Alberto Sols Biomedical Research Institute
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A novel β-TrCP1/NRF2 interaction inhibitor for effective anti-inflammatory therapy
No full textBackground
Non-communicable chronic diseases are characterized by low-grade inflammation and oxidative stress. Extensive research has identified the transcription factor NRF2 as a potential therapeutic target. Current NRF2 activators, designed to inhibit its repressor KEAP1, often exhibit undesirable side effects. As an alternative approach, we previously developed PHAR, a protein–protein interaction inhibitor of β-TrCP1/NRF2, which promotes NRF2 activation. Using the same in silico screening platform, we have now identified a novel compound, P10. This small molecule selectively interferes with the β-TrCP1/NRF2 interaction, leading to NRF2 stabilization and transcriptional activation of its target genes in a β-TrCP1-dependent manner, demonstrating promising effects in a liver model of acute inflammation.
Methods
After an in silico screening of ∼1 million compounds, including molecular docking analysis, ADMET evaluation, and molecular dynamics simulations, we identified and characterized a novel small molecule, P10, which inhibits β-TrCP1/NRF2 interaction. The compound was validated using luciferase reporter assays, co-immunoprecipitation, and ubiquitination experiments. The specificity of P10 was assessed by comparing NRF2 signatures in wild-type and Nrf2-null cells. The impact of NRF2 activation induced by P10 was investigated by evaluating its antioxidant and anti-inflammatory responses against tert-butyl hydroperoxide and lipopolysaccharide, respectively. Finally, wild-type and Nrf2-null mice were administered P10 intraperitoneally at a dose of 20 mg/kg daily for five consecutive days. Four hours before sacrifice, all animals received a lipopolysaccharide (LPS) injection at 10 mg/kg.
Results
P10 selectively disrupts the interaction between β-TrCP1 and NRF2, thereby inhibiting β-TrCP1-mediated ubiquitination of NRF2 and leading to the upregulation of NRF2 target genes. Additionally, P10 mitigates oxidative stress induced by tert-butyl hydroperoxide and reduces pro-inflammatory markers in an NRF2-dependent manner in macrophages treated with lipopolysaccharide. In a preclinical model of liver inflammation, P10 specifically targets the liver, significantly attenuating lipopolysaccharide-induced inflammation through the activation of NRF2. This is demonstrated by decreased expression of inflammatory cytokine genes and a reduction in F4/80-stained liver macrophages. Notably, this anti-inflammatory effect is absent in Nrf2-knockout mice, confirming its NRF2-dependent mechanism of action.
Conclusions
P10 emerges as a promising NRF2 activator by selectively disrupting the β-TrCP1/NRF2 interaction, highlighting its potential as a therapeutic agent for diseases presenting acute liver inflammationThis research was funded by the Spanish Ministry of Economy and Competitiveness (MINECO) (grants PDC2021-121421-I00, PDC2022-1337665-I00, PID2022-141786OB-I00, and PID2019-110061RB-I00). The Autonomous Community of Madrid (grants S2017BMD-3827 and P2022_BMD-7230). EC is the holder of an FPU contract of MIU (Ministry of Universities FPU2021, FPU21/02505
Real-World Clinical, Psychosocial and Financial Burden of Atopic Dermatitis: Results from the Spanish Cohort of the MEASURE-AD Trial
No full textAntecedentes: La dermatitis atópica (DA) es una de las enfermedades cutáneas más prevalentes, pero existen importantes lagunas en la comprensión de su impacto sobre la calidad de vida (CdV) y la salud mental de los pacientes, así como los gastos directos que les ocasiona. La evidencia científica sobre la carga multidimensional de la DA procede habitualmente de estudios en los que se utilizan exclusivamente resultados informados por los pacientes. Métodos: En este contexto, se dise˜ nó el estudio MEASURE-AD, de tipo transversal, multicéntrico e internacional, con resultados informados por los pacientes y por los facultativos con el fin de describir dicha carga multidimensional en adultos con DA moderada o grave. Resultados: En este artículo se presentan los resultados de la cohorte espa˜ nola. Los adultos con DA moderada o grave y EASI entre 21,1 y 72 presentaron una carga significativamente más alta de la enfermedad, síntomas muy intensos, como el prurito y las alteraciones del sue˜ no, afectación de la salud mental y la CdV y mayor consumo de recursos sanitarios y gasto directo que los pacientes con puntuación EASI entre 0-7 o 7,1-21. Conclusiones: El estudio aporta información para comprender mejor la carga que supone la enfermedad y nos permite identificar qué aspectos conviene mejorar en el manejo de la DABackground: Atopic dermatitis (AD) is one of the most prevalent skin diseases, but there are numerous knowledge gaps surrounding the impact this disease has on quality of life (QoL), mental health, and out-of-pocket expenses involved in the management of AD. The available scientific evidence on the multidimensional burden of AD is usually based on studies with measures reported by patients themselves. Methods: In this context, the MEASURE-AD trial was developed as a cross-sectional, multicenter, multinational trial using patient- and physician-reported measures to characterize the multidimensional burden of AD in adults with moderate-to-severe AD. Results: This paper presents the results of the Spanish cohort. We found that Spanish adults with moderate-to-severe AD and high EASI score (21.1-72) had a significantly increased disease burden, high severity of symptoms such as itch and sleep disturbances, impaired mental health and QoL, higher use of health care resources, and more out-of-pocket expenses than patients with low EASI scores (0-7 or 7.1-21). Conclusions: This study provides information to better understand disease burden, and identify aspects to be improved in the management of A
Holographic non-Hermitian lattices and junctions and their RG flows
No full textWe construct and study inhomogeneous non-Hermitian strongly coupled holographic field theories. We consider two models: a lattice where in each site there is some inflow/outflow of matter and a Hermitian/non-Hermitian/Hermitian junction. By tuning a complex external gauge field, we find a non-Hermitian model which can be mapped to a Hermitian one via a complexified U(1) gauge transformation. On the other hand, in the absence of the gauge field we find non-Hermitian solutions with a purely imaginary current.
Despite this, all expectation values respect PT symmetry and thus we expect the system to feature unitary time evolution. Nonetheless, we have not found a map bringing these solutions to a Hermitian description. We study the RG flows of solutions with imaginary
current finding that in the IR they can be mapped to a Hermitian conformal fixed point via a complexified U(1) transformation. Remarkably, we also obtain solutions where the null energy condition is violated near the boundary of the dual geometryWe thank J.L.F. Barbón, P.G. Romeu, and specially K. Landsteiner for valuable discussions.
This work is supported through the grants CEX2020-001007-S and PID2021-123017NB-I00
funded by MCIN/AEI/10.13039/501100011033 and by ERDF “A way of making Europe”.
The work of D.G.F. is supported by FPI grant PRE2022-101810. Some numerical simulations
were carried out at the IFT Hydra cluste
The seeds of futurims in Peru. From ‘sincere little lies’ to indigenist concepts
No full textThis essay outlines the genealogy of Futurism in Peru and investigates how it permeated into the county’s early twentieth-century avant-garde culture. After a brief introduction, I discuss the first reviews and mentions of Marinetti’s movement in the 1910s and the questioning of its aesthetic principles by authors such as Rubén Darío and Francisco García Calderón. In the 1920s, some poets such as Alberto Hidalgo wrote works that were closer to the new Italian aesthetics and were considered ‘Futurists’ by their compatriots, but many of them actually rejected this designation. Finally, I explore how Indigenism adopted and reformu-lated Futurism in order to develop its own concept of national identity. Peruvian Indigenism incorporated the most optimistic part of the utopia of the New and used foreign impulses to convey a new sensibility. Middle-class mestizos seeking their place in the national and foreign cultural fields founded magazines and pub-lished books of an avant-garde nature, which sought to integrate foreign currents into the Peruvian socio-cultural reality. Written in Spanish and aimed at an edu-cated readership, these publications introduced the world of the Indigenous pop-ulation to an audience foreign to their life and culture. Representations of life in the Andes were combined with concepts adopted from Futurism and other avant-garde movements, which thus proved to be of fundamental importance for the in-tellectual evolution of Peru, in the throes of defining its national identit
Del acoplamiento débil al ultrafuerte en las interacciones luz-materia
No full textTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Física Teórica de la Materia Condensada. Fecha de Lectura: 30-06-2025La interacción entre emisores, cavidades y luz a escalas nanométricas reúne una multitud de fenómenos fundamentales. Esta tesis está dedicada al estudio teórico de varios de estos fenómenos, abarcando desde el régimen de acoplamiento débil hasta el de acoplamiento ultrafuerte. Tras introducir el campo de estudio y establecer las herramientas teóricas en los capítulos 1 y 2, respectivamente, desarrollamos un enfoque de sistemas cuánticos abiertos para analizar la dinámica de emisores complejos acoplados débilmente a un entorno en el capítulo 3. Cuando el espectro de energía del emisor presenta varios niveles suficientemente próximos a la degeneración, el entorno induce acoplamientos tanto coherentes como disipativos entre diferentes estados del emisor. Estos acoplamientos no aparecen en la derivación estándar de la ecuación maestra de Lindblad. Partimos de una prescripción propuesta en la literatura para incorporar estos efectos que, sin embargo, no garantiza la obtención de una ecuación de Lindblad salvo en escenarios simplificados. Posteriormente, identificamos dos problemas que surgen al considerar situaciones más complejas, y desarrollamos soluciones para ambos. Como resultado, nuestro trabajo garantiza que siempre se alcanza una ecuación de Lindblad genuina, precisa mientras el entorno sea Markoviano. El capítulo 4 se basa en los resultados metodológicos anteriores para analizar la dinámica de un átomo de hidrógeno acoplado al entorno electromagnético debido a una nanopartícula dieléctrica. El espectro de energía del átomo de hidrógeno presenta una serie de niveles de Bohr bien separados, los cuales se dividen en varios niveles de estructura fina muy próximos entre sí. Aquí estudiamos el efecto de los acoplamientos inducidos por el entorno dentro de los estados de estructura fina de un mismo nivel de Bohr. Nuestros resultados muestran que los autoestados de estructura fina del átomo de hidrógeno se mezclan de manera significativa, incluso para separaciones átomo-nanopartícula del orden de 50 nanómetros. Como consecuencia, el espectro de energía desarrolla múltiples cruces evitados. Además, para un rango específico de parámetros, la mezcla de estados de estructura fina da lugar a un autoestado "oscuro", cuya tasa de disipación disminuye a medida que el átomo se aproxima a la nanopartícula y llega a ser un orden de magnitud menor que la esperada en un modelo que no considera los acoplamientos inducidos por el entorno. Finalmente, el capítulo 5 aborda una cuestión fundamental del régimen de acoplamiento ultrafuerte en las interacciones luz-materia. Demostramos, mediante reglas de suma electromagnéticas, que el acoplamiento ultrafuerte de un único emisor sólo puede alcanzarse mediante el confinamiento en volúmenes por debajo de la longitud de onda del campo eléctrico por una nanocavidad. Esto implica que los campos longitudinales, es decir, puramente de Coulomb, son los responsables de alcanzar estos acoplamientos tan fuertes, en lugar de los campos transversales. En consecuencia, una descripción cuasiestática del sistema emisor-cavidad resulta suficiente para describir adecuadamente los fenómenos de acoplamiento ultrafuerte. Esta conclusión tiene importantes implicaciones teóricas y metodológicas, ya que los modelos que suponen que los campos transversales dominan incluyen diferentes términos cuya relevancia real está muy sobreestimada en el régimen de acoplamiento ultrafuerte. Por lo tanto, tales modelos, aunque ampliamente utilizados, resultan inadecuado
Attitudes guiding social behavior as a function of perceived knowledge: The moderating role of epistemic vs. hedonic mindsets
No full textThe current research introduces a new variable (epistemic vs. hedonic mindset) that helps elucidate the conditions under which a previously established phenomenon reverses: the moderating impact of perceived knowledge on attitude-behavior correspondence (ABC). Four studies (plus four more additional studies reported in the supplementary material), in the domain of person perception and consumer choice show that higher perceived knowledge enhances ABC under an epistemic mindset, but it can reverse under a hedonic mindset. An epistemic mindset involves focusing on making accurate impressions whereas a hedonic mindset focuses people on enjoyment and having fun. Beyond manipulating mindset, perceived knowledge was also either measured or manipulated across the studies (including one pre-registered experiment), holding constant the actual amount of information participants received about the attitude object. Under a hedonic mindset, greater ABC was observed under low (vs. high) perceived knowledge, reversing a classic effect for the first time. However, under an epistemic mindset, attitudes were predicted and found to guide behavior significantly more with high (vs. low) perceived knowledge. This outcome provides a conceptual replication of the traditional effect shown in the attitude strength literature. These effects were driven by changes in the meaning (positive or negative) associated with knowledge in each mindset as shown by both measuring and manipulating the proposed mediator. This research advances the literature on knowledge, attitudes, person perception, and consumer judgment by introducing a new variable in this domain capable of specifying the conditions that facilitate when an important phenomenon occurs in one direction or the other and explaining why these effects occurWe have no known conflict of interest to disclose. This research was supported by the Ministerio de Ciencia, Innovación y Universidades (Spain) (PID2020-116651GB-C31; PID2023-148050NA-I00; PID2023- 148146NB-I00) and the Consejería de Educación, Ciencia y Universidades, Comunidad de Madrid (Spain) (SI4/PJI/2024-00244). This work was supported also by the Templeton World Charity Foundation under Grant TWCF2023-32571. The funding source has not been involved in the design of the study, the collection, analysis or interpretation of data, the writing of the manuscript, or the decision to submit it for publicatio
Ecosystems and biodiversity in the frontiers of the Mar Menor Lagoon: Birds as alert bioindicators of environmental change
No full textThe Mar Menor (Murcia, SE Spain) is the largest coastal lagoon in the western Mediterranean and a system strongly stressed by the transformations occurred in its catchment basin, which together with it constitute a complex socio-ecological system (SES). The main basin of the lagoon has suffered from 2015-16 a succession of environmental crises that include phytoplankton explosions and the disappearance of large areas of submerged meadows due to eutrophication of mainly agricultural origin, and even episodes of mass mortality of aquatic fauna. On the frontiers of the main basin there is a set of wetlands with an important role in protecting the lagoon against the pressures responsible for this change of state. The biodiversity of these wetlands has an intrinsic value but also as a bioindicator of this process, representing an alert system that anticipated the risk of eutrophication of the lagoon several decades before. The chapter synthesizes the ecological values associated with these wetlands, focusing on avifauna as one of the main land-based bioindicator taxocenosis. The typology of existing wetlands around the Mar Menor includes environments located both on the land (salt pans and other perilittoral wetlands) and maritime frontiers (inlets or golas). The latter are home to highly exclusive habitats, unique in the Mediterranean due to their quasi-tidal functioning. The birds of the Mar Menor SES exploit these aquatic habitats and their ecological interfaces (such as the lagoon surface and its islands), for activities such as feeding, resting or nesting. Some examples of the response of bird taxocenoses to external pressures are presented, such as the changes observed in the bird populations of the main lagoon water mass, or the decline of some characteristic species of perilittoral crypto-wetlands (hidden seepages) as an indirect effect of agricultural transformation. The result is the decrease or disappearance of bioindicator bird species, both aquatic and steppe dwelling species. The main changes observed are discussed in the framework of the protection and management instruments that the Mar Menor has been endowed with, showing the inefficiency of those that ignore the interdependence of wetlands with the dynamics of their terrestrial and maritime areas of influence. The monitoring of the Mar Menor Socio-ecological System (MMSES) should take advantage of the indicator value of these taxocenoses, most of are recognized as key elements for protected wetland designation and management. A greater effort is required in monitoring these alert indicators, together with other parameters of the physico-chemical state of the lagoon and its watershe
Fundamental processes of positive change
No full textMany strategies designed to facilitate the generation of positive thoughts (focusing on strengths, imagining the best possible self, reflecting on achievements) are effective in making people feel better and increasing their wellbeing. But, the question is why? We review the underlying processes by which these and other positive actions (from smiling, expressing gratitude, being kind, etc.) can operate. In addition to drawing a distinction between relatively low and high thinking processes relevant to primary cognition, the present article introduces for the first time meta-cognitive processes of change as relevant to this domain. By examining thought validation and invalidation mechanisms, we make predictions about the circumstances in which positive and negative thoughts are more or less likely to produce the desired effects. Also, by identifying moderators of validation process and outcomes, we contribute to improving the benefits of many positive variables even further, specifying why, when, and for whom various positive treatments are more likely to work or to backfireThe work was supported by the Ministerio de Ciencia e Innovación [PID2020-116651GB-C31]; Ministerio de Ciencia e Innovación [PID2023-148146NB-100]; Templeton World Charity Foundation [TWCF-2023-32571
Feature integration strategies for neural speaker diarization in conversational telephone speech
No full textThis paper addresses the challenge of optimizing end-to-end neural diarization systems for conversational telephone speech, focusing on diverse acoustic features beyond traditional Mel-filterbanks. We present a methodological framework for integrating and analyzing different feature types as input to the well-known End-to-End Neural Diarization with Encoder Decoder Attractors (EEND-EDA) model, focusing on Emphasized Channel Attention, Propagation and Aggregation in Time Delay Neural Network (ECAPA-TDNN) embeddings and Geneva Minimalistic Acoustic Parameter Sets (GeMAPS). Our approach combines systematic feature analysis with adaptation strategies, including speaker-count restriction and regularization techniques. Moreover, through comprehensive ablation studies of GeMAPS features, we identify optimal acoustic parameters and temporal contexts for diarization tasks, achieving a reduced feature set that maintains performance while decreasing computational complexity. Experiments on the CallHome corpus demonstrate that our optimized ECAPA-TDNN with Mel-filterbank combination reduces Diarization Error Rate by 29% relative to baseline systems. Our evaluation framework extends beyond traditional metrics, revealing that different feature combinations exhibit distinct strengths in specific diarization aspectsThis work was supported by PID2021-125943OB-I00, MCIN/AEI/10.13039/501100011033/FEDER, UE from the Spanish Ministerio de Ciencia e Innovacion y Agencia del Fondo Europeo de Desarrollo Regional and project SI4/PJI/2024-00237 (COSER-IA), Comunidad de Madri
