dezso, Treveil, Agatha, Olbei, Marton, De Meulder, Bertrand, Ballereau, Stephane, Dugourd, Aurélien, Naldi, Aurélien, Noël, Vincent, Calzone, Laurence, Sander, Chris, Demir, Emek, Korcsmaros, Tamas, Freeman, Tom C, Augé, Franck, Beckmann, Jacques S, Hasenauer, Jan, Wolkenhauer, Olaf, Willighagen, Egon L, Pico, Alexander R, Evelo, Chris T, Gillespie, Marc E, Stein, Lincoln D, Hermjakob, Henning, D'Eustachio, Peter, Saez‐Rodriguez, Julio, Dopazo, Joaquin, Valencia, Alfonso, Kitano, Hiroaki, Barillot, Emmanuel, Auffray, Charles, Balling, Rudi, and Schneider, Reinhard
Published: 2021
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12. Real world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients

Author: Loucera, Carlos, Peña-Chilet, María, Esteban-Medina, Marina, Muñoyerro-Muñiz, Dolores, Villegas, Román, Lopez-Miranda, Jose, Rodriguez-Baño, Jesus, Túnez, Isaac, Bouillon, Roger, Dopazo, Joaquin, and Quesada Gomez, Jose Manuel
Published: 2021
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13. Mechanistic modeling of the SARS-CoV-2 disease map

Author: Rian, Kinza, Esteban-Medina, Marina, Hidalgo, Marta R., Çubuk, Cankut, Falco, Matias M., Loucera, Carlos, Gunyel, Devrim, Ostaszewski, Marek, Peña-Chilet, María, and Dopazo, Joaquín
Published: 2021
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14. COVID19 Disease Map, a computational knowledge repository of virus–host interaction mechanisms

Author: Ostaszewski, Marek, Niarakis, Anna, Mazein, Alexander, Kuperstein, Inna, Phair, Robert, Orta‐Resendiz, Aurelio, Singh, Vidisha, Aghamiri, Sara Sadat, Acencio, Marcio Luis, Glaab, Enrico, Ruepp, Andreas, Fobo, Gisela, Montrone, Corinna, Brauner, Barbara, Frishman, Goar, Monraz Gómez, Luis Cristóbal, Somers, Julia, Hoch, Matti, Kumar Gupta, Shailendra, Scheel, Julia, Borlinghaus, Hanna, Czauderna, Tobias, Schreiber, Falk, Montagud, Arnau, Ponce de Leon, Miguel, Funahashi, Akira, Hiki, Yusuke, Hiroi, Noriko, Yamada, Takahiro G, Dräger, Andreas, Renz, Alina, Naveez, Muhammad, Bocskei, Zsolt, Messina, Francesco, Börnigen, Daniela, Fergusson, Liam, Conti, Marta, Rameil, Marius, Nakonecnij, Vanessa, Vanhoefer, Jakob, Schmiester, Leonard, Wang, Muying, Ackerman, Emily E, Shoemaker, Jason E, Zucker, Jeremy, Oxford, Kristie, Teuton, Jeremy, Kocakaya, Ebru, Summak, Gökçe Yağmur, Hanspers, Kristina, Kutmon, Martina, Coort, Susan, Eijssen, Lars, Ehrhart, Friederike, Rex, Devasahayam Arokia Balaya, Slenter, Denise, Martens, Marvin, Pham, Nhung, Haw, Robin, Jassal, Bijay, Matthews, Lisa, Orlic‐Milacic, Marija, Senff-Ribeiro, Andrea, Rothfels, Karen, Shamovsky, Veronica, Stephan, Ralf, Sevilla, Cristoffer, Varusai, Thawfeek, Ravel, Jean‐Marie, Fraser, Rupsha, Ortseifen, Vera, Marchesi, Silvia, Gawron, Piotr, Smula, Ewa, Heirendt, Laurent, Satagopam, Venkata, Wu, Guanming, Riutta, Anders, Golebiewski, Martin, Owen, Stuart, Goble, Carole, Hu, Xiaoming, Overall, Rupert W, Maier, Dieter, Bauch, Angela, Gyori, Benjamin M, Bachman, John A, Vega, Carlos, Grouès, Valentin, Vazquez, Miguel, Porras, Pablo, Licata, Luana, Iannuccelli, Marta, Sacco, Francesca, Nesterova, Anastasia, Yuryev, Anton, de Waard, Anita, Turei, Denes, Luna, Augustin, Babur, Ozgun, Soliman, Sylvain, Valdeolivas, Alberto, Esteban‐Medina, Marina, Peña‐Chilet, Maria, Rian, Kinza, Helikar, Tomáš, Puniya, Bhanwar Lal, Modos, Dezso, Treveil, Agatha, Olbei, Marton, De Meulder, Bertrand, Ballereau, Stephane, Dugourd, Aurélien, Naldi, Aurélien, Noël, Vincent, Calzone, Laurence, Sander, Chris, Demir, Emek, Korcsmaros, Tamas, Freeman, Tom C, Augé, Franck, Beckmann, Jacques S, Hasenauer, Jan, Wolkenhauer, Olaf, Willighagen, Egon L, Pico, Alexander R, Evelo, Chris T, Gillespie, Marc E, Stein, Lincoln D, Hermjakob, Henning, D'Eustachio, Peter, Saez‐Rodriguez, Julio, Dopazo, Joaquin, Valencia, Alfonso, Kitano, Hiroaki, Barillot, Emmanuel, Auffray, Charles, Balling, Rudi, and Schneider, Reinhard
Published: 2021
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15. Functional Profiling of Soft Tissue Sarcoma Using Mechanistic Models

Author: Payá-Milans, Miriam, primary, Peña-Chilet, María, additional, Loucera, Carlos, additional, Esteban-Medina, Marina, additional, and Dopazo, Joaquín, additional
Published: 2023
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16. The mechanistic functional landscape of Retinitis Pigmentosa: a Machine Learning driven approach to drug Repurposing.

Author: Esteban-Medina, Marina, primary, Loucera, Carlos, additional, Rian, Kinza, additional, Velasco, Sheyla, additional, Olivares-Gonzalez, Lorena, additional, Rodrigo, Regina, additional, Dopazo, Joaquin, additional, and Peña-Chilet, Maria, additional
Published: 2023
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17. Drug repurposing for COVID-19 using machine learning and mechanistic models of signal transduction circuits related to SARS-CoV-2 infection

Author: Loucera, Carlos, Esteban-Medina, Marina, Rian, Kinza, Falco, Matías M., Dopazo, Joaquín, and Peña-Chilet, María
Published: 2020
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18. Real-world evidence with a retrospective cohort of 15,968 Andalusian COVID-19 hospitalized patients suggests 21 new effective treatments and one drug that increases death risk

Author: Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Loucera, Carlos [0000-0001-9598-6965], Carmona, Rosario [0000-0002-4235-2886], Esteban-Medina, Marina [0000-0003-2632-9587], Bostelmann, Gerrit [0000-0002-1690-6347], Villegas-Portero, Román [0000-0003-0845-0172], Dopazo, Joaquín [0000-0003-3318-120X], Loucera, Carlos, Carmona, Rosario, Esteban-Medina, Marina, Bostelmann, Gerrit, Muñoyerro-Muñiz, Dolores, Villegas-Portero, Román, Peña-Chilet, María, Dopazo, Joaquín, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Loucera, Carlos [0000-0001-9598-6965], Carmona, Rosario [0000-0002-4235-2886], Esteban-Medina, Marina [0000-0003-2632-9587], Bostelmann, Gerrit [0000-0002-1690-6347], Villegas-Portero, Román [0000-0003-0845-0172], Dopazo, Joaquín [0000-0003-3318-120X], Loucera, Carlos, Carmona, Rosario, Esteban-Medina, Marina, Bostelmann, Gerrit, Muñoyerro-Muñiz, Dolores, Villegas-Portero, Román, Peña-Chilet, María, and Dopazo, Joaquín
Abstract: Despite the extensive vaccination campaigns in many countries, COVID-19 is still a major worldwide health problem because of its associated morbidity and mortality. Therefore, finding efficient treatments as fast as possible is a pressing need. Drug repurposing constitutes a convenient alternative when the need for new drugs in an unexpected medical scenario is urgent, as is the case with COVID-19. Using data from a central registry of electronic health records (the Andalusian Population Health Database, BPS), the effect of prior consumption of drugs for other indications previous to the hospitalization with respect to patient survival was studied on a retrospective cohort of 15,968 individuals, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020. Covariate-adjusted hazard ratios and analysis of lymphocyte progression curves support a significant association between consumption of 21 different drugs and better patient survival. Contrarily, one drug, furosemide, displayed a significant increase in patient mortality.
Published: 2022

19. An SPM-Enriched Marine Oil Supplement Shifted Microglia Polarization toward M2, Ameliorating Retinal Degeneration in rd10 Mice

Author: Ministerio de Economía, Industria y Competitividad (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Olivares-González, Lorena, Velasco, Sheyla, Gallego, Idoia, Esteban-Medina, Marina, Puras, Gustavo, Loucera, Carlos, Martínez-Romero, Alicia, Peña-Chilet, María, Pedraz, José Luis, Rodrigo, Regina, Ministerio de Economía, Industria y Competitividad (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Olivares-González, Lorena, Velasco, Sheyla, Gallego, Idoia, Esteban-Medina, Marina, Puras, Gustavo, Loucera, Carlos, Martínez-Romero, Alicia, Peña-Chilet, María, Pedraz, José Luis, and Rodrigo, Regina
Abstract: Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy causing progressive vision loss. It is accompanied by chronic and sustained inflammation, including M1 microglia activation. This study evaluated the effect of an essential fatty acid (EFA) supplement containing specialized pro-resolving mediators (SPMs), on retinal degeneration and microglia activation in rd10 mice, a model of RP, as well as on LPS-stimulated BV2 cells. The EFA supplement was orally administered to mice from postnatal day (P)9 to P18. At P18, the electrical activity of the retina was examined by electroretinography (ERG) and innate behavior in response to light were measured. Retinal degeneration was studied via histology including the TUNEL assay and microglia immunolabeling. Microglia polarization (M1/M2) was assessed by flow cytometry, qPCR, ELISA and histology. Redox status was analyzed by measuring antioxidant enzymes and markers of oxidative damage. Interestingly, the EFA supplement ameliorated retinal dysfunction and degeneration by improving ERG recording and sensitivity to light, and reducing photoreceptor cell loss. The EFA supplement reduced inflammation and microglia activation attenuating M1 markers as well as inducing a shift to the M2 phenotype in rd10 mouse retinas and LPS-stimulated BV2 cells. It also reduced oxidative stress markers of lipid peroxidation and carbonylation. These findings could open up new therapeutic opportunities based on resolving inflammation with oral supplementation with SPMs such as the EFA supplement.
Published: 2023

20. Drug-target identification in COVID-19 disease mechanisms using computational systems biology approaches

Author: Sanofi, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), German Research Foundation, Ministero della Salute, European Commission, Generalitat de Catalunya, National Institutes of Health (US), Klaus Tschira Foundation, National Library of Medicine (US), Niarakis, Anna, Ostaszewski, Marek, Mazein, Alexander, Kuperstein, Inna, Kutmon, Martina, Gillespie, Marc E., Funahashi, Akira, Acencio, Marcio Luis, Hemedan, Ahmed, Aichem, Michael, Klein, Karsten, Czauderna, Tobias, Burtscher, Felicia, Yamada, Takahiro G., Hiki, Yusuke, Hiroi, Noriko F., Hu, Finterly, Pham, Nhung, Ehrhart, Friederike, Willighagen, Egon L., Valdeolivas, Alberto, Dugourd, Aurelien, Messina, Francesco, Esteban-Medina, Marina, Peña-Chilet, María, Rian, Kinza, Soliman, Sylvain, Aghamiri, Sara Sadat, Lal Puniya, Bhanwar, Naldi, Aurelien, Helikar, Tomas, Singh, Vidisha, Fariñas Fernández, Marco, Bermudez, Viviam, Tsirvouli, Eirini, Montagud, Arnau, Noël, Vincent, Ponce de León, Miguel, Maier, Dieter, Bauch, Angela, Gyori, Benjamin M., Bachman, John A., Luna, Augustin, Piñero, Janet, Furlong, Laura I., Balaur, Irina BalaurIrina, Rougny, Adrien, Jarosz, Yohan, Overall, Rupert W., Phair, Robert, Perfetto, Livia, Matthews, Lisa, Balaya Rex, Devasahayam Arokia, Orlic-Milacic, Marija, Monraz Gómez, Luis Cristóbal, De Meulder, Bertrand, Ravel, Jean Marie, Jassal, Bijay, Satagopam, Venkata, Wu, Guanming, Golebiewski, Martin, Gawron, Piotr, Calzone, Laurence, Beckmann, Jacques S., Evelo, Chris T., D’Eustachio, Peter, Schreiber, Falk, Sáez-Rodríguez, Julio, Dopazo, Joaquín, Kuiper, Martin, Valencia, Alfonso, Wolkenhauer, Olaf, Kitano, Hiroaki, Barillot, Emmanuel, Auffray, Charles, Balling, Rudi, Schneider, Reinhard, COVID- Disease Map Community the COVID-19 Disease Map Community, Sanofi, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), German Research Foundation, Ministero della Salute, European Commission, Generalitat de Catalunya, National Institutes of Health (US), Klaus Tschira Foundation, National Library of Medicine (US), Niarakis, Anna, Ostaszewski, Marek, Mazein, Alexander, Kuperstein, Inna, Kutmon, Martina, Gillespie, Marc E., Funahashi, Akira, Acencio, Marcio Luis, Hemedan, Ahmed, Aichem, Michael, Klein, Karsten, Czauderna, Tobias, Burtscher, Felicia, Yamada, Takahiro G., Hiki, Yusuke, Hiroi, Noriko F., Hu, Finterly, Pham, Nhung, Ehrhart, Friederike, Willighagen, Egon L., Valdeolivas, Alberto, Dugourd, Aurelien, Messina, Francesco, Esteban-Medina, Marina, Peña-Chilet, María, Rian, Kinza, Soliman, Sylvain, Aghamiri, Sara Sadat, Lal Puniya, Bhanwar, Naldi, Aurelien, Helikar, Tomas, Singh, Vidisha, Fariñas Fernández, Marco, Bermudez, Viviam, Tsirvouli, Eirini, Montagud, Arnau, Noël, Vincent, Ponce de León, Miguel, Maier, Dieter, Bauch, Angela, Gyori, Benjamin M., Bachman, John A., Luna, Augustin, Piñero, Janet, Furlong, Laura I., Balaur, Irina BalaurIrina, Rougny, Adrien, Jarosz, Yohan, Overall, Rupert W., Phair, Robert, Perfetto, Livia, Matthews, Lisa, Balaya Rex, Devasahayam Arokia, Orlic-Milacic, Marija, Monraz Gómez, Luis Cristóbal, De Meulder, Bertrand, Ravel, Jean Marie, Jassal, Bijay, Satagopam, Venkata, Wu, Guanming, Golebiewski, Martin, Gawron, Piotr, Calzone, Laurence, Beckmann, Jacques S., Evelo, Chris T., D’Eustachio, Peter, Schreiber, Falk, Sáez-Rodríguez, Julio, Dopazo, Joaquín, Kuiper, Martin, Valencia, Alfonso, Wolkenhauer, Olaf, Kitano, Hiroaki, Barillot, Emmanuel, Auffray, Charles, Balling, Rudi, Schneider, Reinhard, and COVID- Disease Map Community the COVID-19 Disease Map Community
Abstract: Introduction: The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing., Methods: Extensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors., Results: Results revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19., Discussion: The key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies.
Published: 2023

21. Supplementary Material: Real-world evidence with a retrospective cohort of 15,968 COVID-19 hospitalized patients suggests 21 new effective treatments

Author: Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Junta de Andalucía, European Commission, Loucera, Carlos, Carmona, Rosario, Esteban-Medina, Marina, Bostelmann, Gerrit, Muñoyerro-Muñiz, Dolores, Villegas, Román, Peña-Chilet, María, Dopazo, Joaquín, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Junta de Andalucía, European Commission, Loucera, Carlos, Carmona, Rosario, Esteban-Medina, Marina, Bostelmann, Gerrit, Muñoyerro-Muñiz, Dolores, Villegas, Román, Peña-Chilet, María, and Dopazo, Joaquín
Abstract: [Purpose] Despite the extensive vaccination campaigns in many countries, COVID-19 is still a major worldwide health problem because of its associated morbidity and mortality. Therefore, finding efficient treatments as fast as possible is a pressing need. Drug repurposing constitutes a convenient alternative when the need for new drugs in an unexpected medical scenario is urgent, as is the case with COVID-19., [Methods] Using data from a central registry of electronic health records (the Andalusian Population Health Database), the effect of prior consumption of drugs for other indications previous to the hospitalization with respect to patient outcomes, including survival and lymphocyte progression, was studied on a retrospective cohort of 15,968 individuals, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020., [Results] Covariate-adjusted hazard ratios and analysis of lymphocyte progression curves support a significant association between consumption of 21 different drugs and better patient survival. Contrarily, one drug, furosemide, displayed a significant increase in patient mortality., [Conclusions] In this study we have taken advantage of the availability of a regional clinical database to study the effect of drugs, which patients were taking for other indications, on their survival. The large size of the database allowed us to control covariates effectively.
Published: 2023

22. Real-world evidence with a retrospective cohort of 15,968 COVID-19 hospitalized patients suggests 21 new effective treatments

Author: Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Loucera, Carlos, Carmona, Rosario, Esteban-Medina, Marina, Bostelmann, Gerrit, Muñoyerro-Muñiz, Dolores, Villegas, Román, Peña-Chilet, María, Dopazo, Joaquín, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Loucera, Carlos, Carmona, Rosario, Esteban-Medina, Marina, Bostelmann, Gerrit, Muñoyerro-Muñiz, Dolores, Villegas, Román, Peña-Chilet, María, and Dopazo, Joaquín
Abstract: [Purpose] Despite the extensive vaccination campaigns in many countries, COVID-19 is still a major worldwide health problem because of its associated morbidity and mortality. Therefore, finding efficient treatments as fast as possible is a pressing need. Drug repurposing constitutes a convenient alternative when the need for new drugs in an unexpected medical scenario is urgent, as is the case with COVID-19., [Methods] Using data from a central registry of electronic health records (the Andalusian Population Health Database), the effect of prior consumption of drugs for other indications previous to the hospitalization with respect to patient outcomes, including survival and lymphocyte progression, was studied on a retrospective cohort of 15,968 individuals, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020., [Results] Covariate-adjusted hazard ratios and analysis of lymphocyte progression curves support a significant association between consumption of 21 different drugs and better patient survival. Contrarily, one drug, furosemide, displayed a significant increase in patient mortality., [Conclusions] In this study we have taken advantage of the availability of a regional clinical database to study the effect of drugs, which patients were taking for other indications, on their survival. The large size of the database allowed us to control covariates effectively.
Published: 2023

23. Functional Profiling of Soft Tissue Sarcoma Using Mechanistic Models

Author: Cancer Research UK, Associazione Italiana per la Ricerca sul Cancro, Asociación Española Contra el Cáncer, Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Junta de Andalucía, European Commission, Payá-Milans, Miriam, Peña-Chilet, María, Loucera, Carlos, Esteban-Medina, Marina, Dopazo, Joaquín, Cancer Research UK, Associazione Italiana per la Ricerca sul Cancro, Asociación Española Contra el Cáncer, Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Junta de Andalucía, European Commission, Payá-Milans, Miriam, Peña-Chilet, María, Loucera, Carlos, Esteban-Medina, Marina, and Dopazo, Joaquín
Abstract: Soft tissue sarcoma is an umbrella term for a group of rare cancers that are difficult to treat. In addition to surgery, neoadjuvant chemotherapy has shown the potential to downstage tumors and prevent micrometastases. However, finding effective therapeutic targets remains a research challenge. Here, a previously developed computational approach called mechanistic models of signaling pathways has been employed to unravel the impact of observed changes at the gene expression level on the ultimate functional behavior of cells. In the context of such a mechanistic model, RNA-Seq counts sourced from the Recount3 resource, from The Cancer Genome Atlas (TCGA) Sarcoma project, and non-diseased sarcomagenic tissues from the Genotype-Tissue Expression (GTEx) project were utilized to investigate signal transduction activity through signaling pathways. This approach provides a precise view of the relationship between sarcoma patient survival and the signaling landscape in tumors and their environment. Despite the distinct regulatory alterations observed in each sarcoma subtype, this study identified 13 signaling circuits, or elementary sub-pathways triggering specific cell functions, present across all subtypes, belonging to eight signaling pathways, which served as predictors for patient survival. Additionally, nine signaling circuits from five signaling pathways that highlighted the modifications tumor samples underwent in comparison to normal tissues were found. These results describe the protective role of the immune system, suggesting an anti-tumorigenic effect in the tumor microenvironment, in the process of tumor cell detachment and migration, or the dysregulation of ion homeostasis. Also, the analysis of signaling circuit intermediary proteins suggests multiple strategies for therapy.
Published: 2023

24. Using mechanistic models for the clinical interpretation of complex genomic variation

Author: Peña-Chilet, María, Esteban-Medina, Marina, Falco, Matias M., Rian, Kinza, Hidalgo, Marta R., Loucera, Carlos, and Dopazo, Joaquín
Published: 2019
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25. A versatile and interoperable computational framework for the analysis and modeling of COVID-19 disease mechanisms

Author: Niarakis, Anna, Ostaszewski, Marek, Mazein, Alexander, Kuperstein, Inna, Kutmon, Martina, Gillespie, Marc, Funahashi, Akira, Acencio, Marcio, Hemedan, Ahmed, Aichem, Michael, Klein, Karsten, Czauderna, Tobias, Burtscher, Felicia, Yamada, Takahiro, Hiki, Yusuke, Hiroi, Noriko, Hu, Finterly, Pham, Nhung, Ehrhart, Friederike, Willighagen, Egon, Valdeolivas, Alberto, Dugourd, Aurelien, Messina, Francesco, Esteban-Medina, Marina, Pena-Chilet, Maria, Rian, Kinza, Soliman, Sylvain, Aghamiri, Sara, Puniya, Bhanwar, Naldi, Aurelien, Helikar, Tomas, Singh, Vidisha, Farinas Fernandez, Marco, Bermudez, Viviam, Tsirvouli, Eirini, Montagud, Arnau, Noel, Vincent, Ponce de Leon, Miguel, Maier, Dieter, Bauch, Angela, Gyori, Benjamin, Bachman, John, Luna, Agustin, Pinero, Janet, Furlong, Laura, Balaur, Irina, Rougny, Adrien, Jarosz, Yohan, Overall, Rupert, Phair, Robert, Perfetto, Livia, Matthews, Lisa, Rex, Devasahayam, Orlic-Milacic, Marija, Monraz Gomez, Luis, de Meulder, Bertrand, Ravel, Jean, Jassal, Bijay, Satagopam, Venkata, Wu, Guanming, Golebiewski, Martin, Gawron, Piotr, Calzone, Laurence, Beckmann, Jacques, Evelo, Chris, d'Eustachio, Peter, Schreiber, Falk, Saez-Rodriguez, Julio, Dopazo, Joaquin, Kuiper, Martin, Valencia, Alfonso, Wolkenhauer, Olaf, Kitano, Hiroaki, Barillot, Emmanuel, Auffray, Charles, Balling, Rudi, Schneider, Reinhard, Computational systems biology and optimization (Lifeware), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Laboratoire de recherche européen pour la polyarthrite rhumatoïde (GenHotel), Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay, University of Luxembourg [Luxembourg], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Maastricht Centre for Systems Biology [Maastricht] (MaCSBio), Maastricht University [Maastricht], Ontario Institute for Cancer Research [Canada] (OICR), Ontario Institute for Cancer Research, Keio University, Luxembourg Centre For Systems Biomedicine (LCSB), University of Konstanz, Hochschule Mittweida - University of Applied Sciences, Kanagawa Institute of Technology, Heidelberg University Hospital [Heidelberg], National Institute for Infectious Diseases 'Lazzaro Spallanzani', Hospital Universitario Virgen del Rocío [Sevilla], Biomedicine Institute of Sevilla [Seville, Spain], University of Nebraska–Lincoln, University of Nebraska System, Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), Harvard Medical School [Boston] (HMS), Universitat Pompeu Fabra [Barcelona] (UPF), National Institute of Advanced Industrial Science and Technology (AIST), Humboldt University Of Berlin, Integrative Bioinformatics Inc [Mountain View], Department of Informatics and System Sciences (Sapienza University of Rome), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU), Yenepoya University, Janet Piñero, Laura I. Furlong: IMI2-JU grants, resources which are composed of financial contributions from the European Union’s Horizon 2020 Research and Innovation Programme and EFPIA [GA: 777365 eTRANSAFE], and the EU H2020 Programme [GA:964537 RISKHUNT3R], Project 001-P-001647—Valorisation of EGA for Industry and Society funded by the European Regional Development Fund (ERDF) and Generalitat de Catalunya, and Institute of Health Carlos III (project IMPaCT-Data, exp. IMP/00019), co-funded by the European Union, European Regional Development Fund (ERDF, 'A way to make Europe').
Subjects: SARS-CoV-2, disease maps, systems biology, dynamic models, systems medicine, large-scale community effort, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], mechanistic models
Abstract: The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing. Community-driven and highly interdisciplinary, the project is collaborative and supports community standards, open access, and the FAIR data principles. The coordination of community work allowed for an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework links key molecules highlighted from broad omics data analysis and computational modeling to dysregulated pathways in a cell-, tissue- or patient-specific manner. We also employ text mining and AI-assisted analysis to identify potential drugs and drug targets and use topological analysis to reveal interesting structural features of the map. The proposed framework is versatile and expandable, offering a significant upgrade in the arsenal used to understand virus-host interactions and other complex pathologies.
Published: 2022

26. An SPM-Enriched Marine Oil Supplement Shifted Microglia Polarization toward M2, Ameliorating Retinal Degeneration in rd10 Mice

Author: Olivares-González, Lorena, primary, Velasco, Sheyla, additional, Gallego, Idoia, additional, Esteban-Medina, Marina, additional, Puras, Gustavo, additional, Loucera, Carlos, additional, Martínez-Romero, Alicia, additional, Peña-Chilet, María, additional, Pedraz, José Luis, additional, and Rodrigo, Regina, additional
Published: 2022
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27. Real-world evidence with a retrospective cohort of 15,968 Andalusian COVID-19 hospitalized patients suggests 21 new effective treatments and one drug that increases death risk

Author: Loucera, Carlos, primary, Carmona, Rosario, additional, Esteban-Medina, Marina, additional, Bostelmann, Gerrit, additional, Muñoyerro-Muñiz, Dolores, additional, Villegas, Román, additional, Peña-Chilet, María, additional, and Dopazo, Joaquin, additional
Published: 2022
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28. Endoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell–Matrix Interactions

Author: Puerto-Camacho, Pilar, primary, Díaz-Martín, Juan, additional, Olmedo-Pelayo, Joaquín, additional, Bolado-Carrancio, Alfonso, additional, Salguero-Aranda, Carmen, additional, Jordán-Pérez, Carmen, additional, Esteban-Medina, Marina, additional, Álamo-Álvarez, Inmaculada, additional, Delgado-Bellido, Daniel, additional, Lobo-Selma, Laura, additional, Dopazo, Joaquín, additional, Sastre, Ana, additional, Alonso, Javier, additional, Grünewald, Thomas G. P., additional, Bernabeu, Carmelo, additional, Byron, Adam, additional, Brunton, Valerie G., additional, Amaral, Ana Teresa, additional, and Álava, Enrique De, additional
Published: 2022
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29. An SPM-Enriched Marine Oil Supplement Shifted Microglia Polarization toward M2, Ameliorating Retinal Degeneration in rd10 Mice

Author: Farmacia y ciencias de los alimentos, Farmazia eta elikagaien zientziak, Olivares González, Lorena, Velasco, Sheyla, Gallego Garrido, Idoia, Esteban Medina, Marina, Puras Ochoa, Gustavo, Loucera, Carlos, Martínez Romero, Alicia, Peña Chilet, María, Pedraz Muñoz, José Luis, Rodrigo, Regina, Farmacia y ciencias de los alimentos, Farmazia eta elikagaien zientziak, Olivares González, Lorena, Velasco, Sheyla, Gallego Garrido, Idoia, Esteban Medina, Marina, Puras Ochoa, Gustavo, Loucera, Carlos, Martínez Romero, Alicia, Peña Chilet, María, Pedraz Muñoz, José Luis, and Rodrigo, Regina
Abstract: Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy causing progressive vision loss. It is accompanied by chronic and sustained inflammation, including M1 microglia activation. This study evaluated the effect of an essential fatty acid (EFA) supplement containing specialized pro-resolving mediators (SPMs), on retinal degeneration and microglia activation in rd10 mice, a model of RP, as well as on LPS-stimulated BV2 cells. The EFA supplement was orally administered to mice from postnatal day (P)9 to P18. At P18, the electrical activity of the retina was examined by electroretinography (ERG) and innate behavior in response to light were measured. Retinal degeneration was studied via histology including the TUNEL assay and microglia immunolabeling. Microglia polarization (M1/M2) was assessed by flow cytometry, qPCR, ELISA and histology. Redox status was analyzed by measuring antioxidant enzymes and markers of oxidative damage. Interestingly, the EFA supplement ameliorated retinal dysfunction and degeneration by improving ERG recording and sensitivity to light, and reducing photoreceptor cell loss. The EFA supplement reduced inflammation and microglia activation attenuating M1 markers as well as inducing a shift to the M2 phenotype in rd10 mouse retinas and LPS-stimulated BV2 cells. It also reduced oxidative stress markers of lipid peroxidation and carbonylation. These findings could open up new therapeutic opportunities based on resolving inflammation with oral supplementation with SPMs such as the EFA supplement.
Published: 2022

30. Endoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell-Matrix Interactions

Author: European Commission, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red Cáncer (España), Junta de Andalucía, Fundación CRIS contra el Cáncer, Asociación Candela Riera, Asociación Pablo Ugarte, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación María García Estrada, Universidad de Sevilla, Fundación Mari Paz Jiménez Casado, Grupo Español de Investigación en Sarcomas, Barbara and Wilfried Mohr Foundation, Todos somos Iván, Fundación LaSonrisaDeAlex, Puerto-Camacho, Pilar [0000-0001-5338-2610], Díaz-Martín, J. [0000-0002-3985-6434], Salguero-Aranda, Carmen0000-0001-6010-8302, Alamo-Alvarez, Inmaculada0000-0002-6295-0218, Delgado-Bellido, Daniel0000-0002-9588-4747, Dopazo, Joaquín0000-0003-3318-120X, Alonso, Javier0000-0002-6287-8391, Bernabéu, Carmelo0000-0002-1563-6162, Byron, Adam0000-0002-5939-9883, Brunton, Valerie G. 0000-0002-7778-8794, Álava, Enrique de [0000-0001-8400-046X], Puerto-Camacho, Pilar, Díaz-Martín, J., Olmedo-Pelayo, Joaquín, Bolado Carrancio, Alfonso, Salguero-Aranda, Carmen, Jordán-Pérez, Carmen, Esteban-Medina, Marina, Alamo-Alvarez, Inmaculada, Delgado-Bellido, Daniel, Lobo Selma, Laura, Dopazo, Joaquín, Sastre, Ana, Alonso, Javier, Grünewald, Thomas G. P., Bernabéu, Carmelo, Byron, Adam, Brunton, Valerie G., Amaral, Ana Teresa, Álava, Enrique de, European Commission, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red Cáncer (España), Junta de Andalucía, Fundación CRIS contra el Cáncer, Asociación Candela Riera, Asociación Pablo Ugarte, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación María García Estrada, Universidad de Sevilla, Fundación Mari Paz Jiménez Casado, Grupo Español de Investigación en Sarcomas, Barbara and Wilfried Mohr Foundation, Todos somos Iván, Fundación LaSonrisaDeAlex, Puerto-Camacho, Pilar [0000-0001-5338-2610], Díaz-Martín, J. [0000-0002-3985-6434], Salguero-Aranda, Carmen0000-0001-6010-8302, Alamo-Alvarez, Inmaculada0000-0002-6295-0218, Delgado-Bellido, Daniel0000-0002-9588-4747, Dopazo, Joaquín0000-0003-3318-120X, Alonso, Javier0000-0002-6287-8391, Bernabéu, Carmelo0000-0002-1563-6162, Byron, Adam0000-0002-5939-9883, Brunton, Valerie G. 0000-0002-7778-8794, Álava, Enrique de [0000-0001-8400-046X], Puerto-Camacho, Pilar, Díaz-Martín, J., Olmedo-Pelayo, Joaquín, Bolado Carrancio, Alfonso, Salguero-Aranda, Carmen, Jordán-Pérez, Carmen, Esteban-Medina, Marina, Alamo-Alvarez, Inmaculada, Delgado-Bellido, Daniel, Lobo Selma, Laura, Dopazo, Joaquín, Sastre, Ana, Alonso, Javier, Grünewald, Thomas G. P., Bernabéu, Carmelo, Byron, Adam, Brunton, Valerie G., Amaral, Ana Teresa, and Álava, Enrique de
Abstract: Endoglin (ENG) is a mesenchymal stem cell (MSC) marker typically expressed by active endothelium. This transmembrane glycoprotein is shed by matrix metalloproteinase 14 (MMP14). Our previous work demonstrated potent preclinical activity of first-in-class anti-ENG antibody-drug conjugates as a nascent strategy to eradicate Ewing sarcoma (ES), a devastating rare bone/soft tissue cancer with a putative MSC origin. We also defined a correlation between ENG and MMP14 expression in ES. Herein, we show that ENG expression is significantly associated with a dismal prognosis in a large cohort of ES patients. Moreover, both ENG/MMP14 are frequently expressed in primary ES tumors and metastasis. To deepen in their functional relevance in ES, we conducted transcriptomic and proteomic profiling of in vitro ES models that unveiled a key role of ENG and MMP14 in cell mechano-transduction. Migration and adhesion assays confirmed that loss of ENG disrupts actin filament assembly and filopodia formation, with a concomitant effect on cell spreading. Furthermore, we observed that ENG regulates cell-matrix interaction through activation of focal adhesion signaling and protein kinase C expression. In turn, loss of MMP14 contributed to a more adhesive phenotype of ES cells by modulating the transcriptional extracellular matrix dynamics. Overall, these results suggest that ENG and MMP14 exert a significant role in mediating correct spreading machinery of ES cells, impacting the aggressiveness of the disease.
Published: 2022

31. An SPM-Enriched Marine Oil Supplement Shifted Microglia Polarization toward M2, Ameliorating Retinal Degeneration in rd10 Mice.

Author: Olivares-González, Lorena, Velasco, Sheyla, Gallego, Idoia, Esteban-Medina, Marina, Puras, Gustavo, Loucera, Carlos, Martínez-Romero, Alicia, Peña-Chilet, María, Pedraz, José Luis, and Rodrigo, Regina
Subjects: RETINAL degeneration, MICROGLIA, RETINITIS pigmentosa, ESSENTIAL fatty acids, VISION disorders, DIETARY supplements
Abstract: Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy causing progressive vision loss. It is accompanied by chronic and sustained inflammation, including M1 microglia activation. This study evaluated the effect of an essential fatty acid (EFA) supplement containing specialized pro-resolving mediators (SPMs), on retinal degeneration and microglia activation in rd10 mice, a model of RP, as well as on LPS-stimulated BV2 cells. The EFA supplement was orally administered to mice from postnatal day (P)9 to P18. At P18, the electrical activity of the retina was examined by electroretinography (ERG) and innate behavior in response to light were measured. Retinal degeneration was studied via histology including the TUNEL assay and microglia immunolabeling. Microglia polarization (M1/M2) was assessed by flow cytometry, qPCR, ELISA and histology. Redox status was analyzed by measuring antioxidant enzymes and markers of oxidative damage. Interestingly, the EFA supplement ameliorated retinal dysfunction and degeneration by improving ERG recording and sensitivity to light, and reducing photoreceptor cell loss. The EFA supplement reduced inflammation and microglia activation attenuating M1 markers as well as inducing a shift to the M2 phenotype in rd10 mouse retinas and LPS-stimulated BV2 cells. It also reduced oxidative stress markers of lipid peroxidation and carbonylation. These findings could open up new therapeutic opportunities based on resolving inflammation with oral supplementation with SPMs such as the EFA supplement. [ABSTRACT FROM AUTHOR]
Published: 2023
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32. COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms.

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Ostaszewski, Marek, Niarakis, Anna, Mazein, Alexander, Kuperstein, Inna, Phair, Robert, Orta-Resendiz, Aurelio, Singh, Vidisha, Aghamiri, Sara Sadat, Acencio, Marcio Luis, Glaab, Enrico, Ruepp, Andreas, Fobo, Gisela, Montrone, Corinna, Brauner, Barbara, Frishman, Goar, Monraz Gómez, Luis Cristóbal, Somers, Julia, Hoch, Matti, Kumar Gupta, Shailendra, Scheel, Julia, Borlinghaus, Hanna, Czauderna, Tobias, Schreiber, Falk, Montagud, Arnau, Ponce de Leon, Miguel, Funahashi, Akira, Hiki, Yusuke, Hiroi, Noriko, Yamada, Takahiro G., Dräger, Andreas, Renz, Alina, Naveez, Muhammad, Bocskei, Zsolt, Messina, Francesco, Börnigen, Daniela, Fergusson, Liam, Conti, Marta, Rameil, Marius, Nakonecnij, Vanessa, Vanhoefer, Jakob, Schmiester, Leonard, Wang, Muying, Ackerman, Emily E., Shoemaker, Jason E., Zucker, Jeremy, Oxford, Kristie, Teuton, Jeremy, Kocakaya, Ebru, Summak, Gökçe Yağmur, Hanspers, Kristina, Kutmon, Martina, Coort, Susan, Eijssen, Lars, Ehrhart, Friederike, Rex, Devasahayam Arokia Balaya, Slenter, Denise, Martens, Marvin, Pham, Nhung, Haw, Robin, Jassal, Bijay, Matthews, Lisa, Orlic-Milacic, Marija, Senff Ribeiro, Andrea, Rothfels, Karen, Shamovsky, Veronica, Stephan, Ralf, Sevilla, Cristoffer, Varusai, Thawfeek, Ravel, Jean-Marie, Fraser, Rupsha, Ortseifen, Vera, Marchesi, Silvia, Gawron, Piotr, Smula, Ewa, Heirendt, Laurent, Satagopam, Venkata, Wu, Guanming, Riutta, Anders, Golebiewski, Martin, Owen, Stuart, Goble, Carole, Hu, Xiaoming, Overall, Rupert W., Maier, Dieter, Bauch, Angela, Gyori, Benjamin M., Bachman, John A., Vega, Carlos, Groues, Valentin, Vazquez, Miguel, Porras, Pablo, Licata, Luana, Iannuccelli, Marta, Sacco, Francesca, Nesterova, Anastasia, Yuryev, Anton, de Waard, Anita, Turei, Denes, Luna, Augustin, Babur, Ozgun, Soliman, Sylvain, Valdeolivas, Alberto, Esteban-Medina, Marina, Peña-Chilet, Maria, Rian, Kinza, Helikar, Tomáš, Puniya, Bhanwar Lal, Modos, Dezso, Treveil, Agatha, Olbei, Marton, De Meulder, Bertrand, Ballereau, Stephane, Dugourd, Aurélien, Naldi, Aurélien, Noël, Vincent, Calzone, Laurence, Sander, Chris, Demir, Emek, Korcsmaros, Tamas, Freeman, Tom C., Augé, Franck, Beckmann, Jacques S., Hasenauer, Jan, Wolkenhauer, Olaf, Wilighagen, Egon L., Pico, Alexander R., Evelo, Chris T., Gillespie, Marc E., Stein, Lincoln D., Hermjakob, Henning, D'Eustachio, Peter, Saez-Rodriguez, Julio, Dopazo, Joaquin, Valencia, Alfonso, Kitano, Hiroaki, Barillot, Emmanuel, Auffray, Charles, Balling, Rudi, Schneider, Reinhard, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Ostaszewski, Marek, Niarakis, Anna, Mazein, Alexander, Kuperstein, Inna, Phair, Robert, Orta-Resendiz, Aurelio, Singh, Vidisha, Aghamiri, Sara Sadat, Acencio, Marcio Luis, Glaab, Enrico, Ruepp, Andreas, Fobo, Gisela, Montrone, Corinna, Brauner, Barbara, Frishman, Goar, Monraz Gómez, Luis Cristóbal, Somers, Julia, Hoch, Matti, Kumar Gupta, Shailendra, Scheel, Julia, Borlinghaus, Hanna, Czauderna, Tobias, Schreiber, Falk, Montagud, Arnau, Ponce de Leon, Miguel, Funahashi, Akira, Hiki, Yusuke, Hiroi, Noriko, Yamada, Takahiro G., Dräger, Andreas, Renz, Alina, Naveez, Muhammad, Bocskei, Zsolt, Messina, Francesco, Börnigen, Daniela, Fergusson, Liam, Conti, Marta, Rameil, Marius, Nakonecnij, Vanessa, Vanhoefer, Jakob, Schmiester, Leonard, Wang, Muying, Ackerman, Emily E., Shoemaker, Jason E., Zucker, Jeremy, Oxford, Kristie, Teuton, Jeremy, Kocakaya, Ebru, Summak, Gökçe Yağmur, Hanspers, Kristina, Kutmon, Martina, Coort, Susan, Eijssen, Lars, Ehrhart, Friederike, Rex, Devasahayam Arokia Balaya, Slenter, Denise, Martens, Marvin, Pham, Nhung, Haw, Robin, Jassal, Bijay, Matthews, Lisa, Orlic-Milacic, Marija, Senff Ribeiro, Andrea, Rothfels, Karen, Shamovsky, Veronica, Stephan, Ralf, Sevilla, Cristoffer, Varusai, Thawfeek, Ravel, Jean-Marie, Fraser, Rupsha, Ortseifen, Vera, Marchesi, Silvia, Gawron, Piotr, Smula, Ewa, Heirendt, Laurent, Satagopam, Venkata, Wu, Guanming, Riutta, Anders, Golebiewski, Martin, Owen, Stuart, Goble, Carole, Hu, Xiaoming, Overall, Rupert W., Maier, Dieter, Bauch, Angela, Gyori, Benjamin M., Bachman, John A., Vega, Carlos, Groues, Valentin, Vazquez, Miguel, Porras, Pablo, Licata, Luana, Iannuccelli, Marta, Sacco, Francesca, Nesterova, Anastasia, Yuryev, Anton, de Waard, Anita, Turei, Denes, Luna, Augustin, Babur, Ozgun, Soliman, Sylvain, Valdeolivas, Alberto, Esteban-Medina, Marina, Peña-Chilet, Maria, Rian, Kinza, Helikar, Tomáš, Puniya, Bhanwar Lal, Modos, Dezso, Treveil, Agatha, Olbei, Marton, De Meulder, Bertrand, Ballereau, Stephane, Dugourd, Aurélien, Naldi, Aurélien, Noël, Vincent, Calzone, Laurence, Sander, Chris, Demir, Emek, Korcsmaros, Tamas, Freeman, Tom C., Augé, Franck, Beckmann, Jacques S., Hasenauer, Jan, Wolkenhauer, Olaf, Wilighagen, Egon L., Pico, Alexander R., Evelo, Chris T., Gillespie, Marc E., Stein, Lincoln D., Hermjakob, Henning, D'Eustachio, Peter, Saez-Rodriguez, Julio, Dopazo, Joaquin, Valencia, Alfonso, Kitano, Hiroaki, Barillot, Emmanuel, Auffray, Charles, Balling, Rudi, and Schneider, Reinhard
Abstract: We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.
Published: 2021

33. Real world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients

Author: Universidad de Sevilla. Departamento de Medicina, Consejería de Salud y Familias. Junta de Andalucía (COVID-011-2020; P18-RT-3471; PAIDI2020-DOC_00350), Ministerio de Ciencia e Innovación (PID2020-117979RB-I00), Instituto de Salud Carlos III (IMP/0019; ACCI2018/2; CB16/10/00245; CB16/10/0050; COV20/00788; PI19/00033), Programa H2020 de la Unión Europea. Beca Marie Curie Innovative Training Network "Machine Learning Frontiers in Precision Medicine" (813533), Fundación BBVA (G999088Q), Peña-Chilet, María, Esteban-Medina, Marina, Muñoyerro Muñiz, Dolores, Loucera, Carlos, Villegas, Román, López Miranda, José, Rodríguez-Baño, Jesús, Túnez, Isaac, Bouillon, Roger, Dopazo, Joaquín, Quesada Gómez, José Manuel, Universidad de Sevilla. Departamento de Medicina, Consejería de Salud y Familias. Junta de Andalucía (COVID-011-2020; P18-RT-3471; PAIDI2020-DOC_00350), Ministerio de Ciencia e Innovación (PID2020-117979RB-I00), Instituto de Salud Carlos III (IMP/0019; ACCI2018/2; CB16/10/00245; CB16/10/0050; COV20/00788; PI19/00033), Programa H2020 de la Unión Europea. Beca Marie Curie Innovative Training Network "Machine Learning Frontiers in Precision Medicine" (813533), Fundación BBVA (G999088Q), Peña-Chilet, María, Esteban-Medina, Marina, Muñoyerro Muñiz, Dolores, Loucera, Carlos, Villegas, Román, López Miranda, José, Rodríguez-Baño, Jesús, Túnez, Isaac, Bouillon, Roger, Dopazo, Joaquín, and Quesada Gómez, José Manuel
Abstract: COVID-19 is a major worldwide health problem because of acute respiratory distress syndrome, and mortality. Several lines of evidence have suggested a relationship between the vitamin D endocrine system and severity of COVID-19. We present a survival study on a retrospective cohort of 15,968 patients, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020. Based on a central registry of electronic health records (the Andalusian Population Health Database, BPS), prescription of vitamin D or its metabolites within 15–30 days before hospitalization were recorded. The effect of prescription of vitamin D (metabolites) for other indication previous to the hospitalization was studied with respect to patient survival. Kaplan–Meier survival curves and hazard ratios support an association between prescription of these metabolites and patient survival. Such association was stronger for calcifediol (Hazard Ratio, HR = 0.67, with 95% confidence interval, CI, of [0.50–0.91]) than for cholecalciferol (HR = 0.75, with 95% CI of [0.61–0.91]), when prescribed 15 days prior hospitalization. Although the relation is maintained, there is a general decrease of this effect when a longer period of 30 days prior hospitalization is considered (calcifediol HR = 0.73, with 95% CI [0.57–0.95] and cholecalciferol HR = 0.88, with 95% CI [0.75, 1.03]), suggesting that association was stronger when the prescription was closer to the hospitalization.
Published: 2021

34. Real world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients

Author: Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red Enfermedades Raras (España), European Commission, Fundación BBVA, Junta de Andalucía, Loucera, Carlos, Peña-Chilet, María, Esteban-Medina, Marina, Muñoyerro-Muñiz, Dolores, Villegas-Portero, Román, López-Miranda, José, Rodríguez-Baño, Jesús, Túnez, Isaac, Bouillon, Roger, Dopazo, Joaquín, Quesada-Gómez, José Manuel, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red Enfermedades Raras (España), European Commission, Fundación BBVA, Junta de Andalucía, Loucera, Carlos, Peña-Chilet, María, Esteban-Medina, Marina, Muñoyerro-Muñiz, Dolores, Villegas-Portero, Román, López-Miranda, José, Rodríguez-Baño, Jesús, Túnez, Isaac, Bouillon, Roger, Dopazo, Joaquín, and Quesada-Gómez, José Manuel
Abstract: COVID-19 is a major worldwide health problem because of acute respiratory distress syndrome, and mortality. Several lines of evidence have suggested a relationship between the vitamin D endocrine system and severity of COVID-19. We present a survival study on a retrospective cohort of 15,968 patients, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020. Based on a central registry of electronic health records (the Andalusian Population Health Database, BPS), prescription of vitamin D or its metabolites within 15–30 days before hospitalization were recorded. The effect of prescription of vitamin D (metabolites) for other indication previous to the hospitalization was studied with respect to patient survival. Kaplan–Meier survival curves and hazard ratios support an association between prescription of these metabolites and patient survival. Such association was stronger for calcifediol (Hazard Ratio, HR = 0.67, with 95% confidence interval, CI, of [0.50–0.91]) than for cholecalciferol (HR = 0.75, with 95% CI of [0.61–0.91]), when prescribed 15 days prior hospitalization. Although the relation is maintained, there is a general decrease of this effect when a longer period of 30 days prior hospitalization is considered (calcifediol HR = 0.73, with 95% CI [0.57–0.95] and cholecalciferol HR = 0.88, with 95% CI [0.75, 1.03]), suggesting that association was stronger when the prescription was closer to the hospitalization.
Published: 2021

35. COVID19 Disease Map, a computational knowledge repository of virus–host interaction mechanisms

Author: Fonds National de la Recherche Luxembourg, European Commission, Federal Ministry of Education and Research (Germany), Ministry of Science, Research and Art Baden-Württemberg, German Center for Infection Research, Netherlands Organisation for Health Research and Development, National Institutes of Health (US), European Molecular Biology Laboratory, Ostaszewski, Marek, Niarakis, Anna, Mazein, Alexander, Kuperstein, Inna, Phair, Robert, Orta-Resendiz, Aurelio, Singh, Vidisha, Aghamiri, Sara Sadat, Acencio, Marcio Luis, Glaab, Enrico, Ruepp, Andreas, Schreiber, Falk, Montagud, Arnau, Ponce de León, Miguel, Funahashi, Akira, Hiki, Yusuke, Hiroi, Noriko, Yamada, Takahiro G., Dräger, Andreas, Renz, Alina, Naveez, Muhammad, Orlic-Milacic, Marija, Bocskei, Zsolt, Messina, Francesco, Börnigen, Daniela, Fergusson, Liam, Conti, Marta, Rameil, Marius, Nakonecnij, Vanessa, Vanhoefer, Jakob, Schmiester, Leonard, Wang, Muying, Senff Ribeiro, Andrea, Ackerman, Emily E., Shoemaker, Jason E., Zucker, Jeremy, Oxford, Kristie, Teuton, Jeremy, Kocakaya, Ebru, Summak, Gökçe Yagmu, Hanspers, Kristina, Kutmon, Martina, Coort, Susan, Rothfels, Karen, Eijssen, Lars, Ehrhart, Friederike, Arokia Balaya Rex, Devasahayam, Slenter, Denise, Martens, Marvin, Pham, Nhung, Haw, Robin, Jassal, Bijay, Matthews, Lisa, Shamovsky, Veronic, Stephan, Ralf, Sevilla, Cristoffer, Varusai, Thawfeek, Ravel, Jean-Marie, Fraser, Rupsha, Ortseifen, Vera, Soliman, Sylvain, Marchesi, Silvia, Gawron, Piotr, Smula, Ewa, Heirendt, Laurent, Satagopam, Venkata, Wu, Guanming, Riutta, Anders, Golebiewski, Martin, Owen, Stuart, Goble, Carole, Valdeolivas, Alberto, Hu, Xiaoming, Overall, Rupert W., Maier, Dieter, Bauch, Angela, Gyori, Benjamin M., Bachman, John A., Vega, Carlos, Groues, Valentin, Vázquez, Miguel, Porras, Pablo, Esteban-Medina, Marina, Licata, Luana, Iannuccelli, Marta, Sacco, Francesca, Nesterova, Anastasia, Yuryev, Anton, Waard, Anita de, Turei, Denes, Luna, Augustín, Babur, Ozgun, Peña-Chilet, María, Rian, Kinza, Helikar, Tomas, Lal Puniya, Bhanwar, Modos, Dezso, Treveil, Agatha, Olbe, Marton, Fobo, Gisela, De Meulder, Bertrand, Ballereau, Stephane, Dugourd, Aurelien, Naldi, Aurelien, Noël, Vincent, Calzone, Laurence, Sander, Chris, Demir, Emek, Korcsmaros, Tamas, Freeman, Tom C., Montrone, Corinna, Auge, Franck, Beckmann, Jacques S., Hasenauer, Jan, Wolkenhauer, Olaf, Wilighagen, Egon L ., Pico, Alexander R., Evelo, Chris T., Gillespie, Marc E., Stein, Lincoln D., Hermjakob, Henning, Brauner, Barbara, D’Eustachio, Peter, Sáez-Rodríguez, Julio, Dopazo, Joaquín, Valencia, Alfonso, Kitano, Hiroaki, Barillot, Emmanuel, Auffray, Charles, Balling, Rudi, Schneider, Reinhard, Frishman, Goar, Monraz Gómez, Luis Cristóbal, Somers, Julia, Hoch, Matti, Gupta, Shailendra Kumar, Scheel, Julia, Borlinghaus, Hanna, Czauderna, Tobias, Fonds National de la Recherche Luxembourg, European Commission, Federal Ministry of Education and Research (Germany), Ministry of Science, Research and Art Baden-Württemberg, German Center for Infection Research, Netherlands Organisation for Health Research and Development, National Institutes of Health (US), European Molecular Biology Laboratory, Ostaszewski, Marek, Niarakis, Anna, Mazein, Alexander, Kuperstein, Inna, Phair, Robert, Orta-Resendiz, Aurelio, Singh, Vidisha, Aghamiri, Sara Sadat, Acencio, Marcio Luis, Glaab, Enrico, Ruepp, Andreas, Schreiber, Falk, Montagud, Arnau, Ponce de León, Miguel, Funahashi, Akira, Hiki, Yusuke, Hiroi, Noriko, Yamada, Takahiro G., Dräger, Andreas, Renz, Alina, Naveez, Muhammad, Orlic-Milacic, Marija, Bocskei, Zsolt, Messina, Francesco, Börnigen, Daniela, Fergusson, Liam, Conti, Marta, Rameil, Marius, Nakonecnij, Vanessa, Vanhoefer, Jakob, Schmiester, Leonard, Wang, Muying, Senff Ribeiro, Andrea, Ackerman, Emily E., Shoemaker, Jason E., Zucker, Jeremy, Oxford, Kristie, Teuton, Jeremy, Kocakaya, Ebru, Summak, Gökçe Yagmu, Hanspers, Kristina, Kutmon, Martina, Coort, Susan, Rothfels, Karen, Eijssen, Lars, Ehrhart, Friederike, Arokia Balaya Rex, Devasahayam, Slenter, Denise, Martens, Marvin, Pham, Nhung, Haw, Robin, Jassal, Bijay, Matthews, Lisa, Shamovsky, Veronic, Stephan, Ralf, Sevilla, Cristoffer, Varusai, Thawfeek, Ravel, Jean-Marie, Fraser, Rupsha, Ortseifen, Vera, Soliman, Sylvain, Marchesi, Silvia, Gawron, Piotr, Smula, Ewa, Heirendt, Laurent, Satagopam, Venkata, Wu, Guanming, Riutta, Anders, Golebiewski, Martin, Owen, Stuart, Goble, Carole, Valdeolivas, Alberto, Hu, Xiaoming, Overall, Rupert W., Maier, Dieter, Bauch, Angela, Gyori, Benjamin M., Bachman, John A., Vega, Carlos, Groues, Valentin, Vázquez, Miguel, Porras, Pablo, Esteban-Medina, Marina, Licata, Luana, Iannuccelli, Marta, Sacco, Francesca, Nesterova, Anastasia, Yuryev, Anton, Waard, Anita de, Turei, Denes, Luna, Augustín, Babur, Ozgun, Peña-Chilet, María, Rian, Kinza, Helikar, Tomas, Lal Puniya, Bhanwar, Modos, Dezso, Treveil, Agatha, Olbe, Marton, Fobo, Gisela, De Meulder, Bertrand, Ballereau, Stephane, Dugourd, Aurelien, Naldi, Aurelien, Noël, Vincent, Calzone, Laurence, Sander, Chris, Demir, Emek, Korcsmaros, Tamas, Freeman, Tom C., Montrone, Corinna, Auge, Franck, Beckmann, Jacques S., Hasenauer, Jan, Wolkenhauer, Olaf, Wilighagen, Egon L ., Pico, Alexander R., Evelo, Chris T., Gillespie, Marc E., Stein, Lincoln D., Hermjakob, Henning, Brauner, Barbara, D’Eustachio, Peter, Sáez-Rodríguez, Julio, Dopazo, Joaquín, Valencia, Alfonso, Kitano, Hiroaki, Barillot, Emmanuel, Auffray, Charles, Balling, Rudi, Schneider, Reinhard, Frishman, Goar, Monraz Gómez, Luis Cristóbal, Somers, Julia, Hoch, Matti, Gupta, Shailendra Kumar, Scheel, Julia, Borlinghaus, Hanna, and Czauderna, Tobias
Abstract: We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.
Published: 2021

36. Genome-scale mechanistic modeling of signaling pathways made easy: A bioconductor/cytoscape/web server framework for the analysis of omic data

Author: Ministerio de Economía y Competitividad (España), European Commission, Rian, Kinza, Hidalgo, Marta R., Çubuk, Cankut, Falco, Matias M., Loucera, Carlos, Esteban-Medina, Marina, Alamo-Alvarez, Inmaculada, Peña-Chilet, María, Dopazo, Joaquín, Ministerio de Economía y Competitividad (España), European Commission, Rian, Kinza, Hidalgo, Marta R., Çubuk, Cankut, Falco, Matias M., Loucera, Carlos, Esteban-Medina, Marina, Alamo-Alvarez, Inmaculada, Peña-Chilet, María, and Dopazo, Joaquín
Abstract: Genome-scale mechanistic models of pathways are gaining importance for genomic data interpretation because they provide a natural link between genotype measurements (transcriptomics or genomics data) and the phenotype of the cell (its functional behavior). Moreover, mechanistic models can be used to predict the potential effect of interventions, including drug inhibitions. Here, we present the implementation of a mechanistic model of cell signaling for the interpretation of transcriptomic data as an R/Bioconductor package, a Cytoscape plugin and a web tool with enhanced functionality which includes building interpretable predictors, estimation of the effect of perturbations and assessment of the effect of mutations in complex scenarios.
Published: 2021

37. Mechanistic modeling of the SARS-CoV-2 disease map

Author: Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, European Commission, Fundación BBVA, Rian, Kinza, Esteban-Medina, Marina, Hidalgo, Marta R., Çubuk, Cankut, Falco, Matias M., Loucera, Carlos, Gunyel, Devrim, Ostaszewski, Marek, Peña-Chilet, María, Dopazo, Joaquín, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, European Commission, Fundación BBVA, Rian, Kinza, Esteban-Medina, Marina, Hidalgo, Marta R., Çubuk, Cankut, Falco, Matias M., Loucera, Carlos, Gunyel, Devrim, Ostaszewski, Marek, Peña-Chilet, María, and Dopazo, Joaquín
Abstract: Here we present a web interface that implements a comprehensive mechanistic model of the SARS-CoV-2 disease map. In this framework, the detailed activity of the human signaling circuits related to the viral infection, covering from the entry and replication mechanisms to the downstream consequences as inflammation and antigenic response, can be inferred from gene expression experiments. Moreover, the effect of potential interventions, such as knock-downs, or drug effects (currently the system models the effect of more than 8000 DrugBank drugs) can be studied. This freely available tool not only provides an unprecedentedly detailed view of the mechanisms of viral invasion and the consequences in the cell but has also the potential of becoming an invaluable asset in the search for efficient antiviral treatments.
Published: 2021

38. Real world evidence of calcifediol use and mortality rate of COVID-19 hospitalized in a large cohort of 16,401 Andalusian patients

Author: Loucera, Carlos, primary, Peña-Chilet, María, additional, Esteban-Medina, Marina, additional, Muñoyerro-Muñiz, Dolores, additional, Villegas, Román, additional, Lopez-Miranda, Jose, additional, Rodriguez-Baño, Jesus, additional, Túnez, Isaac, additional, Bouillon, Roger, additional, Dopazo, Joaquin, additional, and Gomez, Jose Manuel Quesada, additional
Published: 2021
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39. Drug repurposing for COVID-19 using machine learning and mechanistic models of signal transduction circuits related to SARS-CoV-2 infection

Author: Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Fundación BBVA, Loucera, Carlos, Esteban-Medina, Marina, Rian, Kinza, Falco, Matias M., Dopazo, Joaquín, Peña-Chilet, María, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Fundación BBVA, Loucera, Carlos, Esteban-Medina, Marina, Rian, Kinza, Falco, Matias M., Dopazo, Joaquín, and Peña-Chilet, María
Abstract: Drug repurposing is a convenient alternative when the need for new drugs in an unexpected medical scenario is urgent, as is the case of emerging pathogens. In recent years, approaches based on network biology have demonstrated to be superior to genecentric ones.1 Here, we use an innovative methodology that combines mechanistic modeling of the signal transduction circuits related to SARS-CoV-2 infection (the COVID-19 disease map) with a machine-learning algorithm that learns potential causal interactions between proteins, already targets of drugs, and specific signaling circuits in the COVID-19 disease map, to suggest potentially repurposable drugs.
Published: 2020

40. Mechanistic modeling of the SARS-CoV-2 disease map

Author: Rian, Kinza, primary, Esteban-Medina, Marina, additional, Hidalgo, Marta R, additional, Çubuk, Cankut, additional, Falco, Matias M, additional, Loucera, Carlos, additional, Gunyel, Devrim, additional, Ostaszewski, Marek, additional, Peña-Chilet, María, additional, and Dopazo, Joaquin, additional
Published: 2020
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41. Abstract 6158: The relevance of endoglin and MMP14 to the metastatic potential of Ewing sarcoma cells

Author: Puerto-Camacho, Pilar, primary, Amaral, Ana Teresa, additional, Diaz-Martin, Juan, additional, Bolado-Carrancio, Alfonso, additional, Jordan-Perez, Carmen, additional, Salguero-Aranda, Carmen, additional, Esteban-Medina, Marina, additional, Alamo-Alvarez, Inmaculada, additional, Dopazo, Joaquin, additional, Bernabeu, Carmelo, additional, Byron, Adam, additional, Brunton, Valerie G., additional, and de Álava, Enrique, additional
Published: 2020
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42. Additional file 2: of Exploring the druggable space around the Fanconi anemia pathway using machine learning and mechanistic models

Author: Esteban-Medina, Marina, Peña-Chilet, María, Loucera, Carlos, and Dopazo, Joaquín
Abstract: Table S2. Genes in the KEGG FA pathway (hsa03460). First column: gene name; second column: KEGG ID; third column: gene symbol; fourth column: ENSEMBL ID; fifth column: OMIM ID. (DOCX 19 kb)
Published: 2019
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43. Exploring the druggable space around the Fanconi anemia pathway using machine learning and mechanistic models

Author: Esteban-Medina, Marina, primary, Peña-Chilet, María, additional, Loucera, Carlos, additional, and Dopazo, Joaquín, additional
Published: 2019
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44. COVID19 Disease Map, a computational knowledge repository of virus–host interaction mechanisms

Author: Ostaszewski, Marek, Niarakis, Anna, Mazein, Alexander, Kuperstein, Inna, Phair, Robert, Orta‐Resendiz, Aurelio, Singh, Vidisha, Aghamiri, Sara Sadat, Acencio, Marcio Luis, Glaab, Enrico, Ruepp, Andreas, Fobo, Gisela, Montrone, Corinna, Brauner, Barbara, Frishman, Goar, Monraz Gómez, Luis Cristóbal, Somers, Julia, Hoch, Matti, Kumar Gupta, Shailendra, Scheel, Julia, Borlinghaus, Hanna, Czauderna, Tobias, Schreiber, Falk, Montagud, Arnau, Ponce De Leon, Miguel, Funahashi, Akira, Hiki, Yusuke, Hiroi, Noriko, Yamada, Takahiro G, Dräger, Andreas, Renz, Alina, Naveez, Muhammad, Bocskei, Zsolt, Messina, Francesco, Börnigen, Daniela, Fergusson, Liam, Conti, Marta, Rameil, Marius, Nakonecnij, Vanessa, Vanhoefer, Jakob, Schmiester, Leonard, Wang, Muying, Ackerman, Emily E, Shoemaker, Jason E, Zucker, Jeremy, Oxford, Kristie, Teuton, Jeremy, Kocakaya, Ebru, Summak, Gökçe Yağmur, Hanspers, Kristina, Kutmon, Martina, Coort, Susan, Eijssen, Lars, Ehrhart, Friederike, Rex, Devasahayam Arokia Balaya, Slenter, Denise, Martens, Marvin, Pham, Nhung, Haw, Robin, Jassal, Bijay, Matthews, Lisa, Orlic‐Milacic, Marija, Senff Ribeiro, Andrea, Rothfels, Karen, Shamovsky, Veronica, Stephan, Ralf, Sevilla, Cristoffer, Varusai, Thawfeek, Ravel, Jean‐Marie, Fraser, Rupsha, Ortseifen, Vera, Marchesi, Silvia, Gawron, Piotr, Smula, Ewa, Heirendt, Laurent, Satagopam, Venkata, Wu, Guanming, Riutta, Anders, Golebiewski, Martin, Owen, Stuart, Goble, Carole, Hu, Xiaoming, Overall, Rupert W, Maier, Dieter, Bauch, Angela, Gyori, Benjamin M, Bachman, John A, Vega, Carlos, Grouès, Valentin, Vazquez, Miguel, Porras, Pablo, Licata, Luana, Iannuccelli, Marta, Sacco, Francesca, Nesterova, Anastasia, Yuryev, Anton, De Waard, Anita, Turei, Denes, Luna, Augustin, Babur, Ozgun, Soliman, Sylvain, Valdeolivas, Alberto, Esteban‐Medina, Marina, Peña‐Chilet, Maria, Rian, Kinza, Helikar, Tomáš, Puniya, Bhanwar Lal, Modos, Dezso, Treveil, Agatha, Olbei, Marton, De Meulder, Bertrand, Ballereau, Stephane, Dugourd, Aurélien, Naldi, Aurélien, Noël, Vincent, Calzone, Laurence, Sander, Chris, Demir, Emek, Korcsmaros, Tamas, Freeman, Tom C, Augé, Franck, Beckmann, Jacques S, Hasenauer, Jan, Wolkenhauer, Olaf, Wilighagen, Egon L, Pico, Alexander R, Evelo, Chris T, Gillespie, Marc E, Stein, Lincoln D, Hermjakob, Henning, D'Eustachio, Peter, Saez‐Rodriguez, Julio, Dopazo, Joaquin, Valencia, Alfonso, Kitano, Hiroaki, Barillot, Emmanuel, Auffray, Charles, Balling, Rudi, Schneider, Reinhard, and Community, The COVID‐19 Disease Map
Subjects: systems biomedicine, open access community effort, large‐scale biocuration, omics data analysis, Articles, computable knowledge repository, EMBO10, EMBO23, Article, 3. Good health
Abstract: Funder: Bundesministerium für Bildung und Forschung (BMBF); Id: http://dx.doi.org/10.13039/501100002347, We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS‐CoV‐2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large‐scale community effort to build an open access, interoperable and computable repository of COVID‐19 molecular mechanisms. The COVID‐19 Disease Map (C19DMap) is a graphical, interactive representation of disease‐relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph‐based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS‐CoV‐2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID‐19 or similar pandemics in the long‐term perspective.

45. COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms

Author: Ostaszewski, Marek, Niarakis, Anna, Mazein, Alexander, Kuperstein, Inna, Phair, Robert, Orta-Resendiz, Aurelio, Singh, Vidisha, Aghamiri, Sara Sadat, Acencio, Marcio Luis, Glaab, Enrico, Ruepp, Andreas, Fobo, Gisela, Montrone, Corinna, Brauner, Barbara, Frishman, Goar, Monraz G��mez, Luis Crist��bal, Somers, Julia, Hoch, Matti, Kumar Gupta, Shailendra, Scheel, Julia, Borlinghaus, Hanna, Czauderna, Tobias, Schreiber, Falk, Montagud, Arnau, Ponce De Leon, Miguel, Funahashi, Akira, Hiki, Yusuke, Hiroi, Noriko, Yamada, Takahiro G, Dr��ger, Andreas, Renz, Alina, Naveez, Muhammad, Bocskei, Zsolt, Messina, Francesco, B��rnigen, Daniela, Fergusson, Liam, Conti, Marta, Rameil, Marius, Nakonecnij, Vanessa, Vanhoefer, Jakob, Schmiester, Leonard, Wang, Muying, Ackerman, Emily E, Shoemaker, Jason E, Zucker, Jeremy, Oxford, Kristie, Teuton, Jeremy, Kocakaya, Ebru, Summak, G��k��e Ya��mur, Hanspers, Kristina, Kutmon, Martina, Coort, Susan, Eijssen, Lars, Ehrhart, Friederike, Rex, Devasahayam Arokia Balaya, Slenter, Denise, Martens, Marvin, Pham, Nhung, Haw, Robin, Jassal, Bijay, Matthews, Lisa, Orlic-Milacic, Marija, Senff Ribeiro, Andrea, Rothfels, Karen, Shamovsky, Veronica, Stephan, Ralf, Sevilla, Cristoffer, Varusai, Thawfeek, Ravel, Jean-Marie, Fraser, Rupsha, Ortseifen, Vera, Marchesi, Silvia, Gawron, Piotr, Smula, Ewa, Heirendt, Laurent, Satagopam, Venkata, Wu, Guanming, Riutta, Anders, Golebiewski, Martin, Owen, Stuart, Goble, Carole, Hu, Xiaoming, Overall, Rupert W, Maier, Dieter, Bauch, Angela, Gyori, Benjamin M, Bachman, John A, Vega, Carlos, Grou��s, Valentin, Vazquez, Miguel, Porras, Pablo, Licata, Luana, Iannuccelli, Marta, Sacco, Francesca, Nesterova, Anastasia, Yuryev, Anton, De Waard, Anita, Turei, Denes, Luna, Augustin, Babur, Ozgun, Soliman, Sylvain, Valdeolivas, Alberto, Esteban-Medina, Marina, Pe��a-Chilet, Maria, Rian, Kinza, Helikar, Tom��, Puniya, Bhanwar Lal, Modos, Dezso, Treveil, Agatha, Olbei, Marton, De Meulder, Bertrand, Ballereau, Stephane, Dugourd, Aur��lien, Naldi, Aur��lien, No��l, Vincent, Calzone, Laurence, Sander, Chris, Demir, Emek, Korcsmaros, Tamas, Freeman, Tom C, Aug��, Franck, Beckmann, Jacques S, Hasenauer, Jan, Wolkenhauer, Olaf, Wilighagen, Egon L, Pico, Alexander R, Evelo, Chris T, Gillespie, Marc E, Stein, Lincoln D, Hermjakob, Henning, D'Eustachio, Peter, Saez-Rodriguez, Julio, Dopazo, Joaquin, Valencia, Alfonso, Kitano, Hiroaki, Barillot, Emmanuel, Auffray, Charles, Balling, Rudi, and Schneider, Reinhard
Subjects: Computable Knowledge Repository, Large-scale Biocuration, Open Access Community Effort, Systems Biomedicine, Omics Data Analysis, 3. Good health
Abstract: Funder: Bundesministerium f��r Bildung und Forschung, Funder: Bundesministerium f��r Bildung und Forschung (BMBF), We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.

46. Real-world evidence with a retrospective cohort of 15,968 Andalusian COVID-19 hospitalized patients suggests 21 new effective treatments and one drug that increases death risk

Author: Carlos Loucera, Rosario Carmona, Marina Esteban-Medina, Gerrit Bostelmann, Dolores Muñoyerro-Muñiz, Román Villegas, María Peña-Chilet, Joaquin Dopazo, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Loucera, Carlos [0000-0001-9598-6965], Carmona, Rosario [0000-0002-4235-2886], Esteban-Medina, Marina [0000-0003-2632-9587], Bostelmann, Gerrit [0000-0002-1690-6347], Villegas-Portero, Román [0000-0003-0845-0172], Dopazo, Joaquín [0000-0003-3318-120X], Loucera, Carlos, Carmona, Rosario, Esteban-Medina, Marina, Bostelmann, Gerrit, Villegas-Portero, Román, and Dopazo, Joaquín
Abstract: Despite the extensive vaccination campaigns in many countries, COVID-19 is still a major worldwide health problem because of its associated morbidity and mortality. Therefore, finding efficient treatments as fast as possible is a pressing need. Drug repurposing constitutes a convenient alternative when the need for new drugs in an unexpected medical scenario is urgent, as is the case with COVID-19. Using data from a central registry of electronic health records (the Andalusian Population Health Database, BPS), the effect of prior consumption of drugs for other indications previous to the hospitalization with respect to patient survival was studied on a retrospective cohort of 15,968 individuals, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020. Covariate-adjusted hazard ratios and analysis of lymphocyte progression curves support a significant association between consumption of 21 different drugs and better patient survival. Contrarily, one drug, furosemide, displayed a significant increase in patient mortality., This research was funded by Spanish Ministry of Science and Innovation (grant PID2020- 117979RB-I00), the Instituto de Salud Carlos III (ISCIII), co-funded with European Regional Development Funds (ERDF) (grant IMP/00019), and has also been funded by Consejería de Salud y Familias, Junta de Andalucía (grants COVID-0012-2020, PS-2020-342 and IE19_259 FPS) and the postdoctoral contract of Carlos Loucera (PAIDI2020- DOC_00350) co-funded by the European Social Fund (FSE) 2014-2020.
Published: 2022
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47. Drug-target identification in COVID-19 disease mechanisms using computational systems biology approaches.

Author: Niarakis A, Ostaszewski M, Mazein A, Kuperstein I, Kutmon M, Gillespie ME, Funahashi A, Acencio ML, Hemedan A, Aichem M, Klein K, Czauderna T, Burtscher F, Yamada TG, Hiki Y, Hiroi NF, Hu F, Pham N, Ehrhart F, Willighagen EL, Valdeolivas A, Dugourd A, Messina F, Esteban-Medina M, Peña-Chilet M, Rian K, Soliman S, Aghamiri SS, Puniya BL, Naldi A, Helikar T, Singh V, Fernández MF, Bermudez V, Tsirvouli E, Montagud A, Noël V, Ponce-de-Leon M, Maier D, Bauch A, Gyori BM, Bachman JA, Luna A, Piñero J, Furlong LI, Balaur I, Rougny A, Jarosz Y, Overall RW, Phair R, Perfetto L, Matthews L, Rex DAB, Orlic-Milacic M, Gomez LCM, De Meulder B, Ravel JM, Jassal B, Satagopam V, Wu G, Golebiewski M, Gawron P, Calzone L, Beckmann JS, Evelo CT, D'Eustachio P, Schreiber F, Saez-Rodriguez J, Dopazo J, Kuiper M, Valencia A, Wolkenhauer O, Kitano H, Barillot E, Auffray C, Balling R, and Schneider R
Subjects: Humans, SARS-CoV-2, Drug Repositioning, Systems Biology, Computer Simulation, COVID-19
Abstract: Introduction: The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing., Methods: Extensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors., Results: Results revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19., Discussion: The key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies., Competing Interests: AN collaborates with SANOFI-AVENTIS R&D via a public–private partnership grant CIFRE contract, n° 2020/0766. DM and AB are employed at Labvantage-Biomax GmbH and will be affected by any effect of this publication on the commercial version of the AILANI software. JB and BG received consulting fees from Two Six Labs, LLC. TH has served as a shareholder and has consulted for Discovery Collective, Inc. RB and RS are founders and shareholders of MEGENO SA and ITTM SA. JS-R reports funding from GSK, Pfizer and Sanofi and fees/honoraria from Travere Therapeutics, Stadapharm, Astex, Owkin, Pfizer and Grunenthal. JP and LF are employees and shareholders of MedBioinformatics Solutions SL. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Niarakis, Ostaszewski, Mazein, Kuperstein, Kutmon, Gillespie, Funahashi, Acencio, Hemedan, Aichem, Klein, Czauderna, Burtscher, Yamada, Hiki, Hiroi, Hu, Pham, Ehrhart, Willighagen, Valdeolivas, Dugourd, Messina, Esteban-Medina, Peña-Chilet, Rian, Soliman, Aghamiri, Puniya, Naldi, Helikar, Singh, Fernández, Bermudez, Tsirvouli, Montagud, Noël, Ponce-de-Leon, Maier, Bauch, Gyori, Bachman, Luna, Piñero, Furlong, Balaur, Rougny, Jarosz, Overall, Phair, Perfetto, Matthews, Rex, Orlic-Milacic, Gomez, De Meulder, Ravel, Jassal, Satagopam, Wu, Golebiewski, Gawron, Calzone, Beckmann, Evelo, D’Eustachio, Schreiber, Saez-Rodriguez, Dopazo, Kuiper, Valencia, Wolkenhauer, Kitano, Barillot, Auffray, Balling, Schneider and the COVID-19 Disease Map Community.)
Published: 2024
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48. Visualization of automatically combined disease maps and pathway diagrams for rare diseases.

Author: Gawron P, Hoksza D, Piñero J, Peña-Chilet M, Esteban-Medina M, Fernandez-Rueda JL, Colonna V, Smula E, Heirendt L, Ancien F, Groues V, Satagopam VP, Schneider R, Dopazo J, Furlong LI, and Ostaszewski M
Abstract: Introduction: Investigation of molecular mechanisms of human disorders, especially rare diseases, require exploration of various knowledge repositories for building precise hypotheses and complex data interpretation. Recently, increasingly more resources offer diagrammatic representation of such mechanisms, including disease-dedicated schematics in pathway databases and disease maps. However, collection of knowledge across them is challenging, especially for research projects with limited manpower. Methods: In this article we present an automated workflow for construction of maps of molecular mechanisms for rare diseases. The workflow requires a standardized definition of a disease using Orphanet or HPO identifiers to collect relevant genes and variants, and to assemble a functional, visual repository of related mechanisms, including data overlays. The diagrams composing the final map are unified to a common systems biology format from CellDesigner SBML, GPML and SBML+layout+render. The constructed resource contains disease-relevant genes and variants as data overlays for immediate visual exploration, including embedded genetic variant browser and protein structure viewer. Results: We demonstrate the functionality of our workflow on two examples of rare diseases: Kawasaki disease and retinitis pigmentosa. Two maps are constructed based on their corresponding identifiers. Moreover, for the retinitis pigmentosa use-case, we include a list of differentially expressed genes to demonstrate how to tailor the workflow using omics datasets. Discussion: In summary, our work allows for an ad-hoc construction of molecular diagrams combined from different sources, preserving their layout and graphical style, but integrating them into a single resource. This allows to reduce time consuming tasks of prototyping of a molecular disease map, enabling visual exploration, hypothesis building, data visualization and further refinement. The code of the workflow is open and accessible at https://gitlab.lcsb.uni.lu/minerva/automap/., Competing Interests: JP and LF are employed by MedBioinformatics Solutions SL. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gawron, Hoksza, Piñero, Peña-Chilet, Esteban-Medina, Fernandez-Rueda, Colonna, Smula, Heirendt, Ancien, Groues, Satagopam, Schneider, Dopazo, Furlong and Ostaszewski.)
Published: 2023
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49. COVID-19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms.

Author: Ostaszewski M, Niarakis A, Mazein A, Kuperstein I, Phair R, Orta-Resendiz A, Singh V, Aghamiri SS, Acencio ML, Glaab E, Ruepp A, Fobo G, Montrone C, Brauner B, Frishman G, Monraz Gómez LC, Somers J, Hoch M, Kumar Gupta S, Scheel J, Borlinghaus H, Czauderna T, Schreiber F, Montagud A, Ponce de Leon M, Funahashi A, Hiki Y, Hiroi N, Yamada TG, Dräger A, Renz A, Naveez M, Bocskei Z, Messina F, Börnigen D, Fergusson L, Conti M, Rameil M, Nakonecnij V, Vanhoefer J, Schmiester L, Wang M, Ackerman EE, Shoemaker JE, Zucker J, Oxford K, Teuton J, Kocakaya E, Summak GY, Hanspers K, Kutmon M, Coort S, Eijssen L, Ehrhart F, Rex DAB, Slenter D, Martens M, Pham N, Haw R, Jassal B, Matthews L, Orlic-Milacic M, Senff-Ribeiro A, Rothfels K, Shamovsky V, Stephan R, Sevilla C, Varusai T, Ravel JM, Fraser R, Ortseifen V, Marchesi S, Gawron P, Smula E, Heirendt L, Satagopam V, Wu G, Riutta A, Golebiewski M, Owen S, Goble C, Hu X, Overall RW, Maier D, Bauch A, Gyori BM, Bachman JA, Vega C, Grouès V, Vazquez M, Porras P, Licata L, Iannuccelli M, Sacco F, Nesterova A, Yuryev A, de Waard A, Turei D, Luna A, Babur O, Soliman S, Valdeolivas A, Esteban-Medina M, Peña-Chilet M, Rian K, Helikar T, Puniya BL, Modos D, Treveil A, Olbei M, De Meulder B, Ballereau S, Dugourd A, Naldi A, Noël V, Calzone L, Sander C, Demir E, Korcsmaros T, Freeman TC, Augé F, Beckmann JS, Hasenauer J, Wolkenhauer O, Willighagen EL, Pico AR, Evelo CT, Gillespie ME, Stein LD, Hermjakob H, D'Eustachio P, Saez-Rodriguez J, Dopazo J, Valencia A, Kitano H, Barillot E, Auffray C, Balling R, and Schneider R
Published: 2021
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