REPISALUD (Instituto de Salud Carlos III)
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Benchmark for Quantitative Global and Redox Proteomics Analysis by Combining Protein-Aggregation Capture and Data Independent Acquisition.
No full textOxidative damage plays a critical role in various diseases including cardiovascular and neurological disorders. Thiol redox reactions, acting as oxidative stress sensors, influence protein structure and function. Redox proteomics, based on the differential alkylation of cysteine sites followed by mass spectrometry, enables the comprehensive analysis of thiol redox status in cells and tissues. However, these approaches require extensive sample manipulation and are not compatible with data-independent acquisition techniques. Here, we introduce PACREDOX, an innovative strategy based on protein aggregation capture (PAC), and demonstrate its compatibility with library-free DIA. Compared with traditional methods such as FASILOX, PACREDOX reduces preparation time and costs while maintaining thiol and proteome coverage. To enable library-free DIA, we corrected spectral libraries in DIA-NN using experimental retention time data from methylthiolated-Cys peptides. PACREDOX with DIA was benchmarked against FASILOX in a myocardial infarction model, yielding the same biological insights, while enhancing peptide and protein coverage. Our results underscore the potential and efficiency of this methodology for studying oxidative damage. Overall, PACREDOX offers an automatable, high-throughput, and cost-effective strategy for redox proteomics.S
Vigilancia centinela de Infección Respiratoria Aguda en Atención Primaria (IRAs) y en Hospitales (IRAG) en España. Gripe, COVID-19 y otros virus respiratorios. Semana 37/2025 (del 08 de septiembre al 14 de septiembre de 2025).
No full textInforme elaborado por el Grupo de Vigilancia de la Gripe. Red Nacional de Vigilancia Epidemiológica Servicio de Vigilancia Epidemiológica. Centro Nacional de Epidemiología. En la elaboración de este Informe ha participado el Grupo de Vigilancia de Gripe y otros virus respiratorios, el Grupo de Monitorización de la Mortalidad Diaria del Área de Vigilancia de la Salud Pública del Centro Nacional de Epidemiología (Instituto de Salud Carlos III) y el Laboratorio de gripe y virus respiratorios del Centro Nacional de Microbiología (Instituto de Salud Carlos III). Este informe es el resultado del trabajo de todos los integrantes del Sistema de Vigilancia de infecciones respiratorias agudas en España (SiVIRA): https://cne.isciii.es/documents/d/cne/grupo-sivira-de-vigilancia-y-efectividad-vacunal-temporada-2024-25.A nivel sindrómico, la tasa de IRAs a nivel nacional es de 253 casos/100.000 habitantes (255,1 casos/100.000 habitantes en la semana previa), permaneciendo por debajo del umbral epidémico. La tasa de síndrome gripal se sitúa en 6,9 casos/100.000 habitantes (6,7 casos/100.000 habitantes en la semana previa), observándose una epidemia de intensidad baja entre las semanas 52/2024 y la 10/2025. La tasa de COVID-19 (síndrome) es de 18,7 casos/100.000 habitantes (18,6 casos/100.000 habitantes en la semana previa) y la de bronquitis y bronquiolitis en menores de 5 años de 70,9 casos/100.000 habitantes (51,1 casos/100.000 habitantes en la semana previa). El porcentaje de positividad es de 2,9% para gripe (2,2% en la semana previa), 29,7% para SARS-CoV-2 (24,5% en la semana previa) y 1% para VRS (0,3% en la semana previa). El proxy de gripe (IRAs x positividad a gripe) estima una incidencia de gripe de 7,3 casos/100.000 habitantes (5,6 casos/100.000 habitantes en la semana previa). El proxy de COVID-19 (IRAs x positividad a COVID-19) estima una incidencia de COVID-19 de 75,1 casos/100.000 habitantes (62,5 casos/100.000 habitantes en la semana previa). El proxy de VRS (IRAs x positividad a VRS) estima una incidencia de VRS de 2,5 casos/100.000 habitantes (0,8 casos/100.000 habitantes en la semana previa).N
The Two Faces of SHOC2: Skin Homeostasis Regulator and RAS-MAPK Pathway Enhancer.
No full textThe signaling pathway composed of RAS-RAF-MEK-ERK proteins regulates essential cellular processes such as cell differentiation, proliferation and migration. This pathway is crucial for embryonic development and tissue homeostasis and it is frequently dysregulated in cancer. The scaffold protein SHOC2 is a key modulator of ERK1/2 signals whose activity depends on its subcellular localization. Recently, SHOC2 has been proposed as a therapeutic target for the treatment of several cancers, either alone or in combination with MEK inhibitors. In this review we focus on the role of SHOC2 in the epithelial skin biology and its interaction with other partners to better understand the potential consequences of SHOC2 inhibition, particularly regarding skin toxicities. SHOC2 interacts with RAPTOR to limit mTORC1 activation, thereby promoting autophagy and limiting cell growth. Through its association with MRAS and PP1C, SHOC2 controls RAF1 dephosphorylation and modulates ERK output. Loss of SHOC2 disrupts E-cadherin turnover, impairing junctional dynamics and epithelial migration. In vivo, SHOC2 is essential for tissue development as complete knockout in mice results in embryonic lethality. We also discuss other important SHOC2 interactions in the epidermis including SCRIBBLE and ERBIN. SHOC2 acts as a signaling hub connecting RAS-MAPK pathways with epithelial polarity and differentiation. Its spatial regulation ensures proper tissue homeostasis, whereas mutation or mis-localization drives cancer and developmental disorders such as Noonan- like syndrome with loose anagen hair (NSLH) which has ectodermal manifestations. Finally, we review the context-dependent role of SHOC2 in cancer where it can be either upregulated or downregulated. Reduced SHOC2 activity in tumors addicted to ERK signaling may activate compensatory pathways highlighting the essential importance of SHOC2 in skin homeostasis and the potential cutaneous toxicities of SHOC2- targeted therapies.The group received support from the AESI-ISCIII (2024 COOP24CIII/00007 and PI20CIII/00029). C.O.R was supported by grant from Comunidad de Madrid (PEJ-2024- AI/SAL-GL-31925).S
Features of the First Case of Foodborne Botulism Caused by Dual-Toxin Subtype A1(B5) in Spain.
No full textThe neurotoxin BoNT/B2 is the predominant subtype in foodborne and infant botulism cases in Spain. This study characterizes a novel case of foodborne botulism in Spain caused by a dual-toxin A1(B5) strain. A 64-year-old male presented with acute, progressive flaccid paralysis including diplopia, dysphagia, and respiratory failure. Although botulism was not initially suspected, the patient recovered with supportive care and without antitoxin administration. Genomic characterization confirmed the presence of both /A1 and silent /B5 genes. The /A1 gene was associated with an X+ neurotoxin gene cluster, while the silent /B5 gene was in an + cluster. Phylogenetic analysis of both /A1 and /B5 sequences showed 100% amino acid identity, respectively, to previously reported A1(B5) strains (e.g., CDC_69094, FE9504ACG). Multi-locus sequence typing (MLST) assigned the ST10, a genotype previously undetected in Spanish botulism cases, yet found in other European countries. This case highlights the importance of considering botulism in differential diagnosis due to its varied presentation and the significance of timely laboratory confirmation for effective management. The identification of this dual-toxin BoNT/A1(B5) X+/+ ST10 strain expands our understanding of epidemiology and genetic diversity in Spain.This study was partially funded by the Ministerio de Ciencia, Innovación y Universidades and the Agencia Estatal de Investigación (https://www.aei.gob.es/, accessed on 27 July 2025) grant PID2021127477OBI00/MPY-302/22 via the Plan Estatal de Investigación Científica, Técnica y de Innovación. N.G. is contracted via grant MPY-302/22-M1. M.V. is contracted via grant PEJ CAM 2021-/TL/BMD-21100 from the Programa Operativo Empleo Juvenil e Iniciativa Empleo Juvenil (YEI).S
Overexpression of Wild-Type TMEM43 Improves Cardiac Function in Arrhythmogenic Right Ventricular Cardiomyopathy Type 5.
No full textArrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5) is the most aggressive type of ARVC, caused by a fully penetrant missense mutation (p.S358L) in TMEM43 (transmembrane protein 43). Pathologically, the disease is characterized by dilation of the cardiac chambers and fibrofatty replacement of the myocardium, which results in heart failure and sudden cardiac death. Current therapeutic options are limited, and no specific therapies targeting the primary cause of the disease have been proposed. We investigated whether overexpression of wild-type (WT) TMEM43 could overcome the detrimental effects of the mutant form. We used transgenic mouse models overexpressing either WT or mutant (S358L) TMEM43 to generate a double transgenic mouse line overexpressing both forms of the protein. In addition, we explored if systemic delivery of a codon-optimized self-complementary adeno-associated virus bearing WT-TMEM43 could improve disease progression assessed by ECG and echocardiography. Double transgenic mice overexpressing both WT and mutant TMEM43 forms showed delayed ARVC5 onset, improved cardiac contraction, and reduced ECG abnormalities compared with mice expressing S358L-TMEM43. In addition, cardiomyocyte death and myocardial fibrosis were reduced, with an overall increase in survival. Finally, we demonstrated that a single systemic administration of an adeno-associated virus carrying codon-optimized WT-TMEM43 prevents ventricular dysfunction and ECG abnormalities induced by S358L-TMEM43. Overexpression of WT-TMEM43 improves the pathological phenotype in a mouse model of ARVC5. Adeno-associated virus-mediated delivery of WT-TMEM43 offers a promising and specific therapy for patients suffering from this highly lethal disease.This study was funded by the Pathfinder Cardiogenomics program of the European Innovation Council of the European Union (DCM-NEXT project; project number: 101115416) and grants PID2021-124629OB-I00, TED2021-129774BC22, and PLEC2022-009235 funded by the Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033), the European Union’s NextGenerationEU/PRTR (Plan de Recuperación, Transformación y Resiliencia de España), and Fondo Europeo de Desarrollo Regional (FEDER) to E. Lara-Pezzi.
The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MICIU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIU/AEI/10.13039/501100011033).S
Pharmacogenomics and chronotherapy of drug-induced cardioprotection in acute myocardial infarction.
No full textAcute myocardial infarction remains a leading cause of morbidity and mortality worldwide. Pharmacogenetic and chronotherapeutic approaches are increasingly applied to optimize therapy in chronic cardiovascular diseases. While gene variants are known to influence long-term drug efficacy, their role in modulating drug-induced cardioprotection in acute conditions such as myocardial infarction is unclear. Similarly, the impact of circadian timing on cardioprotective responses remains insufficiently defined. To address these questions, we evaluated metoprolol as a model cardioprotective agent. Here we examine, in a non-pre-specified exploratory analysis of the METOCARD-CNIC trial (NCT01311700), the influence of ADRB1 Arg389Gly polymorphism and the time of AMI onset on metoprolol efficacy. We found that metoprolol reduced infarct size only in patients homozygous for the ADRB1 Arg389 allele, consistent with its genotype-dependent inhibition of neutrophil migration. In-silico docking and binding studies revealed unstable interactions of metoprolol with the Gly389 variant of ADRB1. Moreover, metoprolol was associated with reduced infarct size when AMI onset occurred between 6:00 and 12:00 h. Restricted cardioprotection to the light phase was confirmed in male mice and in neutrophil-specific Adrb1-knockout models. Collectively, these findings highlight the critical roles of genetic background and circadian timing in shaping the efficacy of acute cardioprotective therapies, supporting the rationale for personalized interventions in acute myocardial infarction.This study received funding from the Spanish Ministry of Science, Innovation and Universities (PID2022−140176OB-I00 to B.I.), the European Research Council (ERC) under the European Union Horizon 2020 Research and Innovation Programme (ERC-Consolidator Grant agreement No. 819775 to B.I.), and the Comunidad de Madrid through the Red Madrileña de Nanomedicina en Imagen Molecular (P2022/BMD-7403 RENIM-CM). E.O. is supported by funding from Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación MCIN/
AEI/10.13039/501100011033 and by “ERDF A way of making Europe” (PID2021-123167OB-I00), and CSIC Talent Attraction program (20222AT010). A.C-M. was supported by a fellowship from the Ministerio de Ciencia e Innovación (MCN) and ISCIII (FPU2017/01932). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MICIU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020- 001041-S funded by MICIU/AEI/10.13039/501100011033).S
CRISPR activation to repair electrocardiogram abnormalities caused by a FLNC truncating variant in mice.
No full textThis project was funded by the Pathfinder Cardiogenomics programme of the European Innovation Council of the European Union
(DCM-NEXT project; project number: 101115416) to E.L.-P. and P.G.-P. and grants PID2021-124629OB-I00, TED2021-129774B-C22,
and PLEC2022-009235 funded by the Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033), by the European
Union’s NextGenerationEU/PRTR (‘Plan de Recuperación, Transformación y Resiliencia de España’) and by FEDER to E.L.-P. and grants PID2022-136942OB-I00, CB16/11/00399 (CIBER CV) from MICIU/AEI/10.13039/501100011033, and La Caixa Research Health Foundation (HR23-00084) to J.L.d.l.P. The CNIC is supported by the
Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MICIU), and the Pro CNIC Foundation
and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIU/AEI/10.13039/501100011033). A.C. was supported
by NIH Grant DP2NS131566-01 and a Career Award for Medical Scientists from the Burroughs Wellcome Foundation.S
Discontinuous EBOV RNA synthesis events in patients with Ebola virus disease and their relationship to viral load and outcome of infection.
No full textEbola virus (EBOV) is a negative strand RNA virus that causes Ebola virus disease (EVD) with a high case fatality rate. During the acute phase of infection, a subsequent fatal outcome is characterized by an increased upregulation of interferon and inflammatory pathways compared to survivors. Replication of genomes from negative strand RNA viruses (and RNA viruses in general) can result in the generation of defective genomes that may interfere with viral replication and stimulation of the innate immune response. We characterized the presence of defective genomes in blood samples from humans who were positive for EBOV and processed by the European Mobile Laboratory during the 2013-2016 West African EVD outbreak. A bioinformatics tool, DI-tector, was used to identify sequence motifs associated with the four different types of defective genomes. The analysis indicated that sequence features indicative of defective genomes were present in blood samples in patients during the acute phase of infection. The most common type of defective genome identified was insertion followed by deletion, 5' copy back and then 3' copy back. In general, the abundance of defective genomes correlated with viral load, but particularly with patient outcome. We postulate that the presence of defective genomes correlates with an upregulation in the interferon response and resultant inflammation and may, therefore, be an important contributory factor in patients with severe EVD.IMPORTANCEEBOV and filoviruses in general are high consequence infectious diseases whose outbreaks can severely impact the lives of those affected. In this study, we show that during EBOV replication in humans, defective genomes can be produced, which complements previous studies in nonhuman primate models of disease and in cell culture. The abundance of these defective genomes correlates with disease outcome in acutely ill patients. In people who go on to die from EVD, they appear to have higher levels of defective genomes than in people who go on to survive infection. This may, in turn, cause a greater upregulation of interferon and inflammation, which are some of the biggest factors in determining disease severity and adverse patient outcome. Therefore, we caution the potential use of defective genomes as a therapy for EVD, as has been proposed for other negative strand RNA viruses.The work was funded by the Food and Drug Administration (USA), Ebola Virus Disease—correlates of protection, determinants of outcome, and clinical management, number HHSF223201510104C. This work was supported by the Defence Advanced Research Projects Agency award through the INTERfering and Co-Evolving Prevention and Therapy (INTERCEPT) program. P.D. acknowledges funding from the BBSRC (BB/P013740/1). This work was supported by Liverpool Shared Research Facilities (LIV-SRF) Voucher Scheme R6 to X.D.S
Presentado en el ISCIII un informe de la Alianza de Institutos de Investigación Sanitaria sobre el próximo Programa Marco de investigación en la UE
No full textPuede consultar el informe completo en: https://hdl.handle.net/20.500.12105/26705El Instituto de Salud Carlos III (ISCIII) ha presentado y publicado un informe estratégico que recoge diversas claves y recomendaciones para reforzar la investigación sanitaria en el próximo Programa Marco de Investigación e Innovación de la Unión Europea (FP10). Bajo el título 'Visión de la Alianza de los Institutos de Investigación Sanitaria ante el próximo Programa Marco de la UE: evolución y proyecciones', el documento reúne las aportaciones de los Institutos de Investigación Sanitaria (IIS) acreditados por el ISCIII, con una visión compartida sobre el desarrollo y evolución de la ciencia biomédica europea en los próximos años. Los resultados, analizados a principios de 2025, se han plasmado en un documento de consenso estructurado en cuatro grandes bloques: una introducción al actual Programa Horizonte Europa; la participación del Sistema Nacional de Salud (SNS) en convocatorias europeas en salud; el contexto político de cara al nuevo marco financiero plurianual (2028-2034); y una síntesis de los retos y propuestas planteadas por los IIS
Araceli López-Guillén, directora de la Escuela Nacional de Medicina del Trabajo (ENMT) del ISCIII
No full textLa doctora Araceli López-Guillén García ha sido nombrada directora de la Escuela Nacional de Medicina del Trabajo (ENMT), centro del Instituto de Salud Carlos III (ISCIII) especializado en salud laboral y Medicina y Enfermería del Trabajo. López-Guillén proviene del Instituto Nacional de la Seguridad Social (INSS), donde desde 2007 y hasta este año ha ejercido como Inspectora Médico. Sustituye en el cargo a María José Terradillos, que desempeñó el cargo entre 2019 y 2024. La Escuela Nacional de Medicina del Trabajo del ISCIII, un centro con más de 70 años de historia, es un centro especializado de referencia para la formación, investigación, asesoramiento y divulgación en Medicina y Enfermería del Trabajo