Computational assessment of the impact of Cu(II) and Al(III) on β-amyloid fibrils : Binding sites, structural stability, and possible physiological implications

One of Alzheimer's disease major hallmarks is the aggregation of β-amyloid peptide, a process in which metal ions play an important role. In the present work, an integrative computational study has been performed to identify the metal-binding regions and determine the conformational impact of Cu(II) and Al(III) ion binding to the β-amyloid (Aβ) fibrillary structure. Through classical and Gaussian accelerated molecular dynamics, it has been observed that the metal-free fiber shows a hinge fan-like motion of the S-shaped structure, maintaining the general conformation. Upon metal coordination, distinctive patterns are observed depending on the metal. Cu(II) binds to the flexible N-terminal region and induces structural changes that could ultimately disrupt the fibrillary structure. In contrast, Al(III) binding takes place with the residues Glu22 and Asp23, and its binding reinforces the core stability of the system. These results give clues on the molecular impact of the interaction of metal ions with the aggregates and sustain their non-innocent roles in the evolution of the illness

Computational assessment of the impact of Cu(II) and Al(III) on β-amyloid42 fibrils: Binding sites, structural stability, and possible physiological implications

One of Alzheimer’s disease major hallmarks is the aggregation of β-amyloid peptide, a process in which metal ions play an important role. In the present work, an integrative computational study has been performed to identify the metal-binding regions and determine the conformational impact of Cu(II) and Al(III) ion binding to the β-amyloid (Aβ42) fibrillary structure. Through classical and Gaussian accelerated molecular dynamics, it has been observed that the metal-free fiber shows a hinge fan-like motion of the S-shaped structure, maintaining the general conformation. Upon metal coordination, distinctive patterns are observed depending on the metal. Cu(II) binds to the flexible N-terminal region and induces structural changes that could ultimately disrupt the fibrillary structure. In contrast, Al(III) binding takes place with the residues Glu22 and Asp23, and its binding reinforces the core stability of the system. These results give clues on the molecular impact of the interaction of metal ions with the aggregates and sustain their non-innocent roles in the evolution of the illness

Amyloid Fibrils Formed by Short Prion-Inspired Peptides Are Metalloenzymes

Altres ajuts: acords transformatius de la UABEnzymes typically fold into defined 3D protein structures exhibiting a high catalytic efficiency and selectivity. It has been proposed that the earliest enzymes may have arisen from the self-assembly of short peptides into supramolecular amyloid-like structures. Several artificial amyloids have been shown to display catalytic activity while offering advantages over natural enzymes in terms of modularity, flexibility, stability, and reusability. Hydrolases, especially esterases, are the most common artificial amyloid-like nanozymes with some reported to act as carbonic anhydrases (CA). Their hydrolytic activity is often dependent on the binding of metallic cofactors through a coordination triad composed of His residues in the β-strands, which mimic the arrangement found in natural metalloenzymes. Tyr residues contribute to the coordination of metal ions in the active center of metalloproteins; however, their use has been mostly neglected in the design of metal-containing amyloid-based nanozymes. We recently reported that four different polar prion-inspired heptapeptides spontaneously self-assembled into amyloid fibrils. Their sequences lack His but contain three alternate Tyr residues exposed to solvent. We combine experiments and simulations to demonstrate that the amyloid fibrils formed by these peptides can efficiently coordinate and retain different divalent metal cations, functioning as both metal scavengers and nanozymes. The metallized fibrils exhibit esterase and CA activities without the need for a histidine triad. These findings highlight the functional versatility of prion-inspired peptide assemblies and provide a new sequential context for the creation of artificial metalloenzymes. Furthermore, our data support amyloid-like structures acting as ancestral catalysts at the origin of life

Prionoid Proteins in the Central Nervous System : both sides of the coin

Prionoid proteins are those proteins which can have different conformations, one of which can self-perpetuate and spread within an organism, but not between individuals. Traditionally, such proteins have been related to pathological conditions, such as various neurodegenerative diseases. Nonetheless, increasing evidence has been found that prionoid proteins may also perform functional roles when adopting the aggregated conformation, such as the ability to maintain long-term memory. However, the stimuli inducing the conformational switch of these proteins are still unknown, but various possibilities will be mentioned in this paper. Altogether, the study of pathological and functional prionoids is extremely important in order to understand their different aggregation process. Furthermore, acquiring a deeper knowledge may be of special interest with regard to the development of treatments both for memory deficiency diseases and neurodegenerative disease

Heat stress induces ferroptosis-like cell death in plants

In plants, regulated cell death (RCD) plays critical roles during development and is essential for plant-specific responses to abiotic and biotic stresses. Ferroptosis is an iron-dependent, oxidative, nonapoptotic form of cell death recently described in animal cells. In animal cells, this process can be triggered by depletion of glutathione (GSH) and accumulation of lipid reactive oxygen species (ROS). We investigated whether a similar process could be relevant to cell death in plants. Remarkably, heat shock (HS)-induced RCD, but not reproductive or vascular development, was found to involve a ferroptosis-like cell death process. In root cells, HS triggered an iron-dependent cell death pathway that was characterized by depletion of GSH and ascorbic acid and accumulation of cytosolic and lipid ROS. These results suggest a physiological role for this lethal pathway in response to heat stress in Arabidopsis thaliana. The similarity of ferroptosis in animal cells and ferroptosis-like death in plants suggests that oxidative, iron-dependent cell death programs may be evolutionarily ancient.Instituto de Fisiología Vegeta

Contribuciones potenciales al bienestar humano de los mamíferos en Argentina

Mammals are key components of biodiversity mediating ecosystem functions, mainly because of the diversity of forms and functions of this group. Understanding and making explicit the role of mammals underpinning Nature's Contributions to People (NCP) or directly contributing to human well-being would help to influence policy formulation towards sustainable development and nature conservation. Through a workshop held at the XXXII Jornadas Argentinas de Mastozoología and subsequent collaborative work, we compiled information related to Mammal's Contributions to People in Argentina (MCP-Arg) based on participants' interpretation of the available literature and their field experience. Argentinian mammals contribute to 12 of the 18 defined NCPs. We derived numerous MCP-Arg from studies that focused mainly on ecological processes and conservation, revealing an information gap in MCP- Arg description, quantification, and mapping. All taxa contribute similarly to the overall contributions, highlighting the importance of preserving mammal diversity. Conservation should also be framed at the local community rather than regional scales, aiming to preserve ecological functioning and contributions to human well-being, especially within regulation contributions. Our results show destructive feedback between threats and habitat-related contributions, with habitat degradation being the greatest threat to mammalian contributions and habitat maintenance the most threatened one. Our research indicates that a substantial amount of knowledge about MCP-Arg is available through narratives and interpretations. Considering the NCP approach to mammalian research, we can make significant contributions to both mammal conservation and human well-being.Debido a su diversidad de formas y funciones, los mamíferos son componentes clave de la biodiversidad y cumplen importantes funciones ecosistémicas. Para formular políticas que permitan un desarrollo sostenible y la conservación de la naturaleza, es fundamental comprender y explicitar el papel de los mamíferos en sustentar las Contribuciones de la Naturaleza a las Personas (CNP). Durante un taller realizado en las XXXII Jornadas Argentinas de Mastozoología y un posterior estudio colaborativo, hemos recopilado información relacionada con las CNP de mamíferos en Argentina (CMP-Arg) en base a la interpretación de la literatura disponible y la experiencia de campo. En la Argentina, los mamíferos contribuyen en 12 de las 18 CNP definidas. Deducimos numerosas CMP-Arg de estudios centrados principalmente en procesos ecológicos y de conservación, que muestran un vacío de información en cuanto a descripción, cuantificación y mapeo de CMP-Arg. Todos los taxones realizan aportes similares a las contribuciones totales, lo que destaca la importancia de preservar la diversidad de mamíferos. Los esfuerzos de conservación deben enmarcarse no solo a escala regional, sino también a escala local, con el objetivo de preservar las CNP. Nuestros resultados han mostrado una asociación entre amenazas y contribuciones relacionadas con el hábitat: la degradación de este ha sido la principal amenaza para las contribuciones y su mantenimiento la contribución más amenazada. Nuestra investigación muestra que una cantidad importante de conocimiento sobre CMP-Arg está disponible a través de narrativas y representaciones sociales. Mediante la implementación del enfoque del CNP en la investigación mastozoológica, podemos hacer aportes significativos tanto para la conservación de los mamíferos como para el bienestar humano.Fil: Alonso Roldán, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico para el Estudio de los Ecosistemas Continentales; Argentina. Universidad Tecnologica Nacional. Facultad Regional Chubut. Grupo de Investigacion En Gestion, Desarrollo Territorial y Ambiente.; ArgentinaFil: Camino, Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Centro de Ecología Aplicada del Litoral. Universidad Nacional del Nordeste. Centro de Ecología Aplicada del Litoral; Argentina. Sociedad Zoológica de Londres; Reino Unido. Proyecto Quimilero; ArgentinaFil: Argoitia, María Antonella. Universidad Nacional del Nordeste; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Campos, Claudia Monica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Investigaciones de las Zonas Áridas. Provincia de Mendoza. Instituto Argentino de Investigaciones de las Zonas Áridas. Universidad Nacional de Cuyo. Instituto Argentino de Investigaciones de las Zonas Áridas; ArgentinaFil: Caruso, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Ciencias Biológicas y Biomédicas del Sur. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia. Instituto de Ciencias Biológicas y Biomédicas del Sur; ArgentinaFil: Eder, Elena Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Centro para el Estudio de Sistemas Marinos; ArgentinaFil: Baldi, Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico para el Estudio de los Ecosistemas Continentales; Argentina. Wildlife Conservation Society; Estados UnidosFil: Birochio, Diego Enrique. Universidad Nacional de Rio Negro. Centro de Investigaciones y Transferencia de Rio Negro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia de Rio Negro; ArgentinaFil: Cappa, Flavio Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Centro de Investigaciones de la Geosfera y Biosfera. Universidad Nacional de San Juan. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones de la Geosfera y Biosfera; ArgentinaFil: Lassaga, Maria Victoria. Universidad Nacional de Córdoba; Argentina. Natura International; ArgentinaFil: Olmedo, María Luz. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo. Programa de Investigación de Biodiversidad Argentina; Argentina. Programa de Conservación de los Murciélagos de Argentina; ArgentinaFil: Formoso, Anahí Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico para el Estudio de los Ecosistemas Continentales; Argentina. Universidad del Chubut; ArgentinaFil: D'agostino, Valeria Carina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Centro para el Estudio de Sistemas Marinos; ArgentinaFil: González Noschese, Camila Sofía. Programa de Conservación de los Murciélagos de Argentina; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo. Programa de Investigación de Biodiversidad Argentina; ArgentinaFil: Udrizar Sauthier, Daniel Edgardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico para el Estudio de los Ecosistemas Continentales; Argentina. Universidad Nacional de la Patagonia "San Juan Bosco"; ArgentinaFil: Juárez, Cecilia Paola. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Formosa. Facultad de Recursos Naturales. Centro de Ecologia y Diversidad del Chaco.; ArgentinaFil: Degrati, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Centro para el Estudio de Sistemas Marinos; Argentina. Universidad Nacional de la Patagonia "San Juan Bosco"; ArgentinaFil: Iglesias, Martin. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Biodiversidad y Biología Experimental. Grupo de Estudios sobre Biodiversidad en Agroecosistemas; ArgentinaFil: Coelho, Lorena. Instituto de Investigaciones Biológicas "Clemente Estable"; UruguayFil: Sosa Drouville, Ailin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Centro para el Estudio de Sistemas Marinos; Argentina. Universidad Nacional del Comahue; ArgentinaFil: Priotto, Jose Waldemar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Instituto de Ciencias de la Tierra, Biodiversidad y Ambiente; Argentin

Heat stress induces ferroptosis-like cell death in plants

In plants, regulated cell death (RCD) plays critical roles during development and is essential for plant-specific responses to abiotic and biotic stresses. Ferroptosis is an iron-dependent, oxidative, nonapoptotic form of cell death recently described in animal cells. In animal cells, this process can be triggered by depletion of glutathione (GSH) and accumulation of lipid reactive oxygen species (ROS). We investigated whether a similar process could be relevant to cell death in plants. Remarkably, heat shock (HS)-induced RCD, but not reproductive or vascular development, was found to involve a ferroptosis-like cell death process. In root cells, HS triggered an iron-dependent cell death pathway that was characterized by depletion of GSH and ascorbic acid and accumulation of cytosolic and lipid ROS. These results suggest a physiological role for this lethal pathway in response to heat stress in Arabidopsis thaliana. The similarity of ferroptosis in animal cells and ferroptosis-like death in plants suggests that oxidative, iron-dependent cell death programs may be evolutionarily ancient.Instituto de Fisiología Vegeta

A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis

We report a medium‐throughput drug‐screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood–brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug‐screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality