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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Laura Polivka; Marine Madrange; Cristina Bulai-Livideanu; Stéphane Barete; +52 Authors

    Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the recurrent involvement of KIT mutations, the pathophysiologic origin of mastocytosis and MMAS is unclear. Although hereditary α-tryptasemia (HαT, related to TPSAB1 gene duplication) is abnormally frequent in these diseases, it is not known whether the association is coincidental or causal.We evaluated the prevalence of HαT in all mastocytosis subtypes and MMAS and assessed the pathophysiologic association with HαT.Clinical data, laboratory data, KIT mutations, TPSAB1 duplication (assessed by droplet digital PCR), and HαT prevalence were retrospectively recorded for all patients with mastocytosis and MMAS registered in the French national referral center database and compared to a control cohort. To increase the power of our analysis for advanced systemic mastocytosis (advSM), we pooled our cohort with literature cases.We included 583 patients (27 with MMAS and 556 with mastocytosis). The prevalence of HαT in mastocytosis was 12.6%, significantly higher than in the general population (5.7%, P = .002) and lower than in MMAS (33.3%, P = .02). HαTHere we confirm the increase incidence of anaphylaxis in HαT

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Journal of Allergy a...arrow_drop_down
    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Journal of Allergy and Clinical Immunology
    Article . 2024 . Peer-reviewed
    License: CC BY NC ND
    Data sources: Crossref
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Journal of Allergy a...arrow_drop_down
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      Journal of Allergy and Clinical Immunology
      Article . 2024 . Peer-reviewed
      License: CC BY NC ND
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Bastard, Paul; Vazquez, Sara; Liu, Jamin; Laurie, Matthew, T; +199 Authors

    Life-threatening ‘breakthrough’ cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population. International audience

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ UGD Academic Reposit...arrow_drop_down
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    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
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    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Leonardo W Heyerdahl; Yanina Borzykh; Benedetta Lana; Anna-Maria Volkmann; +6 Authors

    Background In this era of global health crises, public trust in scientists is a crucial determinant of adherence to public health recommendations. Studies of trust in scientists often link sociodemographic and other factors to such adherence but rely on assumptions about scientists and neglect scientific uncertainty. We undertook a cross-sectional mixed-methods study evaluating factors associated with public trust of scientists in Europe, investigating how and why respondents embraced certain claims in scientific debates.Methods A survey was administered to 7000 participants across seven European countries in December 2020. Data concerning sociodemographic characteristics, trust in scientists, information source preferences, COVID-19 experiences and beliefs about pandemic origins were analysed using a multiple regression model. We employed thematic analysis to interpret open-text responses about pandemic origins and likely acceptance of treatments and vaccination.Results Trust in scientists was associated with multiple sociodemographic characteristics, including higher age and educational levels, left/centre political affiliation and use of certain information sources. Respondents claiming that COVID-19 was deliberately released and that 5G technology worsened COVID-19 symptoms had lower levels of trust in scientists. Explaining their positions in debates about pandemic origins, respondents trusting and not trusting scientists invoked scientific results and practices, arguing that scientists were not the most important actors in these debates.Conclusions Although our quantitative analyses align with prior studies, our qualitative analyses of scientists, their practices and perceived roles are more varied than prior research presumed. Further investigation of these variations is needed to strengthen scientific literacy and trust in scientists. International audience

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    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    https://doi.org/10.1136/bmjph-...
    Article . 2023 . Peer-reviewed
    License: CC BY
    Data sources: Crossref
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      https://doi.org/10.1136/bmjph-...
      Article . 2023 . Peer-reviewed
      License: CC BY
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Melchior, Maria; Figueiredo, Natasha; Roversi, Aurélia; Dubanchet, Alexandre; +19 Authors

    Abstract Background The COVID-19 pandemic has had an impact on population-wide mental health and well-being. Although people experiencing socioeconomic disadvantage may be especially vulnerable, they experience barriers in accessing mental health care. To overcome these barriers, the World Health Organization (WHO) designed two scalable psychosocial interventions, namely the web-based Doing What Matters in Times of Stress (DWM) and the face-to-face Problem Management Plus (PM+), to help people manage stressful situations. Our study aims to test the effectiveness of a stepped-care program using DWM and PM + among individuals experiencing unstable housing in France – a majority of whom are migrant or have sought asylum. Methods This is a randomised controlled trial to evaluate the effectiveness and cost effectiveness of a stepped-care program using DWM and PM + among persons with psychological distress and experiencing unstable housing, in comparison to enhanced care as usual (eCAU). Participants (N = 210) will be randomised to two parallel groups: eCAU or eCAU plus the stepped-care program. The main study outcomes are symptoms of depression and anxiety measured using the Patient Health Questionnaire Anxiety and Depression Scale (PHQ-ADS). Discussion This randomised controlled trial will contribute to a better understanding of effective community-based scalable strategies that can help address the mental health needs of persons experiencing socioeconomic disadvantage, whose needs are high yet who frequently have limited access to mental health care services. Trial registration this randomised trial has been registered at ClinicalTrials.gov under the number NCT05033210.

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ IRIS - Università de...arrow_drop_down
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    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
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    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
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    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    BMC Public Health
    Article . 2023
    Data sources: DOAJ
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Castro, Victoria; Pérez-Berna, Ana Joaquina; Calvo, Gema; Pereiro, Eva; +1 Authors

    This study was funded by ALBA Synchrotron standard proposals 2022065884 and 2021024899, the Spanish National Research Council (grant number PIE-RD-COVID-19 ref E202020E079) and PID2020-115476RB-I00 funded by MCIN/AEI/10.13039/501100011033, and by “ERDF A way of making Europe” to the CNB-CSIC. This research work was also funded by the European Commission – NextGenerationEU (Regulation EU 2020/2094), through CSIC’s Global Health Platform (PTI Salud Global). G.C. was initially supported by SAF2017-87846-R from the Spanish Ministry of Science, and V.C. was initially supported by PIE-RD-COVID-19. A.J.P.-B., G.C., V.C., E.P., and P.G. are part of the CoCID Consortium (cocid.eu), which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 1010171162. We acknowledge R. Molenkamp (Erasmus University Medical Center, Rotterdam, The Netherlands; participant of the EU-funded EVA-GLOBAL project, grant agreement 871029) for the SARS-CoV-2 strain NL/2020 virus, Ralf Bartenschlager lab for the SARS-CoV-2 reporter construct, L. Enjuanes (Department of Molecular and Cell Biology, CNB-CSIC) for the Vero-E6 cells, and Urtzi Garaigorta (Department of Molecular and Cell Biology, CNB-CSIC) for critically reading the manuscript. We acknowledge the outstanding technical support from the BSL3 laboratory, Advanced Microscopy, Electron Microscopy and Cryoelectron Microscopy Core facilities personnel at the CNB as well as the support of ALBA staff, in particular Andrea Sorrentino and Ricardo Valcarcel from the MISTRAL beamline. Plus-strand RNA viruses are proficient at remodeling host cell membranes for optimal viral genome replication and the production of infectious progeny. These ultrastructural alterations result in the formation of viral membranous organelles and may be observed by different imaging techniques, providing nanometric resolution. Guided by confocal and electron microscopy, this study describes the generation of wide-field volumes using cryogenic soft-X-ray tomography (cryo-SXT) on SARS-CoV-2-infected human lung adenocarcinoma cells. Confocal microscopy showed accumulation of double-stranded RNA (dsRNA) and nucleocapsid (N) protein in compact perinuclear structures, preferentially found around centrosomes at late stages of the infection. Transmission electron microscopy (TEM) showed accumulation of membranous structures in the vicinity of the infected cell nucleus, forming a viral replication organelle containing characteristic double-membrane vesicles and virus-like particles within larger vesicular structures. Cryo-SXT revealed viral replication organelles very similar to those observed by TEM but indicated that the vesicular organelle observed in TEM sections is indeed a vesiculo-tubular network that is enlarged and elongated at late stages of the infection. Overall, our data provide additional insight into the molecular architecture of the SARS-CoV-2 replication organelle. Peer reviewed

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    ACS Nano
    Article . 2023 . Peer-reviewed
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    ACS Nano
    Article . 2023
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      ACS Nano
      Article . 2023 . Peer-reviewed
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      ACS Nano
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Prieto Santamaría, Lucía;

    Developing a drug for a specific condition is a remarkably costly task in terms of money, time, and risks. An alternative approach to this lengthy process is drug repurposing, which tries to identify other uses for drugs that already exist. The problem is addressed by using already known drugs to treat other diseases different from the ones they were developed for. This way, some of the phases of developing a drug can be skipped, being more efficient and reducing the investment. Although this process used to occur by chance in the beginning, nowadays drug repurposing can be targeted. Some of the most promising strategies derive from data-driven methodologies. In this context, one of the emerging paradigms to structure enormous amounts of biomedical data comes with the so-called “network medicine”. This field abandons the individual study of each disease, integrating large-scale and heterogenous data in the form of graphs to achieve a better understanding of how diseases work and how they are connected. In particular, a disease network is a complex network in which the nodes are the different diseases or disorders, while the edges represent the relationships among them. The first human disease network was based on diseasecausing genes, but other networks have been designed around different factors such as metabolic pathways, drugs, or symptoms, among others. Following the ideas and concepts of disease networks, one can find the DISNET project, which had the ultimate goal of dug repurposing. The present doctoral thesis has been developed under the scope of this project, pursuing the general objective of obtaining and integrating biomedical knowledge from public sources to create disease networks that enable a better disease understanding and, ultimately, enhance drug repurposing. Within this thesis and the DISNET project, a large-scale multi-layered heterogeneous biomedical knowledge base around the concept of disease has been built. The data has been obtained from publicly accessible sources, both structured and unstructured. This information has been integrated and organized in three different levels: the phenotypic (with information regarding diseases and their associated symptoms), the biologic (which stores molecular-shifted data related to diseases including genes, proteins, metabolic pathways, genetic variants, non-coding RNAs and so on) and the pharmacologic (containing information of the drugs, their interactions, and their connections to diseases). The two main lines in which the present thesis has delved into are disease understanding and drug repurposing. On the one hand and regarding disease understanding, a set of new arrangements of disease groups has been proposed via clustering techniques. These groups can be thought as novel nosological models that integrate molecular information, in contrast with traditional taxonomies mostly relying on solely phenotypic data. On the other hand and with respect to drug repurposing, two complementary methodologies to repurpose drugs have been put forward. Differences between data related to known successful repurposing cases and non-repurposing data have been identified, and analyses within the genes, symptoms and categories have been performed to uncover patterns. Threshold values in the association scores between diseases and different features have been pinpointed in order to evaluate the potential of new repurposing hypotheses. Moreover, a straightforward methodology consisting of five information paths and based on gene and symptom relationships has been developed to suggest repurposing candidates to treat COVID-19. A list of 13 drugs was obtained. This doctoral thesis has followed the structure of a compendium of publications: it comprises three articles published in scientific journals with high impact factor. The publications have contributed to accomplish the different research objectives and have been developed under the same thematic unit. RESUMEN Desarrollar un fármaco para una enfermedad específica es una tarea muy costosa en términos de dinero, tiempo y riesgos. Una alternativa a este largo proceso es el reposicionamiento de fármacos, que trata de identificar otros usos para medicamentos ya existentes. Es decir, se utilizan fármacos ya conocidos para tratar enfermedades diferentes de aquellas para las que fueron desarrollados. De esta forma, se pueden saltar algunas de las fases del desarrollo de un fármaco, acortando los tiempos y reduciendo la inversión. Aunque al principio este proceso solía producirse por casualidad, hoy en día se puede dirigir el reposicionamiento de fármacos. Algunas de las estrategias más prometedoras derivan de metodologías basadas en datos. En este contexto, uno de los paradigmas emergentes para estructurar las enormes cantidades de datos biomédicos surge con la llamada “medicina de redes”. Este campo abandona el estudio individual de cada enfermedad, integrando datos heterogéneos y a gran escala en forma de grafos para lograr una mejor comprensión de cómo funcionan y se conectan las enfermedades. En concreto, una red de enfermedades es un grafo complejo en el que los vértices son las distintas enfermedades y las aristas representan las relaciones entre ellas. La primera red se basó en los genes causantes de las enfermedades, pero se han desarrollado otras redes en torno a diferentes factores como rutas metabólicas, fármacos o síntomas, entre otros. Siguiendo las ideas de las redes de enfermedades, se encuentra el proyecto DISNET, cuyo objetivo final es el reposicionamiento de fármacos. La presente tesis doctoral se ha desarrollado en el marco de este proyecto, persiguiendo el objetivo general de obtener e integrar conocimiento biomédico de fuentes públicas para crear redes de enfermedades que permitan un mejor entendimiento de las mismas y potenciar el reposicionamiento de fármacos. En esta tesis y en el proyecto DISNET se ha construido una base de conocimiento biomédico heterogéneo a gran escala y multicapa en torno al concepto de enfermedad. La información se ha obtenido de fuentes públicas, aunando datos tanto estructurados como no estructurados. Esta información se ha integrado y organizado en tres niveles: el fenotípico (con información relativa a las enfermedades y sus síntomas), el biológico (que almacena datos de las enfermedades de tipo molecular, incluyendo genes, proteínas, rutas metabólicas, variantes genéticas, etc.) y el farmacológico (que contiene información de los fármacos, sus interacciones y sus conexiones con las enfermedades). Las dos líneas principales en las que se ha profundizado en la presente tesis son el entendimiento de las enfermedades y el reposicionamiento de fármacos. Por una parte, y en relación al entendimiento de las enfermedades, se ha propuesto un conjunto de nuevos grupos de enfermedades mediante técnicas de clustering. Estos grupos pueden concebirse como nuevos modelos nosológicos que integran información de tipo molecular, a diferencia de las taxonomías tradicionales, que se basan principalmente en datos fenotípicos. Por otra parte, y con respecto al reposicionamiento de fármacos, se han propuesto dos metodologías complementarias para sugerir hipótesis de reposicionamiento. Se han identificado diferencias entre los datos relacionados con casos conocidos y exitosos de reposicionamiento y los datos no relacionados con reposicionamiento, y se han realizado análisis a nivel de los genes, síntomas y categorías para descubrir patrones. Se han identificado umbrales en los valores de asociación entre enfermedades y diferentes características con el fin de evaluar el potencial de nuevas hipótesis de reposicionamiento. Además, se ha desarrollado una metodología directa que consta de cinco vías de información y que se basa en las relaciones entre genes y síntomas para sugerir candidatos de reposicionamiento para tratar la COVID-19, obteniendo una lista de 13 fármacos. Esta tesis doctoral ha seguido la estructura de un compendio de publicaciones: consta de tres artículos publicados en revistas científicas con alto factor de impacto. Las publicaciones han contribuido a alcanzar los diferentes objetivos de la investigación y se han desarrollado bajo una misma unidad temática.

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    https://doi.org/10.20868/upm.t...
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      https://doi.org/10.20868/upm.t...
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    Authors: Benjamin Dupuis; Akiko Kato; Nicolas Joly; Claire Saraux; +3 Authors

    International audience; The COVID-19 pandemic and its lock-down measures have resulted in periods of reduced human activity, known as anthropause. While this period was expected to be favorable for the marine ecosystem, due to a probable reduction of pollution, shipping traffic, industrial activity and fishing pressure, negative counterparts such as reduced fisheries surveillance could counterbalance these positive effects. Simultaneously, on-land pressure due to human disturbance and tourism should have drastically decreased, potentially benefiting land-breeding marine animals such as seabirds. We analyzed 11 breeding seasons of data on several biological parameters of little penguins from a popular tourist attraction at Phillip Island, Australia. We investigated the impact of anthropogenic activities on penguin behavior during the breeding season measured by (1) distribution at sea, (2) colony attendance, (3) isotopic niche (4) chick meal mass, and (5) offspring investment against shipping traffic and number of tourists. The 2020 lock-downs resulted in a near absence of tourists visiting the Penguin Parade®, which was otherwise visited by 800,000+ visitors on average per breeding season. However, our long-term analysis showed no effect of the presence of visitors on little penguins' activities. Surprisingly, the anthropause did not trigger any changes in maritime traffic intensity and distribution in the region. We found inter- and intra-annual variations for most parameters, we detected a negative effect of marine traffic on the foraging efficiency. Our results suggest that environmental variations have a greater influence on the breeding behavior of little penguins compared to short-term anthropause events. Our long-term dataset was key to test whether changes in anthropogenic activities affected the wildlife during the COVID-19 pandemic.

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    ZENODO; Biological Conservation
    Article . 2023 . Peer-reviewed
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    Authors: Alessandro De Gaetano; Paolo Bajardi; Nicolò Gozzi; Nicola Perra; +2 Authors

    Background During the initial phases of the vaccination campaign worldwide, nonpharmaceutical interventions (NPIs) remained pivotal in the fight against the COVID-19 pandemic. In this context, it is important to understand how the arrival of vaccines affected the adoption of NPIs. Indeed, some individuals might have seen the start of mass vaccination campaigns as the end of the emergency and, as a result, relaxed their COVID-safe behaviors, facilitating the spread of the virus in a delicate epidemic phase such as the initial rollout.Objective The aim of this study was to collect information about the possible relaxation of protective behaviors following key events of the vaccination campaign in four countries and to analyze possible associations of these behavioral tendencies with the sociodemographic characteristics of participants. Methods We developed an online survey named “COVID-19 Prevention and Behavior Survey” that was conducted between November 26 and December 22, 2021. Participants were recruited using targeted ads on Facebook in four different countries: Brazil, Italy, South Africa, and the United Kingdom. We measured the onset of relaxation of protective measures in response to key events of the vaccination campaign, namely personal vaccination and vaccination of the most vulnerable population. Through calculation of odds ratios (ORs) and regression analysis, we assessed the strength of association between compliance with NPIs and sociodemographic characteristics of participants.Results We received 2263 questionnaires from the four countries. Participants reported the most significant changes in social activities such as going to a restaurant or the cinema and visiting relatives and friends. This is in good agreement with validated psychological models of health-related behavioral change such as the Health Belief Model, according to which activities with higher costs and perceived barriers (eg, social activities) are more prone to early relaxation. Multivariate analysis using a generalized linear model showed that the two main determinants of the drop of social NPIs were (1) having previously tested positive for COVID-19 (after the second vaccine dose: OR 2.46, 95% CI 1.73-3.49) and (2) living with people at risk (after the second vaccine dose: OR 1.57, 95% CI 1.22-2.03).Conclusions This work shows that particular caution has to be taken during vaccination campaigns. Indeed, people might relax their safe behaviors regardless of the dynamics of the epidemic. For this reason, it is crucial to maintain high compliance with NPIs to avoid hindering the beneficial effects of the vaccine. International audience

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    Journal of Medical Internet Research
    Article . 2023 . Peer-reviewed
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      Journal of Medical Internet Research
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    Authors: Victor Chardès; Andrea Mazzolini; Thierry Mora; Aleksandra M. Walczak;

    Antigenic variation is the main immune escape mechanism for RNA viruses like influenza or SARS-CoV-2. While high mutation rates promote antigenic escape, they also induce large mutational loads and reduced fitness. It remains unclear how this cost–benefit trade-off selects the mutation rate of viruses. Using a traveling wave model for the coevolution of viruses and host immune systems in a finite population, we investigate how immunity affects the evolution of the mutation rate and other nonantigenic traits, such as virulence. We first show that the nature of the wave depends on how cross-reactive immune systems are, reconciling previous approaches. The immune-virus system behaves like a Fisher wave at low cross-reactivities, and like a fitness wave at high cross-reactivities. These regimes predict different outcomes for the evolution of nonantigenic traits. At low cross-reactivities, the evolutionarily stable strategy is to maximize the speed of the wave, implying a higher mutation rate and increased virulence. At large cross-reactivities, where our estimates place H3N2 influenza, the stable strategy is to increase the basic reproductive number, keeping the mutation rate to a minimum and virulence low. International audience

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    Proceedings of the National Academy of Sciences
    Article . 2023 . Peer-reviewed
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    https://doi.org/10.48550/arxiv...
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      Proceedings of the National Academy of Sciences
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    Authors: Rodrigo Lázaro‐Gorines; Patricia Pérez; Ignacio Heras‐Murillo; Irene Adán‐Barrientos; +29 Authors

    SARS-CoV-2 B.1.351 and B.1.167.2 viruses used in this study were obtained through the European Virus Archive Global (EVA-GLOBAL) project that has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 653316. SARS-CoV-2 B.1 (MAD6 isolate) was kindly provided by José M. Honrubia and Luis Enjuanes (CNB-CSIC, Madrid, Spain). The authors thank Centro de Investigación en Sanidad Animal (CISA)-Instituto Nacional de Investigaciones Agrarias (INIA-CSIC) (Valdeolmos, Madrid, Spain) for the BSL-3 facilities. Research in LA-V laboratory was funded by the BBVA Foundation (Ayudas Fundación BBVA a Equipos de Investigación Científica SARS-CoV-2 y COVID-19); the MCIN/AEI/10.13039/501100011033 (PID2020-117323RB-I00 and PDC2021-121711-I00), partially supported by the European Regional Development Fund (ERDF); the Carlos III Health Institute (ISCIII) (DTS20/00089), partially supported by the ERDF, the Spanish Association Against Cancer (AECC 19084); the CRIS Cancer Foundation (FCRIS-IFI-2018 and FCRIS-2021-0090), the Fundación Caixa-Health Research (HR21-00761 project IL7R_LungCan), and the Comunidad de Madrid (P2022/BMD-7225 NEXT_GEN_CART_MAD-CM). Work in the DS laboratory was funded by the CNIC; the European Union's Horizon 2020 research and innovation program under grant agreement ERC-2016-Consolidator Grant 725091; MCIN/AEI/10.13039/501100011033 (PID2019-108157RB); Comunidad de Madrid (B2017/BMD-3733 Immunothercan-CM); Atresmedia (Constantes y Vitales prize); Fondo Solidario Juntos (Banco Santander); and “La Caixa” Foundation (LCF/PR/HR20/00075). The CNIC was supported by the ISCIII, the MCIN and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (CEX2020-001041-S funded by MCIN/AEI/10.13039/501100011033). Research in RD laboratory was supported by the ISCIII (PI2100989) and CIBERINFEC; the European Commission Horizon 2020 Framework Programme (grant numbers 731868 project VIRUSCAN FETPROACT-2016, and 101046084 project EPIC-CROWN-2); and the Fundación Caixa-Health Research (grant number HR18-00469 project StopEbola). Research in CNB-CSIC laboratory was funded by Fondo Supera COVID-19 (Crue Universidades-Banco Santander) grant, CIBERINFEC, and Spanish Research Council (CSIC) grant 202120E079 (to J.G.-A.), CSIC grant 2020E84 (to M.E.), MCIN/AEI/10.13039/501100011033 (PID2020-114481RB-I00 to J.G-A. and M.E.), and by the European Commission-NextGenerationEU, through CSIC's Global Health Platform (PTI Salud Global) to J.G.-A. and M.E. Work in the CIB-CSIC laboratory was supported by MCIN/AEI/10.13039/501100011033 (PID2019-104544GB-I00 and 2023AEP105 to CA, and PID2020-113225GB-I00 to F.J.B.). Cryo-EM data were collected at the Maryland Center for Advanced Molecular Analyses which was supported by MPOWER (The University of Maryland Strategic Partnership). I.H.-M. receives the support of a fellowship from la Caixa Foundation (ID 100010434, fellowship code: LCF/BQ/IN17/11620074) and from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 71367. L.R.-P. was supported by a predoctoral fellowship from the Immunology Chair, Universidad Francisco de Vitoria/Merck. Administration of neutralizing antibodies (nAbs) has proved to be effective by providing immediate protection against SARS-CoV-2. However, dual strategies combining virus neutralization and immune response stimulation to enhance specific cytotoxic T cell responses, such as dendritic cell (DC) cross-priming, represent a promising field but have not yet been explored. Here, a broadly nAb, TNT, are first generated by grafting an anti-RBD biparatopic tandem nanobody onto a trimerbody scaffold. Cryo-EM data show that the TNT structure allows simultaneous binding to all six RBD epitopes, demonstrating a high-avidity neutralizing interaction. Then, by C-terminal fusion of an anti-DNGR-1 scFv to TNT, the bispecific trimerbody TNTDNGR-1 is generated to target neutralized virions to type 1 conventional DCs (cDC1s) and promote T cell cross-priming. Therapeutic administration of TNTDNGR-1, but not TNT, protects K18-hACE2 mice from a lethal SARS-CoV-2 infection, boosting virus-specific humoral responses and CD8+ T cell responses. These results further strengthen the central role of interactions with immune cells in the virus-neutralizing antibody activity and demonstrate the therapeutic potential of the Fc-free strategy that can be used advantageously to provide both immediate and long-term protection against SARS-CoV-2 and other viral infections. Peer reviewed 17 p.-4 fig.

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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Laura Polivka; Marine Madrange; Cristina Bulai-Livideanu; Stéphane Barete; +52 Authors

    Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the recurrent involvement of KIT mutations, the pathophysiologic origin of mastocytosis and MMAS is unclear. Although hereditary α-tryptasemia (HαT, related to TPSAB1 gene duplication) is abnormally frequent in these diseases, it is not known whether the association is coincidental or causal.We evaluated the prevalence of HαT in all mastocytosis subtypes and MMAS and assessed the pathophysiologic association with HαT.Clinical data, laboratory data, KIT mutations, TPSAB1 duplication (assessed by droplet digital PCR), and HαT prevalence were retrospectively recorded for all patients with mastocytosis and MMAS registered in the French national referral center database and compared to a control cohort. To increase the power of our analysis for advanced systemic mastocytosis (advSM), we pooled our cohort with literature cases.We included 583 patients (27 with MMAS and 556 with mastocytosis). The prevalence of HαT in mastocytosis was 12.6%, significantly higher than in the general population (5.7%, P = .002) and lower than in MMAS (33.3%, P = .02). HαTHere we confirm the increase incidence of anaphylaxis in HαT

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    Journal of Allergy and Clinical Immunology
    Article . 2024 . Peer-reviewed
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      Journal of Allergy and Clinical Immunology
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Bastard, Paul; Vazquez, Sara; Liu, Jamin; Laurie, Matthew, T; +199 Authors

    Life-threatening ‘breakthrough’ cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population. International audience

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    Authors: Leonardo W Heyerdahl; Yanina Borzykh; Benedetta Lana; Anna-Maria Volkmann; +6 Authors

    Background In this era of global health crises, public trust in scientists is a crucial determinant of adherence to public health recommendations. Studies of trust in scientists often link sociodemographic and other factors to such adherence but rely on assumptions about scientists and neglect scientific uncertainty. We undertook a cross-sectional mixed-methods study evaluating factors associated with public trust of scientists in Europe, investigating how and why respondents embraced certain claims in scientific debates.Methods A survey was administered to 7000 participants across seven European countries in December 2020. Data concerning sociodemographic characteristics, trust in scientists, information source preferences, COVID-19 experiences and beliefs about pandemic origins were analysed using a multiple regression model. We employed thematic analysis to interpret open-text responses about pandemic origins and likely acceptance of treatments and vaccination.Results Trust in scientists was associated with multiple sociodemographic characteristics, including higher age and educational levels, left/centre political affiliation and use of certain information sources. Respondents claiming that COVID-19 was deliberately released and that 5G technology worsened COVID-19 symptoms had lower levels of trust in scientists. Explaining their positions in debates about pandemic origins, respondents trusting and not trusting scientists invoked scientific results and practices, arguing that scientists were not the most important actors in these debates.Conclusions Although our quantitative analyses align with prior studies, our qualitative analyses of scientists, their practices and perceived roles are more varied than prior research presumed. Further investigation of these variations is needed to strengthen scientific literacy and trust in scientists. International audience

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    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    https://doi.org/10.1136/bmjph-...
    Article . 2023 . Peer-reviewed
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
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      https://doi.org/10.1136/bmjph-...
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    Authors: Melchior, Maria; Figueiredo, Natasha; Roversi, Aurélia; Dubanchet, Alexandre; +19 Authors

    Abstract Background The COVID-19 pandemic has had an impact on population-wide mental health and well-being. Although people experiencing socioeconomic disadvantage may be especially vulnerable, they experience barriers in accessing mental health care. To overcome these barriers, the World Health Organization (WHO) designed two scalable psychosocial interventions, namely the web-based Doing What Matters in Times of Stress (DWM) and the face-to-face Problem Management Plus (PM+), to help people manage stressful situations. Our study aims to test the effectiveness of a stepped-care program using DWM and PM + among individuals experiencing unstable housing in France – a majority of whom are migrant or have sought asylum. Methods This is a randomised controlled trial to evaluate the effectiveness and cost effectiveness of a stepped-care program using DWM and PM + among persons with psychological distress and experiencing unstable housing, in comparison to enhanced care as usual (eCAU). Participants (N = 210) will be randomised to two parallel groups: eCAU or eCAU plus the stepped-care program. The main study outcomes are symptoms of depression and anxiety measured using the Patient Health Questionnaire Anxiety and Depression Scale (PHQ-ADS). Discussion This randomised controlled trial will contribute to a better understanding of effective community-based scalable strategies that can help address the mental health needs of persons experiencing socioeconomic disadvantage, whose needs are high yet who frequently have limited access to mental health care services. Trial registration this randomised trial has been registered at ClinicalTrials.gov under the number NCT05033210.

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    BMC Public Health
    Article . 2023
    Data sources: DOAJ
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    Authors: Castro, Victoria; Pérez-Berna, Ana Joaquina; Calvo, Gema; Pereiro, Eva; +1 Authors

    This study was funded by ALBA Synchrotron standard proposals 2022065884 and 2021024899, the Spanish National Research Council (grant number PIE-RD-COVID-19 ref E202020E079) and PID2020-115476RB-I00 funded by MCIN/AEI/10.13039/501100011033, and by “ERDF A way of making Europe” to the CNB-CSIC. This research work was also funded by the European Commission – NextGenerationEU (Regulation EU 2020/2094), through CSIC’s Global Health Platform (PTI Salud Global). G.C. was initially supported by SAF2017-87846-R from the Spanish Ministry of Science, and V.C. was initially supported by PIE-RD-COVID-19. A.J.P.-B., G.C., V.C., E.P., and P.G. are part of the CoCID Consortium (cocid.eu), which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 1010171162. We acknowledge R. Molenkamp (Erasmus University Medical Center, Rotterdam, The Netherlands; participant of the EU-funded EVA-GLOBAL project, grant agreement 871029) for the SARS-CoV-2 strain NL/2020 virus, Ralf Bartenschlager lab for the SARS-CoV-2 reporter construct, L. Enjuanes (Department of Molecular and Cell Biology, CNB-CSIC) for the Vero-E6 cells, and Urtzi Garaigorta (Department of Molecular and Cell Biology, CNB-CSIC) for critically reading the manuscript. We acknowledge the outstanding technical support from the BSL3 laboratory, Advanced Microscopy, Electron Microscopy and Cryoelectron Microscopy Core facilities personnel at the CNB as well as the support of ALBA staff, in particular Andrea Sorrentino and Ricardo Valcarcel from the MISTRAL beamline. Plus-strand RNA viruses are proficient at remodeling host cell membranes for optimal viral genome replication and the production of infectious progeny. These ultrastructural alterations result in the formation of viral membranous organelles and may be observed by different imaging techniques, providing nanometric resolution. Guided by confocal and electron microscopy, this study describes the generation of wide-field volumes using cryogenic soft-X-ray tomography (cryo-SXT) on SARS-CoV-2-infected human lung adenocarcinoma cells. Confocal microscopy showed accumulation of double-stranded RNA (dsRNA) and nucleocapsid (N) protein in compact perinuclear structures, preferentially found around centrosomes at late stages of the infection. Transmission electron microscopy (TEM) showed accumulation of membranous structures in the vicinity of the infected cell nucleus, forming a viral replication organelle containing characteristic double-membrane vesicles and virus-like particles within larger vesicular structures. Cryo-SXT revealed viral replication organelles very similar to those observed by TEM but indicated that the vesicular organelle observed in TEM sections is indeed a vesiculo-tubular network that is enlarged and elongated at late stages of the infection. Overall, our data provide additional insight into the molecular architecture of the SARS-CoV-2 replication organelle. Peer reviewed

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    ACS Nano
    Article . 2023 . Peer-reviewed
    License: CC BY NC ND
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    ACS Nano
    Article . 2023
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      ACS Nano
      Article . 2023 . Peer-reviewed
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      ACS Nano
      Article . 2023
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    Authors: Prieto Santamaría, Lucía;

    Developing a drug for a specific condition is a remarkably costly task in terms of money, time, and risks. An alternative approach to this lengthy process is drug repurposing, which tries to identify other uses for drugs that already exist. The problem is addressed by using already known drugs to treat other diseases different from the ones they were developed for. This way, some of the phases of developing a drug can be skipped, being more efficient and reducing the investment. Although this process used to occur by chance in the beginning, nowadays drug repurposing can be targeted. Some of the most promising strategies derive from data-driven methodologies. In this context, one of the emerging paradigms to structure enormous amounts of biomedical data comes with the so-called “network medicine”. This field abandons the individual study of each disease, integrating large-scale and heterogenous data in the form of graphs to achieve a better understanding of how diseases work and how they are connected. In particular, a disease network is a complex network in which the nodes are the different diseases or disorders, while the edges represent the relationships among them. The first human disease network was based on diseasecausing genes, but other networks have been designed around different factors such as metabolic pathways, drugs, or symptoms, among others. Following the ideas and concepts of disease networks, one can find the DISNET project, which had the ultimate goal of dug repurposing. The present doctoral thesis has been developed under the scope of this project, pursuing the general objective of obtaining and integrating biomedical knowledge from public sources to create disease networks that enable a better disease understanding and, ultimately, enhance drug repurposing. Within this thesis and the DISNET project, a large-scale multi-layered heterogeneous biomedical knowledge base around the concept of disease has been built. The data has been obtained from publicly accessible sources, both structured and unstructured. This information has been integrated and organized in three different levels: the phenotypic (with information regarding diseases and their associated symptoms), the biologic (which stores molecular-shifted data related to diseases including genes, proteins, metabolic pathways, genetic variants, non-coding RNAs and so on) and the pharmacologic (containing information of the drugs, their interactions, and their connections to diseases). The two main lines in which the present thesis has delved into are disease understanding and drug repurposing. On the one hand and regarding disease understanding, a set of new arrangements of disease groups has been proposed via clustering techniques. These groups can be thought as novel nosological models that integrate molecular information, in contrast with traditional taxonomies mostly relying on solely phenotypic data. On the other hand and with respect to drug repurposing, two complementary methodologies to repurpose drugs have been put forward. Differences between data related to known successful repurposing cases and non-repurposing data have been identified, and analyses within the genes, symptoms and categories have been performed to uncover patterns. Threshold values in the association scores between diseases and different features have been pinpointed in order to evaluate the potential of new repurposing hypotheses. Moreover, a straightforward methodology consisting of five information paths and based on gene and symptom relationships has been developed to suggest repurposing candidates to treat COVID-19. A list of 13 drugs was obtained. This doctoral thesis has followed the structure of a compendium of publications: it comprises three articles published in scientific journals with high impact factor. The publications have contributed to accomplish the different research objectives and have been developed under the same thematic unit. RESUMEN Desarrollar un fármaco para una enfermedad específica es una tarea muy costosa en términos de dinero, tiempo y riesgos. Una alternativa a este largo proceso es el reposicionamiento de fármacos, que trata de identificar otros usos para medicamentos ya existentes. Es decir, se utilizan fármacos ya conocidos para tratar enfermedades diferentes de aquellas para las que fueron desarrollados. De esta forma, se pueden saltar algunas de las fases del desarrollo de un fármaco, acortando los tiempos y reduciendo la inversión. Aunque al principio este proceso solía producirse por casualidad, hoy en día se puede dirigir el reposicionamiento de fármacos. Algunas de las estrategias más prometedoras derivan de metodologías basadas en datos. En este contexto, uno de los paradigmas emergentes para estructurar las enormes cantidades de datos biomédicos surge con la llamada “medicina de redes”. Este campo abandona el estudio individual de cada enfermedad, integrando datos heterogéneos y a gran escala en forma de grafos para lograr una mejor comprensión de cómo funcionan y se conectan las enfermedades. En concreto, una red de enfermedades es un grafo complejo en el que los vértices son las distintas enfermedades y las aristas representan las relaciones entre ellas. La primera red se basó en los genes causantes de las enfermedades, pero se han desarrollado otras redes en torno a diferentes factores como rutas metabólicas, fármacos o síntomas, entre otros. Siguiendo las ideas de las redes de enfermedades, se encuentra el proyecto DISNET, cuyo objetivo final es el reposicionamiento de fármacos. La presente tesis doctoral se ha desarrollado en el marco de este proyecto, persiguiendo el objetivo general de obtener e integrar conocimiento biomédico de fuentes públicas para crear redes de enfermedades que permitan un mejor entendimiento de las mismas y potenciar el reposicionamiento de fármacos. En esta tesis y en el proyecto DISNET se ha construido una base de conocimiento biomédico heterogéneo a gran escala y multicapa en torno al concepto de enfermedad. La información se ha obtenido de fuentes públicas, aunando datos tanto estructurados como no estructurados. Esta información se ha integrado y organizado en tres niveles: el fenotípico (con información relativa a las enfermedades y sus síntomas), el biológico (que almacena datos de las enfermedades de tipo molecular, incluyendo genes, proteínas, rutas metabólicas, variantes genéticas, etc.) y el farmacológico (que contiene información de los fármacos, sus interacciones y sus conexiones con las enfermedades). Las dos líneas principales en las que se ha profundizado en la presente tesis son el entendimiento de las enfermedades y el reposicionamiento de fármacos. Por una parte, y en relación al entendimiento de las enfermedades, se ha propuesto un conjunto de nuevos grupos de enfermedades mediante técnicas de clustering. Estos grupos pueden concebirse como nuevos modelos nosológicos que integran información de tipo molecular, a diferencia de las taxonomías tradicionales, que se basan principalmente en datos fenotípicos. Por otra parte, y con respecto al reposicionamiento de fármacos, se han propuesto dos metodologías complementarias para sugerir hipótesis de reposicionamiento. Se han identificado diferencias entre los datos relacionados con casos conocidos y exitosos de reposicionamiento y los datos no relacionados con reposicionamiento, y se han realizado análisis a nivel de los genes, síntomas y categorías para descubrir patrones. Se han identificado umbrales en los valores de asociación entre enfermedades y diferentes características con el fin de evaluar el potencial de nuevas hipótesis de reposicionamiento. Además, se ha desarrollado una metodología directa que consta de cinco vías de información y que se basa en las relaciones entre genes y síntomas para sugerir candidatos de reposicionamiento para tratar la COVID-19, obteniendo una lista de 13 fármacos. Esta tesis doctoral ha seguido la estructura de un compendio de publicaciones: consta de tres artículos publicados en revistas científicas con alto factor de impacto. Las publicaciones han contribuido a alcanzar los diferentes objetivos de la investigación y se han desarrollado bajo una misma unidad temática.

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    https://doi.org/10.20868/upm.t...
    Thesis . 2023 . Peer-reviewed
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      https://doi.org/10.20868/upm.t...
      Thesis . 2023 . Peer-reviewed
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    Authors: Benjamin Dupuis; Akiko Kato; Nicolas Joly; Claire Saraux; +3 Authors

    International audience; The COVID-19 pandemic and its lock-down measures have resulted in periods of reduced human activity, known as anthropause. While this period was expected to be favorable for the marine ecosystem, due to a probable reduction of pollution, shipping traffic, industrial activity and fishing pressure, negative counterparts such as reduced fisheries surveillance could counterbalance these positive effects. Simultaneously, on-land pressure due to human disturbance and tourism should have drastically decreased, potentially benefiting land-breeding marine animals such as seabirds. We analyzed 11 breeding seasons of data on several biological parameters of little penguins from a popular tourist attraction at Phillip Island, Australia. We investigated the impact of anthropogenic activities on penguin behavior during the breeding season measured by (1) distribution at sea, (2) colony attendance, (3) isotopic niche (4) chick meal mass, and (5) offspring investment against shipping traffic and number of tourists. The 2020 lock-downs resulted in a near absence of tourists visiting the Penguin Parade®, which was otherwise visited by 800,000+ visitors on average per breeding season. However, our long-term analysis showed no effect of the presence of visitors on little penguins' activities. Surprisingly, the anthropause did not trigger any changes in maritime traffic intensity and distribution in the region. We found inter- and intra-annual variations for most parameters, we detected a negative effect of marine traffic on the foraging efficiency. Our results suggest that environmental variations have a greater influence on the breeding behavior of little penguins compared to short-term anthropause events. Our long-term dataset was key to test whether changes in anthropogenic activities affected the wildlife during the COVID-19 pandemic.

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    ZENODO; Biological Conservation
    Article . 2023 . Peer-reviewed
    License: Elsevier TDM
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    Authors: Alessandro De Gaetano; Paolo Bajardi; Nicolò Gozzi; Nicola Perra; +2 Authors

    Background During the initial phases of the vaccination campaign worldwide, nonpharmaceutical interventions (NPIs) remained pivotal in the fight against the COVID-19 pandemic. In this context, it is important to understand how the arrival of vaccines affected the adoption of NPIs. Indeed, some individuals might have seen the start of mass vaccination campaigns as the end of the emergency and, as a result, relaxed their COVID-safe behaviors, facilitating the spread of the virus in a delicate epidemic phase such as the initial rollout.Objective The aim of this study was to collect information about the possible relaxation of protective behaviors following key events of the vaccination campaign in four countries and to analyze possible associations of these behavioral tendencies with the sociodemographic characteristics of participants. Methods We developed an online survey named “COVID-19 Prevention and Behavior Survey” that was conducted between November 26 and December 22, 2021. Participants were recruited using targeted ads on Facebook in four different countries: Brazil, Italy, South Africa, and the United Kingdom. We measured the onset of relaxation of protective measures in response to key events of the vaccination campaign, namely personal vaccination and vaccination of the most vulnerable population. Through calculation of odds ratios (ORs) and regression analysis, we assessed the strength of association between compliance with NPIs and sociodemographic characteristics of participants.Results We received 2263 questionnaires from the four countries. Participants reported the most significant changes in social activities such as going to a restaurant or the cinema and visiting relatives and friends. This is in good agreement with validated psychological models of health-related behavioral change such as the Health Belief Model, according to which activities with higher costs and perceived barriers (eg, social activities) are more prone to early relaxation. Multivariate analysis using a generalized linear model showed that the two main determinants of the drop of social NPIs were (1) having previously tested positive for COVID-19 (after the second vaccine dose: OR 2.46, 95% CI 1.73-3.49) and (2) living with people at risk (after the second vaccine dose: OR 1.57, 95% CI 1.22-2.03).Conclusions This work shows that particular caution has to be taken during vaccination campaigns. Indeed, people might relax their safe behaviors regardless of the dynamics of the epidemic. For this reason, it is crucial to maintain high compliance with NPIs to avoid hindering the beneficial effects of the vaccine. International audience

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    Journal of Medical Internet Research
    Article . 2023 . Peer-reviewed
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      Journal of Medical Internet Research
      Article . 2023 . Peer-reviewed
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    Authors: Victor Chardès; Andrea Mazzolini; Thierry Mora; Aleksandra M. Walczak;

    Antigenic variation is the main immune escape mechanism for RNA viruses like influenza or SARS-CoV-2. While high mutation rates promote antigenic escape, they also induce large mutational loads and reduced fitness. It remains unclear how this cost–benefit trade-off selects the mutation rate of viruses. Using a traveling wave model for the coevolution of viruses and host immune systems in a finite population, we investigate how immunity affects the evolution of the mutation rate and other nonantigenic traits, such as virulence. We first show that the nature of the wave depends on how cross-reactive immune systems are, reconciling previous approaches. The immune-virus system behaves like a Fisher wave at low cross-reactivities, and like a fitness wave at high cross-reactivities. These regimes predict different outcomes for the evolution of nonantigenic traits. At low cross-reactivities, the evolutionarily stable strategy is to maximize the speed of the wave, implying a higher mutation rate and increased virulence. At large cross-reactivities, where our estimates place H3N2 influenza, the stable strategy is to increase the basic reproductive number, keeping the mutation rate to a minimum and virulence low. International audience

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    Proceedings of the National Academy of Sciences
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    arXiv.org e-Print Archive
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    https://doi.org/10.48550/arxiv...
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      Proceedings of the National Academy of Sciences
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    Authors: Rodrigo Lázaro‐Gorines; Patricia Pérez; Ignacio Heras‐Murillo; Irene Adán‐Barrientos; +29 Authors

    SARS-CoV-2 B.1.351 and B.1.167.2 viruses used in this study were obtained through the European Virus Archive Global (EVA-GLOBAL) project that has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 653316. SARS-CoV-2 B.1 (MAD6 isolate) was kindly provided by José M. Honrubia and Luis Enjuanes (CNB-CSIC, Madrid, Spain). The authors thank Centro de Investigación en Sanidad Animal (CISA)-Instituto Nacional de Investigaciones Agrarias (INIA-CSIC) (Valdeolmos, Madrid, Spain) for the BSL-3 facilities. Research in LA-V laboratory was funded by the BBVA Foundation (Ayudas Fundación BBVA a Equipos de Investigación Científica SARS-CoV-2 y COVID-19); the MCIN/AEI/10.13039/501100011033 (PID2020-117323RB-I00 and PDC2021-121711-I00), partially supported by the European Regional Development Fund (ERDF); the Carlos III Health Institute (ISCIII) (DTS20/00089), partially supported by the ERDF, the Spanish Association Against Cancer (AECC 19084); the CRIS Cancer Foundation (FCRIS-IFI-2018 and FCRIS-2021-0090), the Fundación Caixa-Health Research (HR21-00761 project IL7R_LungCan), and the Comunidad de Madrid (P2022/BMD-7225 NEXT_GEN_CART_MAD-CM). Work in the DS laboratory was funded by the CNIC; the European Union's Horizon 2020 research and innovation program under grant agreement ERC-2016-Consolidator Grant 725091; MCIN/AEI/10.13039/501100011033 (PID2019-108157RB); Comunidad de Madrid (B2017/BMD-3733 Immunothercan-CM); Atresmedia (Constantes y Vitales prize); Fondo Solidario Juntos (Banco Santander); and “La Caixa” Foundation (LCF/PR/HR20/00075). The CNIC was supported by the ISCIII, the MCIN and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (CEX2020-001041-S funded by MCIN/AEI/10.13039/501100011033). Research in RD laboratory was supported by the ISCIII (PI2100989) and CIBERINFEC; the European Commission Horizon 2020 Framework Programme (grant numbers 731868 project VIRUSCAN FETPROACT-2016, and 101046084 project EPIC-CROWN-2); and the Fundación Caixa-Health Research (grant number HR18-00469 project StopEbola). Research in CNB-CSIC laboratory was funded by Fondo Supera COVID-19 (Crue Universidades-Banco Santander) grant, CIBERINFEC, and Spanish Research Council (CSIC) grant 202120E079 (to J.G.-A.), CSIC grant 2020E84 (to M.E.), MCIN/AEI/10.13039/501100011033 (PID2020-114481RB-I00 to J.G-A. and M.E.), and by the European Commission-NextGenerationEU, through CSIC's Global Health Platform (PTI Salud Global) to J.G.-A. and M.E. Work in the CIB-CSIC laboratory was supported by MCIN/AEI/10.13039/501100011033 (PID2019-104544GB-I00 and 2023AEP105 to CA, and PID2020-113225GB-I00 to F.J.B.). Cryo-EM data were collected at the Maryland Center for Advanced Molecular Analyses which was supported by MPOWER (The University of Maryland Strategic Partnership). I.H.-M. receives the support of a fellowship from la Caixa Foundation (ID 100010434, fellowship code: LCF/BQ/IN17/11620074) and from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 71367. L.R.-P. was supported by a predoctoral fellowship from the Immunology Chair, Universidad Francisco de Vitoria/Merck. Administration of neutralizing antibodies (nAbs) has proved to be effective by providing immediate protection against SARS-CoV-2. However, dual strategies combining virus neutralization and immune response stimulation to enhance specific cytotoxic T cell responses, such as dendritic cell (DC) cross-priming, represent a promising field but have not yet been explored. Here, a broadly nAb, TNT, are first generated by grafting an anti-RBD biparatopic tandem nanobody onto a trimerbody scaffold. Cryo-EM data show that the TNT structure allows simultaneous binding to all six RBD epitopes, demonstrating a high-avidity neutralizing interaction. Then, by C-terminal fusion of an anti-DNGR-1 scFv to TNT, the bispecific trimerbody TNTDNGR-1 is generated to target neutralized virions to type 1 conventional DCs (cDC1s) and promote T cell cross-priming. Therapeutic administration of TNTDNGR-1, but not TNT, protects K18-hACE2 mice from a lethal SARS-CoV-2 infection, boosting virus-specific humoral responses and CD8+ T cell responses. These results further strengthen the central role of interactions with immune cells in the virus-neutralizing antibody activity and demonstrate the therapeutic potential of the Fc-free strategy that can be used advantageously to provide both immediate and long-term protection against SARS-CoV-2 and other viral infections. Peer reviewed 17 p.-4 fig.

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    DDFV
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