Identification of new kinase substrates involved in the DNA Damage Response pathway and its implication in carcinogenesis

One of the most relevant altered pathways in cancer is the DNA Damage Response (DDR), a well-coordinated network of signalling cascades that cells have developed during evolution in order to maintain genomic integrity. These pathways are activated when genomic material is damaged with the aim of transmit the damage signals to effector proteins, and induce cellular responses including cell cycle arrest, activation of DNA repair pathways, and cell death; thus preventing tumorigenesis. CHK2 and DYRK2 are key downstream kinases of the DDR, involved mainly in the regulation of cell cycle and DNA repair. The identification of new substrates for these kinases will delve into knowledge of their functions within the DDR, which leads to tumor development and progression when deregulated. In the present work we demonstrate how CHK2 presents the ability to phosphorylate the E3 Ubiquitin ligase SIAH2, affecting its activity on certain substrates. Additionally, SIAH2 regulates CHK2 basal turnover through ubiquitination and proteasomal degradation. In response to DNA damage, the interaction between both proteins is disrupted, which favors CHK2 stabilization. This new CHK2 regulation mechanism has an influence on cell cycle progression and on the ability of hypoxia to alter DDR pathway in cancer cells, since resistance to apoptosis induced by genotoxic agents in cells subjected to hypoxia could be partly explained by the mutual regulation between CHK2 and SIAH2. We also describe the capacity of DYRK2 to modulate the turnover of the checkpoint phosphatase CDC25A through an ubiquitin/proteasome and DYRK2 kinase activity dependent process. DYRK2 directly phosphorylates CDC25A in vitro, although DSG or KEN motifs are not involved in the CDC25A degradation by the proteasome mediated by DYRK2. Different stimuli, such as DNA damage or serum starvation, result in an inverse correlation of DYRK2 and CDC25A expression, which is also observed at endogenous levels in human lung cancer cell lines and human lung cancer tissues. Taken together, our findings report new substrates (SIAH2 and CDC25A) for two relevant kinases involved in the DDR pathway (CHK2 and DYRK2), helping to elucidate the molecular mechanisms through which this pathway operates. These data certainly help to improve the understanding of the regulation processes of these relevant kinases and will extend the knowledge about the molecular biology of cancer as well as provide new therapeutic opportunities for cancer treatment

The use of social networking sites as an innovative tool at university: Facebook as a collaborative learning tool in Immunology

En la actualidad los docentes universitarios tienen el reto de enseñar a la conocida como “generación Y”, alumnos nacidos entre los años 1980 y 2000, los cuales no han conocido el mundo sin internet o teléfono móvil. Esto por supuesto implica que el acercamiento al conocimiento, y por tanto los modos de aprendizaje, son completamente diferentes a los de generaciones anteriores. Esto unido a la implementación de las nuevas titulaciones acordes con el proceso de convergencia europea y el sistema de créditos ECTS, y siguiendo los desafíos de la enseñanza contemplados en el Espacio Europeo de Educación Superior (EEES), hace inevitable la implementación de nuevas formas de comunicación entre los alumnos y los profesores en el ámbito Universitario. Aunque en este aspecto la mayoría de las Universidades cuentan ya con diferentes herramientas de e-Learning, su uso e implementación en algunas ocasiones puede resultar insuficiente. En este escenario, por el contrario, son muchas las posibilidades que ofrecen las redes sociales y su extenso uso entre el alumnado, quien accede generalmente con mucha frecuencia a sus perfiles y grupos, proporcionando una comunicación rápida, fácil y flexible. En el presente proyecto de innovación docente hemos combinado el uso de un grupo de Facebook con los recursos tradicionales en la docencia relativa a la asignatura de Inmunología, usando esta red social como herramienta de apoyo para compartir materiales e información. Todo ello buscando un nuevo ambiente de comunicación más directo entre alumnos y profesorado, sin por supuesto tener que sustituir las vías de comunicación formales como el correo electrónico y Moodle. Esto nos ha permitido evaluar su uso, participación y satisfacción entre el alumnado que ha participado en el proyecto.Nowadays, University teachers face the challenge of teaching the so-called “Y generation”, students born between 1980 and 2000, who haven't experienced their lives without the Internet or the mobile phone. This has a direct consequence on their approach to knowledge and, therefore, to the learning styles, which are completely different to those of former generations. This fact, together with the implementation of new degrees more in line with the European convergence process and the ECTS credit system, and following the educative challenges included in the new European Space of Higher Education (EEES), makes it necessary to implement new forms of communication between pupils and teachers in the university context. Although most universities already make use of different e-Learning tools, their use and implementation can sometimes be insufficient. In this scenery, on the contrary, the social networking sites and their extended use by students, who check their profiles and groups very often, offer a lot of possibilities, as they allow a fast, easy and flexible communication. In the present project of teaching innovation, we have combined the use of a Facebook group with the traditional resources used in Immunology, so that this social networking site becomes a support tool to share materials and information. In the same sense, we look for a new atmosphere where a more direct communication between students and teachers is possible, without avoiding the more formal forms of communication such as the email or Moodle. This has allowed us to evaluate its use, participation and satisfaction, both between the students and the teachers taking part in the project

Hydrogen technologies

1 figura.[EN] The interest in hydrogen technologies has grown in recent years, mainly because an economy based on hydrogen can help to solve important challenges related to the global economy of the future: energy security and climate change. Taking advantage of this momentum, more and more countries are implementing a growing number of policies related to hydrogen. Indeed, the European Hydrogen Strategy establishes hydrogen as essential drivers for the total decarbonization of the current energy system in order to achieve the EU’s commitment related to carbon neutrality by 2050. However, the successful development of the hydrogen technologies requires the collaboration of the public and private sectors to accelerate its deployment and make more competitive its implementation at large-scale. The research groups that take part of the line of work dedicated to hydrogen technologies, within the CSIC Interdisciplinary Thematic Platform PTI Mobility 2030, work in this regard, developing their investigations in several important areas related to the hydrogen technologies such as hydrogen generation, storage, distribution and uses.[ES] El interés por las tecnologías del hidrógeno ha crecido en los últimos años, principalmente porque una economía basada en el hidrógeno puede dar respuesta a los grandes desafíos de la economía global del futuro: seguridad energética y cambio climático. Aprovechando este impulso, cada vez son más los países que están implementando un número creciente de políticas en favor del hidrógeno. Prueba de ello es la Estrategia Europea del Hidrógeno que establece al hidrógeno como un elemento esencial en la descarbonización total del actual sistema energético para alcanzar el compromiso de la UE con la neutralidad de carbono en 2050. No obstante, el desarrollo exitoso de las tecnologías del hidrógeno requiere que todos los actores, incluidos los sectores público y privado, aumenten sus esfuerzos para acelerar su despliegue y hacer que su implantación a gran escala resulte competitiva. Los grupos de investigación que forman parte del área de trabajo de tecnologías del hidrógeno, dentro de la Plataforma Temática Interdisciplinar PTI Mobility 2030 del CSIC, trabajan en este sentido, desarrollando su labor en áreas tan diversas como la generación, el almacenamiento, la distribución y los usos del hidrógeno.Peer reviewe

Informe elaborado desde la Plataforma Temática Interdisciplinar Salud Global / Global Health del CSIC

Victoria Moreno, Vicepresidencia Adjunta de Áreas Científico-Técnicas, coordinadora del informe.Newsletter PTI Salud Global / Global Health Cov19. Píldoras: https://cutt.ly/sgmXa2vLa pandemia COVID-19, causada por un nuevo coronavirus, el SARS-CoV-2, se ha convertido en pocos meses en una amenaza para la humanidad, desencadenando la peor crisis sanitaria de este siglo. Más de veinte millones de personas han sido ya infectadas por el virus y más de 700.000 han muerto en todo el mundo como resultado de esta infección. En el ámbito de la investigación, esta pandemia ha obligado a un esfuerzo extraordinario de colaboración nacional e internacional. El Consejo Superior de Investigaciones Científicas (CSIC) ha canalizado este esfuerzo creando una Plataforma Temática Interdisciplinar (PTI) denominada Salud Global/Global Health, con el objetivo de encontrar soluciones a corto, medio y largo plazo, para reducir el impacto de esta pandemia en nuestra sociedad. La plataforma ha movilizado y coordina a más de 300 grupos de investigación de más de 90 centros del CSIC, en seis grupos de trabajo temáticos, que tratan de cubrir con un enfoque interdisciplinar todos los aspectos de la pandemia: Prevención, Enfermedad, Contención y Diagnóstico, Tratamiento y Vacunas, Impacto social, y Comunicación. Este informe, elaborado desde esta plataforma, presenta por una parte el conocimiento actual a nivel global que tenemos en estas temáticas sobre la pandemia, basado en las publicaciones e informes científicos y técnicos publicados hasta el momento, y en paralelo los proyectos de investigación en desarrollo por los grupos de investigación del CSIC. Gracias al apoyo a través de convocatorias y donaciones directas de entidades públicas y privadas, y también de particulares, a quienes desde aquí queremos agradecer la confianza depositada, el CSIC ha puesto en marcha más de 80 proyectos y acciones de investigación, que abarcan desde el estudio del genoma del virus, la genética de los pacientes, su respuesta inmune, la gravedad de la infección, hasta el desarrollo de antivirales, vacunas, sistemas de diagnóstico, de monitorización, de protección, de desinfección, etc. Nuestro conocimiento sobre la pandemia y su evolución está cambiando rápidamente, y por ello una parte importante de los contenidos de este informe deberán actualizarse, esperamos que tanto la investigación en el CSIC como a escala nacional y global logren que podamos describir en el futuro como estos avances han logrado que la pandemia quede controlada.Peer reviewe

Informe elaborado desde la Plataforma Temática Interdisciplinar Salud Global/Global Health del CSIC

Informe elaborado desde la Plataforma Temática Interdisciplinar Salud Global/Global Health del CSIC.-- Coordinadores: M.Victoria Moreno-Arribas y Jesús Marco de Lucas.La pandemia COVID-19, causada por el coronavirus SARS-CoV-2, se ha convertido durante este último año en una de las peores amenazas para la historia de la humanidad. Su impacto en todo el planeta ha planteado un desafío sin precedentes para la sociedad. El CSIC tomó la iniciativa en marzo de 2020 con el lanzamiento de la Plataforma Salud Global, orientada a buscar soluciones desde la ciencia ante la pandemia, y ha canalizado este esfuerzo contando desde el primer momento con el trabajo coordinado e ininterrumpido de nuestros investigadores y con el apoyo de la sociedad en su conjunto. La plataforma ha movilizado y coordina a más de 300 grupos de investigación de más de 90 centros del CSIC, en seis temáticas de trabajo, que tratan de cubrir con un enfoque interdisciplinar todos los aspectos de la pandemia: Prevención, Enfermedad, Contención y Diagnóstico, Tratamiento y Vacunas, Impacto social, y Comunicación. Gracias al apoyo recibido a través de nuestro ministerio, convocatorias y donaciones directas de entidades públicas y privadas, y de particulares, a quienes queremos agradecer la confianza depositada, el CSIC desarrolla más de 100 proyectos de investigación, que abarcan desde el desarrollo de antivirales, anticuerpos y antiinflamatorios, la monitorización de la transmisión, el estudio del genoma del virus y el impacto de las mutaciones, las características del microbioma intestinal y la genética de los pacientes, su respuesta inmune a la infección y a la vacunación, hasta la fabricación y puesta en el mercado de mascarillas, sistemas de diagnóstico y contención del virus, así como estudios realizados sobre la percepción social de las medidas, especialmente sobre el impacto en residencias de mayores. Los tres proyectos de desarrollo de vacunas que lidera el CSIC arrancaron también al comienzo de la pandemia, como una apuesta estratégica para demostrar la capacidad de desarrollar de principio a fin una vacuna propia en España. Los proyectos de investigación han dado lugar por el momento a más de 800 resultados de investigación, más de 150 artículos en revistas de alto impacto, más de 180 resultados de transferencia protegidos, un máster propio, así como numerosos informes y guías científicas, y múltiples acciones de comunicación, divulgación y educación. Este documento tiene como objetivo difundir desde un enfoque global las principales investigaciones a nivel mundial, y las respuestas y soluciones basadas en proyectos en los dominios en que los grupos de investigación del CSIC son expertos. En estos intensos meses de trabajo, la plataforma Salud Global se ha convertido en una estructura estable de cooperación científica dimensionada a las expectativas cambiantes que ha demandado esta brutal pandemia. Su consolidación, reforzando su estructura y mecanismos de coordinación, en particular el enlace con el sector clínico, nos prepara para hacer frente a los nuevos desafíos y oportunidades, y el desarrollo de iniciativas con empresas en nuestro país, tan necesario para configurar una respuesta ante esta y futuras pandemias.1. ACTUACIONES EN PREVENCIÓN. 1.1. Modelos de predicción. 1.2. Origen y ecología del virus SARS-CoV-2, emergencia de nuevos virus. 1.3. Apps de seguimiento: Llegar a tiempo para frenar nuevos brotes. 1.4. Movilidad: incidencia y propagación de la enfermedad. 1.5. Proyectos en la temática PREVENCIÓN que se desarrollan en el CSIC.-- 2. ACTUACIONES SOBRE LA ENFERMEDAD Y LA CONEXIÓN CON LA CLÍNICA. 2.1. Entendiendo la enfermedad: dónde, cómo, cuándo y quién transmite el SARS-CoV-2. Presintomáticos, sintomáticos, y asintomáticos. Transmisión en personas asintomáticas. 2.2. Epidemiología genómica para rastrear la transmisión. 2.3. Genética del virus, evolución de la pandemia y respuesta ante la enfermedad. 2.4. Población infantil. COVID-19 y los niños. 2.5. Gravedad de la enfermedad. Factores de riesgo. Nuevos síntomas y secuelas. 2.6. Genética humana y otros factores en fase de estudio y su conexión con la gravedad de la enfermedad. 2.7. Inmunidad y respuesta inflamatoria ante el SARS-CoV-2. 2.8. Proyectos en la temática ENFERMEDAD que se desarrollan en el CSIC.-- 3. ACTUACIONES EN CONTENCIÓN Y DIAGNÓSTICO. 3.1. Conociendo cómo se trasmite el virus y los protocolos de desinfección. 3.2. Protección específica de las mucosas frente a la entrada del SARS-CoV-2. 3.3. Proyectos en la temática TRANSMISIÓN Y CONTENCIÓN que se desarrollan en el CSIC. 3.4. El papel del diagnóstico frente a la pandemia. 3.5. Proyectos en la temática DIAGNÓSTICO que se desarrollan en el CSIC.-- 4. ACTUACIONES EN TRATAMIENTO Y VACUNAS. 4.1. Tratamiento: el esfuerzo desde la investigación para curar la Covid-19. 4.2. Vacunas. 4.3. Proyectos en la temática TRATAMIENTO que se desarrollan en el CSIC.-- 5. IMPACTO GLOBAL DE LA PANDEMIA. 5.1. Residencias de ancianos. 5.2. Covid-19 y efectos en la salud mental. 5.3. Habitabilidad 5.4. El trabajo después de la COVID-19. 5.5. Publicación científica urgente: los cambios en la comunicación científica. 5.6. Proyectos en la temática IMPACTO GLOBAL que se desarrollan en el CSIC.-- 6. TRANSFERENCIA EN TIEMPOS COVID-19.-- 7. DIVULGACIÓN Y COMUNICACIÓN. 7.1. ExpoCovid, Exposición itinerante: ¿Qué sabemos hoy del SARS-CoV-2?Peer reviewe

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Respiratory support in patients with severe COVID-19 in the International Severe Acute Respiratory and Emerging Infection (ISARIC) COVID-19 study: a prospective, multinational, observational study

Background: Up to 30% of hospitalised patients with COVID-19 require advanced respiratory support, including high-flow nasal cannulas (HFNC), non-invasive mechanical ventilation (NIV), or invasive mechanical ventilation (IMV). We aimed to describe the clinical characteristics, outcomes and risk factors for failing non-invasive respiratory support in patients treated with severe COVID-19 during the first two years of the pandemic in high-income countries (HICs) and low middle-income countries (LMICs). Methods: This is a multinational, multicentre, prospective cohort study embedded in the ISARIC-WHO COVID-19 Clinical Characterisation Protocol. Patients with laboratory-confirmed SARS-CoV-2 infection who required hospital admission were recruited prospectively. Patients treated with HFNC, NIV, or IMV within the first 24 h of hospital admission were included in this study. Descriptive statistics, random forest, and logistic regression analyses were used to describe clinical characteristics and compare clinical outcomes among patients treated with the different types of advanced respiratory support. Results: A total of 66,565 patients were included in this study. Overall, 82.6% of patients were treated in HIC, and 40.6% were admitted to the hospital during the first pandemic wave. During the first 24 h after hospital admission, patients in HICs were more frequently treated with HFNC (48.0%), followed by NIV (38.6%) and IMV (13.4%). In contrast, patients admitted in lower- and middle-income countries (LMICs) were less frequently treated with HFNC (16.1%) and the majority received IMV (59.1%). The failure rate of non-invasive respiratory support (i.e. HFNC or NIV) was 15.5%, of which 71.2% were from HIC and 28.8% from LMIC. The variables most strongly associated with non-invasive ventilation failure, defined as progression to IMV, were high leukocyte counts at hospital admission (OR [95%CI]; 5.86 [4.83–7.10]), treatment in an LMIC (OR [95%CI]; 2.04 [1.97–2.11]), and tachypnoea at hospital admission (OR [95%CI]; 1.16 [1.14–1.18]). Patients who failed HFNC/NIV had a higher 28-day fatality ratio (OR [95%CI]; 1.27 [1.25–1.30]). Conclusions: In the present international cohort, the most frequently used advanced respiratory support was the HFNC. However, IMV was used more often in LMIC. Higher leucocyte count, tachypnoea, and treatment in LMIC were risk factors for HFNC/NIV failure. HFNC/NIV failure was related to worse clinical outcomes, such as 28-day mortality. Trial registration This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable

Respiratory support in patients with severe COVID-19 in the International Severe Acute Respiratory and Emerging Infection (ISARIC) COVID-19 study: a prospective, multinational, observational study

Background: Up to 30% of hospitalised patients with COVID-19 require advanced respiratory support, including high-flow nasal cannulas (HFNC), non-invasive mechanical ventilation (NIV), or invasive mechanical ventilation (IMV). We aimed to describe the clinical characteristics, outcomes and risk factors for failing non-invasive respiratory support in patients treated with severe COVID-19 during the first two years of the pandemic in high-income countries (HICs) and low middle-income countries (LMICs). Methods: This is a multinational, multicentre, prospective cohort study embedded in the ISARIC-WHO COVID-19 Clinical Characterisation Protocol. Patients with laboratory-confirmed SARS-CoV-2 infection who required hospital admission were recruited prospectively. Patients treated with HFNC, NIV, or IMV within the first 24 h of hospital admission were included in this study. Descriptive statistics, random forest, and logistic regression analyses were used to describe clinical characteristics and compare clinical outcomes among patients treated with the different types of advanced respiratory support. Results: A total of 66,565 patients were included in this study. Overall, 82.6% of patients were treated in HIC, and 40.6% were admitted to the hospital during the first pandemic wave. During the first 24 h after hospital admission, patients in HICs were more frequently treated with HFNC (48.0%), followed by NIV (38.6%) and IMV (13.4%). In contrast, patients admitted in lower- and middle-income countries (LMICs) were less frequently treated with HFNC (16.1%) and the majority received IMV (59.1%). The failure rate of non-invasive respiratory support (i.e. HFNC or NIV) was 15.5%, of which 71.2% were from HIC and 28.8% from LMIC. The variables most strongly associated with non-invasive ventilation failure, defined as progression to IMV, were high leukocyte counts at hospital admission (OR [95%CI]; 5.86 [4.83-7.10]), treatment in an LMIC (OR [95%CI]; 2.04 [1.97-2.11]), and tachypnoea at hospital admission (OR [95%CI]; 1.16 [1.14-1.18]). Patients who failed HFNC/NIV had a higher 28-day fatality ratio (OR [95%CI]; 1.27 [1.25-1.30]). Conclusions: In the present international cohort, the most frequently used advanced respiratory support was the HFNC. However, IMV was used more often in LMIC. Higher leucocyte count, tachypnoea, and treatment in LMIC were risk factors for HFNC/NIV failure. HFNC/NIV failure was related to worse clinical outcomes, such as 28-day mortality. Trial registration This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable

Characteristics and outcomes of an international cohort of 600 000 hospitalized patients with COVID-19

Background: We describe demographic features, treatments and clinical outcomes in the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) COVID-19 cohort, one of the world's largest international, standardized data sets concerning hospitalized patients. Methods: The data set analysed includes COVID-19 patients hospitalized between January 2020 and January 2022 in 52 countries. We investigated how symptoms on admission, co-morbidities, risk factors and treatments varied by age, sex and other characteristics. We used Cox regression models to investigate associations between demographics, symptoms, co-morbidities and other factors with risk of death, admission to an intensive care unit (ICU) and invasive mechanical ventilation (IMV). Results: Data were available for 689 572 patients with laboratory-confirmed (91.1%) or clinically diagnosed (8.9%) SARS-CoV-2 infection from 52 countries. Age [adjusted hazard ratio per 10 years 1.49 (95% CI 1.48, 1.49)] and male sex [1.23 (1.21, 1.24)] were associated with a higher risk of death. Rates of admission to an ICU and use of IMV increased with age up to age 60 years then dropped. Symptoms, co-morbidities and treatments varied by age and had varied associations with clinical outcomes. The case-fatality ratio varied by country partly due to differences in the clinical characteristics of recruited patients and was on average 21.5%. Conclusions: Age was the strongest determinant of risk of death, with a ∼30-fold difference between the oldest and youngest groups; each of the co-morbidities included was associated with up to an almost 2-fold increase in risk. Smoking and obesity were also associated with a higher risk of death. The size of our international database and the standardized data collection method make this study a comprehensive international description of COVID-19 clinical features. Our findings may inform strategies that involve prioritization of patients hospitalized with COVID-19 who have a higher risk of death