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Modulation of large-scale brain networks by transcranial direct current stimulation evidenced by resting-state functional MRI
(Elsevier, 2011-08-11) Peña-Gómez, Cleofé; Sala Llonch, Roser; Junqué i Plaja, Carme, 1955-; Clemente, Immaculada; Vidal Piñeiro, Dídac; Bargalló Alabart, Núria; Falcón Falcón, Carles Maria; Valls Solé, Josep; Pascual Leone, Álvaro, 1961-; Bartrés Faz, David
Background: Brain areas interact mutually to perform particular complex brain functions such as memory or language. Furthermore, under resting-state conditions several spatial patterns have been identified that resemble functional systems involved in cognitive functions. Among these, the default-mode network (DMN), which is consistently deactivated during task periods and is related to a variety of cognitive functions, has attracted most attention. In addition, in resting-state conditions some brain areas engaged in focused attention (such as the anticorrelated network, AN) show a strong negative correlation with DMN; as task demand increases, AN activity rises, and DMN activity falls. Objective: We combined transcranial direct current stimulation (tDCS) with functional magnetic resonance imaging (fMRI) to investigate these brain network dynamics. Methods: Ten healthy young volunteers underwent four blocks of resting-state fMRI (10-minutes), each of them immediately after 20 minutes of sham or active tDCS (2 mA), on two different days. On the first day the anodal electrode was placed over the left dorsolateral prefrontal cortex (DLPFC) (part of the AN) with the cathode over the contralateral supraorbital area, and on the second day, the electrode arrangement was reversed (anode right-DLPFC, cathode left-supraorbital). Results: After active stimulation, functional network connectivity revealed increased synchrony within the AN components and reduced synchrony in the DMN components. Conclusions: Our study reveals a reconfiguration of intrinsic brain activity networks after active tDCS. These effects may help to explain earlier reports of improvements in cognitive functions after anodal-tDCS, where increasing cortical excitability may have facilitated reconfiguration of functional brain networks to address upcoming cognitive demands.
Nuclear stiffness through lamin A/C overexpression differentially modulates chromosomal instability biomarkers
(Wiley, 2025-02-25) Bosch Calvet, Mireia; Pérez Venteo, Alejandro; Cebria Xart, Alex; Garcia Cajide, Marta; Mauvezin, Caroline
Background Information Mitosis is crucial for the faithful transmission of genetic material, and disruptions can result in chromosomal instability (CIN), a hallmark of cancer. CIN is a known driver of tumor heterogeneity and anti-cancer drug resistance, thus highlighting the need to assess CIN levels in cancer cells to design effective targeted therapy. While micronuclei are widely recognized as CIN markers, we have recently identified the toroidal nucleus, a novel ring-shaped nuclear phenotype arising as well from chromosome mis-segregation. Results Here, we examined whether increasing nuclear envelope stiffness through lamin A/C overexpression could affect the formation of toroidal nuclei and micronuclei. Interestingly, lamin A/C overexpression led to an increase in toroidal nuclei while reducing micronuclei prevalence. We demonstrated that chromatin compaction and nuclear stiffness drive the formation of toroidal nuclei. Furthermore, inhibition of autophagy and lysosomal function elevated the frequency of toroidal nuclei without affecting the number of micronuclei in the whole cell population. We demonstrated that this divergence between the two CIN biomarkers is independent of defects in lamin A processing. Conclusions and Significance These findings uncover a complex interplay between nuclear architecture and levels of CIN, advancing our understanding of the mechanisms supporting genomic stability and further contributing to cancer biology.
Early-life cognitive intervention preserves brain function in aged TgF344-AD rats with sex-specific effects
(Elsevier, 2026-01-16) Molina Porcel, Laura; Malagelada Grau, Cristina; Soria Rodriguez, Guadalupe; Casanova-Pagola, Julia; Varriano, Federico; López-Gil, Xavier; Campoy Campos, Genís; Abellí Deulofeu, Enric; García-González, Clara; López-Bravo, Elisa; Tudela Fernández, Raúl; Muñoz-Moreno, Emma; Aguado Tomàs, Fernando; Prats Galino, Alberto
Alzheimer’s disease is characterized by progressive cognitive decline, and its effects are mitigated by cognitivereserve. We investigated whether long-term cognitive stimulation, initiated before amyloid deposition,preserves brain function in male and female TgF344-AD rats. Transgenic and wild-type (WT) rats underwentcognitive training or remained untrained. Resting-state fMRI assessed functional connectivity, the novel objectrecognition test evaluated memory, and molecular analyses examined synaptic plasticity, inhibitorysignaling, and microglial reactivity. At baseline, females showed greater task engagement and higher synapticprotein levels (PSD95, TrkB, and VGLUT) than males. Cognitive training improved connectivity and memoryin males, with limited benefits in females. At 19 months, trained transgenic rats maintained entorhinal-hippocampalconnectivity resembling WT rats, with males showing sustained plasticity markers and reducedparvalbumin-positive interneurons. Trained 11-month-old rats showed enhanced microglial recruitment toplaques and a less reactive phenotype. Overall, early and sustained cognitive stimulation enhances brain resilience,with sex-specific mechanisms shaping outcomes.
Competing signaling pathways controls electrotaxis
(Elsevier, 2025-05-16) Kulkarni, Shardool; Tebar Ramon, Francesc; Rentero Alfonso, Carles; Zhao, Min; Sáez, Pablo
Understanding how cells follow exogenous cues is a key question for biology, medicine, and bioengineering. Growing evidence shows that electric fields represent a precise and programmable method to control cell migration. Most data suggest that the polarization of membrane proteins and the following downstream signaling are central to electrotaxis. Unfortunately, how these multiple mechanisms coordinate with the motile machinery of the cell is still poorly understood. Here, we develop a mechanistic model that explains electrotaxis across different cell types. Using the zebrafish proteome, we identify membrane proteins directly related to migration signaling pathways that polarize anodally and cathodally. Further, we show that the simultaneous and asymmetric distribution of these membrane receptors establish multiple cooperative and competing stimuli for directing the anodal and cathodal migration of the cell. Using electric fields, we enhance, cancel, or switch directed cell migration, with clear implications in promoting tissue regeneration or arresting tumor progression.
Altered Intra- and Inter-Network Resting-State Functional Connectivity is Associated with Neuropsychological Functioning and Clinical Symptoms in Patients with Isolated Rapid Eye Movement Sleep Behavior Disorder
(Wiley, 2025-01-28) Roura, Ignacio; Pardo, Jèssica; Martín Barceló, Cristina; Oltra González, Javier; Campabadal Delgado, Anna; Sala Llonch, Roser; Bargalló Alabart, Núria; Serradell, Mónica; Pont-Sunyer, Claustre; Gaig Ventura, Carles; Mayà, Gerard; Montini, Angelica; Junqué i Plaja, Carme, 1955-; Iranzo, Alex; Segura i Fàbregas, Bàrbara
Background: Isolated rapid-eye movement (REM) sleep behavior disorder (iRBD) is characterized by abnormal behaviors in REM sleep and is considered as a prodromal symptom of alpha-synucleinopathies. Resting-state functional magnetic resonance imaging (rsfMRI) studies have unveiled altered functional connectivity (rsFC) in patients with iRBD. However, the associations between intra- and inter-network rsFC with clinical symptoms and neuropsychological functioning in iRBD remain unclear. Objective: To characterize intra- and inter-network rsFC in iRBD patients using a data-driven approach and to assess its associations with clinical features and cognitive functioning. Methods: Forty-two patients with iRBD and 45 healthy controls (HC) underwent rsfMRI and comprehensive neuropsychological testing. Resting-state networks were characterized using independent component analyses. Group differences in intra- and inter-network rsFC and their associations with clinical and neuropsychological data were studied. A threshold of corrected P < 0.05 was used in all the analyses. Results: iRBD patients displayed lower intra-network rsFC within basal ganglia, visual, sensorimotor, and cerebellar networks, relative to HC. Mean rsFC strength within the basal ganglia network positively correlated with processing speed and negatively with the non-motor symptoms in iRBD patients. Reduced inter-network rsFC between sensorimotor and visual medial networks was observed in iRBD patients, which was associated with global cognitive status. Conclusions: iRBD is characterized by both reductions in intra-network rsFC in cortical and subcortical networks and inter-network dysconnectivity between sensorimotor and visual networks. Abnormalities in intra- and inter-network rsFC are associated with cognitive performance and non-motor symptoms, suggesting the utility of both rsFC measures as imaging markers in prodromal alpha-synucleinopathies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders
(Nature Publishing Group, 2025-03-14) Cilleros-Portet, Ariadna; Lesseur, Corina; Marí, Sergi; Cosín Tomàs, Marta; Lozano Relaño, Manuel; Irizar, Amaia; Burt, Amber; García-Santisteban, Iraia; Garrido Martín, Diego, 1992-; Escaramís Babiano, Geòrgia; Hernangomez-Laderas, Alba; Soler-Blasco, Raquel; Breeze, Charles E.; Gonzalez-Garcia, Bárbara P.; Santa Marina, Loreto; Chen, Jia; Llop, Sabrina; Fernández, Mariana F.; Vrijheid, Martine; Ibarluzea, Jesús; Guxens, Mònica; Marsit, Carmen; Bustamante Pineda, Mariona; Bilbao, Jose Ramon; Fernandez-Jimenez, Nora
Increasing evidence supports the role of the placenta in neurodevelopment and in the onset of neuropsychiatric disorders. Recently, mQTL and iQTL maps have proven useful in understanding relationships between SNPs and GWAS that are not captured by eQTL. In this context, we propose that part of the genetic predisposition to complex neuropsychiatric disorders acts through placental DNA methylation. We construct a public placental cis-mQTL database including 214,830 CpG sites calculated in 368 fetal placenta DNA samples from the INMA project, and run cell type-, gestational age- and sex-imQTL models. We combine these data with summary statistics of GWAS on ten neuropsychiatric disorders using summary-based Mendelian randomization and colocalization. We also evaluate the influence of identified DNA methylation sites on placental gene expression in the RICHS cohort. We find that placental cis-mQTLs are enriched in placenta-specific active chromatin regions, and establish that part of the genetic burden for schizophrenia, bipolar disorder, and major depressive disorder confers risk through placental DNA methylation. The potential causality of several of the observed associations is reinforced by secondary association signals identified in conditional analyses, the involvement of cell type-imQTLs, and the correlation of identified DNA methylation sites with the expression levels of relevant genes in the placenta.
Sertraline treatment prevents motor dysfunction in a Huntington's disease mouse model and functional decline in patients
(Springer Verlag, 2025-07-25) Garcia-Forn, Marta; Castany-Pladevall, Carla; Creus Muncunill, Jordi; Golbano, Arantxa; Escaramís Babiano, Geòrgia; Pérez Pérez, Jesús; Balantzategi, Uxue; Hernan-Godoy, Marina; Brito, Verónica; Kulisevsky, Jaime; Martí Puig, Eulàlia; Pérez Navarro, Ester
Molecular alterations underlying Huntington's disease (HD) are not fully elucidated and no curative therapies are available. We have described that increased translation efficiency participates in the motor symptoms in the R6/1 HD mouse model. Here, we evaluated whether sertraline, a widely used antidepressant drug, that modulates translation in cancer cells, could ameliorate motor and cognitive symptoms in HD. We also investigated if alterations in translation efficiency occur in fibroblasts from HD patients and serve as a possible biomarker. As an index of translation efficiency levels, we analyzed puromycin incorporation and phosphorylated 4E-BP1 levels in striatal primary cultures and striatum from R6/1 mice, and in HD patients' fibroblasts, with or without sertraline treatment. Motor learning and coordination were analyzed in treated mice by accelerating rotarod, balance beam and vertical pole tests. Clinical data from the Enroll-HD dataset were analyzed to evaluate the potential effects of sertraline treatment in the disease progression. We report that sertraline treatment: 1) modulates translation efficiency in striatal primary neurons expressing mutant huntingtin; 2) prevents motor dysfunction in R6/1 mice and normalizes translation efficiency in the striatum, and 3) delays the decline in functional performance of HD patients. Moreover, puromycin incorporation is increased in fibroblasts from HD patients in a CAG length-dependent manner and is modulated by sertraline treatment. Altogether, our results suggest sertraline as a promising candidate for HD clinical trials to slow down disease progression and that puromycin incorporation in fibroblasts could serve as a pharmacological biomarker for certain treatments
Increased translation in adult mouse striatum is sufficient to induce motor dysfunction
(Oxford University Press, 2025-06-19) Castany Pladevall, Carla; Creus Muncunill, Jordi; Bergé-Gardeñes, Maria; Golbano, Arantxa; Brito, Verónica; Pérez Navarro, Ester
Protein synthesis is a process finely regulated in all cell types but specially in neurons as they need rapid changes in protein concentration for synaptic plasticity. Alterations in translation rates have been shown in diseases affecting the brain. In Huntington's disease (HD), an autosomal dominant neurodegenerative disorder characterized by the presence of motor, cognitive and psychiatric symptoms, we have shown that translation is increased in the striatum contributing to motor symptoms. However, very little is known about how translation modulates motor function in physiological conditions. To study this, we overexpressed a constitutively active mutant form of 4E-BP1 (4E-BP1^F113A), a translation repressor, in the striatum of wild-type mice and performed motor tests. One month after striatal injection of adeno-associated viral vectors expressing 4E-BP1^F113A, mice exhibited motor symptoms similar to those observed in the R6/1 HD mouse model. Unexpectedly, de novo protein synthesis and 4E-BP1 phosphorylation were enhanced in the striatum of wild-type mice overexpressing 4E-BP1^F113A. Moreover, the striatum of these animals showed alterations in protein levels of neuronal markers similar to that observed in HD striatum. Altogether, our results indicate that enhanced protein synthesis in the striatum induces neuronal dysfunction and motor symptoms, and reinforce the idea that increased translation is involved in HD pathogenesis.
Pulmonary vascular reactivity in growth restricted fetuses using computational modelling and machine learning analysis of fetal Doppler waveforms
(Nature Publishing Group, 2024-03-11) Vellvé, Kilian; Garcia Canadilla, Patricia; Nogueira, Mariana; Youssef, Lina; Arranz Betegón, Angela; Nakaki, Ayako; Boada, David; Blanco Vich, Isabel; Faner, Rosa; Figueras Retuerta, Francesc; Agustí García-Navarro, Àlvar; Gratacós Solsona, Eduard; Crovetto, Francesca; Bijnens, Bart; Crispi Brillas, Fàtima
The aim of this study was to investigate the pulmonary vasculature in baseline conditions and after maternal hyperoxygenation in growth restricted fetuses (FGR). A prospective cohort study of singleton pregnancies including 97 FGR and 111 normally grown fetuses was carried out. Ultrasound Doppler of the pulmonary vessels was obtained at 24–37 weeks of gestation and data were acquired before and after oxygen administration. After, Machine Learning (ML) and a computational model were used on the Doppler waveforms to classify individuals and estimate pulmonary vascular resistance (PVR). Our results showed lower mean velocity time integral (VTI) in the main pulmonary and intrapulmonary arteries in baseline conditions in FGR individuals. Delta changes of the main pulmonary artery VTI and intrapulmonary artery pulsatility index before and after hyperoxygenation were significantly greater in FGR when compared with controls. Also, ML identified two clusters: A (including 66% controls and 34% FGR) with similar Doppler traces over time and B (including 33% controls and 67% FGR) with changes after hyperoxygenation. The computational model estimated the ratio of PVR before and after maternal hyperoxygenation which was closer to 1 in cluster A (cluster A 0.98 ± 0.33 vs cluster B 0.78 ± 0.28, p = 0.0156). Doppler ultrasound allows the detection of significant changes in pulmonary vasculature in most FGR at baseline, and distinct responses to hyperoxygenation. Future studies are warranted to assess its potential applicability in the clinical management of FGR.
Low-cost, open-source device for applying controlled olfactory stimuli during functional magnetic resonance imaging (fMRI) of the brain
(Elsevier Ltd., 2025-09-23) Salama, Raffaella; Rodríguez Lázaro, Miguel A.; Castelo-Branco Flores, Camil; Herrero Vidaurre, Iñigo; Ribera Torres, Laura; Muñoz-Moreno, Emma; Farré Ventura, Ramon; Otero Hermo, Jorge
Using functional magnetic resonance imaging (fMRI) to assess brain activity in response to olfactory stimuli is of great biomedical and clinical interest. However, application of controlled sequences of olfactory stimuli within the setting of fMRI equipment is challenging since the associated limitations for non-magnetic and non-conducive materials. Here, we have developed and tested a simple, low-cost, open-source, stand-alone device to apply selectable controlled sequences of olfactory stimuli in subjects undergoing fMRI. The device consists of an Arduino-controlled unit containing a blower-based airflow generator and a multichannel air valves system, a set of long air conducting tubing, and bubbler-based odor sources. The device was first validated on the bench to characterize the range of achievable flows, ensuring that the device can be adapted to a variety of applications and fMRI settings. The effectiveness of device performance was subsequently assessed in female patients with sexual dysfunction using a fMRI protocol based on subjecting them to controlled sequences of olfactive stimuli with pheromone, phenethyl alcohol (a rose fragrance) or neutral clean air. Therefore, the device facilitates biomedical research and clinical assessment of the neural pathways modulated by the olfactory system
Prevalence, diagnostic accuracy, and healthcare utilization patterns in patients with COPD in primary healthcare: a population-based study
(Springer Nature, 2025-03-21) Vila Muntadas, Marc; Sisó Almirall, Antoni; Ocaña, Andrea; Agustí García-Navarro, Àlvar; Faner, Rosa; Borras-Santos, Alicia; González de Paz, Luis
Underdiagnosis and overdiagnosis commonly occur in Chronic Obstructive Pulmonary Disease (COPD) patients. We assessed diagnostic accuracy, clinical characteristics, healthcare utilization, and care plan registration for patients undergoing primary care. We conducted a cross-sectional, population-based study using a health record registry from four primary healthcare centers in Catalonia (Spain) for patients aged ≥15 years. The variables included sociodemographic characteristics, dyspnea, comorbidities, spirometry results, treatments, and healthcare use. Logistic regression models were used to analyze differences between patients with and without airflow limitation, and ordinal logistic regression models were used to examine the association between disease severity and healthcare use. Among the 2610 patients, 54% had spirometry data, 29.5% had confirmed airflow obstruction, and 24% were overdiagnosed according to the GOLD criteria. Patients without airflow obstruction were younger (OR: 0.98, 95% CI: 0.96-0.99) and more likely to be current smokers (OR: 1.44, 95% CI: 1.13-1.84). Airflow obstruction severity was significantly associated with increased use of emergency home ambulance use (OR: 1.7, 95% CI: 1.23-2.35), emergency department visits (OR: 1.48, 95% CI: 1.11-1.99), and hospital admission (OR: 1.8, 95% CI: 1.32-2.47), but not primary care visits and follow-up frequency. COPD is frequently overdiagnosed in primary healthcare settings. The severity of airflow obstruction is associated with increased healthcare utilization, including hospital admissions. Improved diagnostic accuracy and management may enhance COPD care and reduce healthcare costs.
Structural brain changes in post-COVID condition and its relationship with cognitive impairment
(Oxford University Press, 2025-02-12) Pacheco Jaime, Laura; Garcia Vicente, Carla; Ariza González, Mar; Cano, Neus; Garolera i Freixa, Maite; Carreras Vidal, Lourdes; Roura, Ignacio ; Capdevila Lacasa, Clara; Oltra González, Javier; Pardo, Jèssica ; Martín Barceló, Cristina ; Campabadal Delgado, Anna; Sala Llonch, Roser ; Bargalló Alabart, Núria; Barrué, Cristian ; Bejar, Javier ; Cortés, Claudio Ulises ; Junqué i Plaja, Carme, 1955-; Segura i Fàbregas, Bàrbara; NAUTILUS-Project Collaborative Group
It has been estimated that ∼4% of individuals infected with SARS-CoV-2 will be diagnosed with post-COVID condition. Previous studies have evidenced the presence of cognitive dysfunction and structural brain changes in infected individuals; however, the relationship between structural changes and cognitive alterations in post-COVID condition is still not clear. Consequently, the aim of this work is to study structural brain alterations in post-COVID condition patients after almost 2 years of infection and their likely relationship with patients' cognitive impairment. Additionally, the association with blood biomarkers and clinical variables was also explored. One hundred and twenty-eight individuals with post-COVID condition and 37 non-infected healthy controls from the Nautilus Project (ClinicalTrials.gov IDs: NCT05307549 and NCT05307575) underwent structural brain magnetic resonance imaging and a comprehensive neuropsychological assessment. A subsample of 66 post-COVID participants also underwent blood extraction to obtain levels of blood biomarkers. Cortical thickness and subcortical volumes were obtained and analysed using FreeSurfer (v7.1). FMRIB Software Library software (v6.0.4) was used to perform grey matter voxel-based analysis and to study microstructural white matter integrity. Patients with post-COVID performed significantly worse in working and verbal memory, processing speed, verbal fluency and executive functions, compared to healthy controls. Moreover, patients with post-COVID showed increased cortical thickness in the right superior frontal and the right rostral middle frontal gyri that negatively correlated with working memory performance. Diffusion tensor imaging data showed lower fractional anisotropy in patients in the right superior longitudinal fasciculus, the splenium and genu of the corpus callosum, the right uncinate fasciculus and the forceps major, that negatively correlated with subjective memory failures. No differences in blood biomarkers were found. Once patients were classified according to their cognitive status, post-COVID clinically cognitively altered presented increased cortical thickness compared to those classified as non-cognitively altered. In conclusion, our study showed that grey and white matter brain changes are relevant in this condition after almost 2 years of infection and partly explain long-term cognitive sequelae. These findings underscore the critical importance of monitoring this at-risk population over time.
Follow-Up After Myocardial Infarction to Explore the Stability of Arrhythmogenic Substrate: The Footprint Study.
(Elsevier, 2020-02-06) Perea Palazón, Rosario Jesús; Morales Ruiz, Manuel; Jiménez Povedano, Wladimiro; Lasalvia, Luis; Bosch Genover, Xavier; Ortiz Pérez, José Tomás; Berruezo Sánchez, Antonio; Jáuregui Garrido, Beatriz; Soto Iglesias, David; Penela, Diego; Acosta, Juan; Fernández Armenta, Juan; Linhart, Markus; Terés Castillo, Cheryl; Syrovnev, Vladimir; Zaraket, Fatima; Hervás Durán, Vanessa; Prat González, Susanna
Objectives This study aimed to characterize the long-term scar remodeling process after an acute myocardial infarction (AMI) and the underlying scar-related arrhythmogenic substrate using serial late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). Background Little is known about the time course needed for completion of the scar healing process after an AMI, which can be assessed by noninvasive cardiac imaging techniques such as LGE-CMR. Methods Fifty-six patients with revascularized ST-segment elevation AMI (STEMI) were consecutively included. LGE-CMR (3-T) was obtained at 7 days, 6 months, and 4 years after STEMI. The myocardium was segmented into 10 layers from the endocardium to epicardium, characterizing the core, border zone (BZ), and BZ channels (BZCs) using a dedicated post-processing software. Results Mean age of the patients was 57 ± 11 years; 77% were men. Left ventricular ejection fraction improved at 6 months from 47% to 51% (p < 0.001) and remained stable at 4 years (53%; p = 0.21). Total scar mass decreased from 20.3 ± 14.6 g to 15.3 ± 13.3 g (6 months) and to 12.7 ± 11.7 g (4 years) (p < 0.001). Thirty of 56 (53%) patients showed a mean of 1.5 ± 1.3 BZCs/patient at 7 days, decreasing to 1.2 ± 1.3 (6 months) and 0.8 ± 1.0 (4 years) (p < 0.01). Only 42% of the initial BZCs remained present after 4 years. There were no arrhythmic events after a mean follow-up of 62.5 ± 7.4 months. Conclusions CMR data post-processing permitted a dynamic assessment of quantitative and qualitative post-AMI scar characteristics. Scar size and number of BZCs steadily decreased 4 years after AMI. BZC distribution was significantly modified during this time. These dynamic parameters could be reliably assessed with CMR; their evaluation might be of prognostic value.
Preclinical development of three novel CARs targeting CD79b for the treatment of non-Hodgkin's lymphoma and characterization of the loss of the target antigen.
(BMJ Publishing Group, 2024-12-18) Esquinas, Esperanza; Moreno-Sanz, Álvaro; Sandá, Víctor; Stodulski-Ciesla, Damian; Borregón, Jennifer; Peña-Blanque, Virginia; Fernández Calles, Javier; Fernandez-Fuentes, Narcís; Serrano-Lopez, Juana; Juan, Manel; Engel Rocamora, Pablo; Llamas-Sillero, Pilar; Solán-Blanco, Laura; Martin-Antonio, Beatriz
Background: Infusion of T cells modified with a chimeric antigen receptor (CAR) targeting CD19 has achieved exceptional responses in patients with non-Hodgkin's lymphoma (NHL), which led to the approval of CAR targeting CD19 (CART19) (Axi-cel and Liso-cel) as second line of treatment for adult patients with relapsed/refractory NHL. Unfortunately, 60% of patients still relapse after CART19 due to either a loss of expression of the target antigen (CD19) in the tumor cell, observed in 27% of relapsed patients, a limited CAR-T persistence, and additional mechanisms, including the suppression of the tumor microenvironment. Clinic strategies to prevent target antigen loss include sequential treatment with CARs directed at CD20 or CD22, which have caused loss of the second antigen, suggesting targeting other antigens less prone to disappear. CD79b, expressed in NHL, is a target in patients treated with antibody-drug conjugates (ADC). However, the limited efficacy of ADC suggests that a CAR therapy targeting CD79b might improve results. Methods: We designed three new CARs against CD79b termed CAR for Lymphoma (CARLY)1, 2 and 3. We compared their efficacy, phenotype, and inflammatory profiles with CART19 (ARI0001) and CARTBCMA (ARI0002h), which can treat NHL. We also analyzed the target antigen's expression loss (CD79b, CD19, and B-cell maturation antigen(BCMA)). Results: We found that CARLY2 and CARLY3 had high affinity and specificity towards CD79b on B cells. In vitro, all CAR-T cells had similar anti-NHL efficacy, which was retained in an NHL model of CD19- relapse. In vivo, CARLY3 showed the highest efficacy. Analysis of the loss of the target antigen demonstrated that CARLY cells induced CD79b and CD19 downregulation on NHL cells with concomitant trogocytosis of these antigens to T cells, being most notorious in CARLY2, which had the highest affinity towards CD79b and CD19, and supporting the selection of CARLY3 to design a new treatment for patients with NHL. Finally, we created a CAR treatment based on dual targeting of CD79b and BCMA to avoid losing the target antigen. This treatment showed the highest efficacy and did not cause loss of the target antigen. Conclusions: Based on specificity, efficacy, and loss of the target antigen, CARLY3 represents a potential novel CAR treatment for NHL.
Photoactivated adenylyl cyclase in cortical astrocytes promotes synaptic potentiation and reveals alterations in Huntington’s Disease
(Elsevier, 2025-09-24) Sitjà Roqueta, Laia; Ngum, Neville M.; Zherebstov, Evgenii; Küçükerden, Melike; Givehchi, Maryam; Bova, Valentina; Delicata, Francis; Anaya Cubero, Elena; Santamaria, Enrique; Fernández Irigoyen, Joaquín; Conde-Berriozabal, Sara; Castañé, Anna; Sokolovski, Sergei; Rafailov, Edik; Rodríguez Allué, Manuel José; Alberch i Vié, Jordi, 1959-; Dalkara, Deniz; Möglich, Andreas; Bykov,Alexander; Meglinski, Igor; Rheinallt Parri, Harri; Masana Nadal, Mercè
Coordinated neuron-astrocyte interactions are crucial for synaptic plasticity and brain function. Cyclic adenosine monophosphate (cAMP) pathways have a key role in modulating plasticity and are disrupted in neurodegenerative diseases. Yet, the role of astrocytic cAMP remains unclear. We addressed this by expressing the photoactivatable adenylyl cyclase DdPAC in cortical astrocytes, enabling cAMP synthesis under red light stimulation. Using electrophysiological and comprehensive proteomic analyses, we determined its effects in wild-type mice. The modulation of astrocytic cAMP triggered long-term synaptic potentiation and rapidly induced the phosphorylation of proteins involved in synaptic transmission, including PKA. In Huntington's Disease (HD) models, DdPAC activation in cortical astrocytes differentially enhanced brain hemodynamics and induced motor learning, while specifically increasing grooming and impairing coordination in HD mice. Thus, we reveal a mechanism of astrocyte-driven plasticity mediated by cAMP elevation and underscore the alterations in astrocytic cAMP signaling associated with HD.
MITF regulates autophagy and extracellular vesicle cargo in gastrointestinal stromal tumors
(Springer Nature, 2025-10-31) Proaño Pérez, Elizabeth; Serrano Candelas, Eva, 1982-; Guerrero, Mario; Gómez Peregrina, David; Llorens, Carlos; Soriano, Beatriz; Gámez Valero, Ana; Herrero Lorenzo, Marina; Martí, Eulalia; Serrano, César; Martín Andorrà, Margarita
The role of Microphthalmia-associated Transcription Factor (MITF) in gastrointestinal stromal tumors (GISTs) remains unclear, although previous studies suggest it contributes to tumor growth regulation. Previously, we demonstrated that MITF depletion reduces GIST cell proliferation and viability, accompanied by decreased expression of BCL-2 and CDK2. To elucidate the mechanisms underlying MITF function in GISTs, we performed chromatin immunoprecipitation and sequencing (ChIP-seq) as well as RNA sequencing. Integrated analyses revealed that MITF directly regulates genes involved in lysosome biogenesis, vesicle trafficking, autophagy, and the mTOR signaling pathway. Transcriptomic profiling following MITF silencing further demonstrated enrichment of differentially expressed genes in PI3K/ mTOR signaling, with downstream effects on tumor growth and autophagy. We next examined the functional consequences of MITF loss on mTOR inhibition-induced autophagy and on extracellular vesicle (EV) content and secretion, given their known interplay in tumor progression. MITF depletion reduced LC3-II levels and impaired autophagy flux, confirming its role in regulating autophagy in GISTs. EV size and number remained unaffected; however, silencing MITF altered EV cargo and notably decreased KIT expression in both cells and EVs. As KIT-containing EVs have been implicated in GIST invasion, these findings suggest that MITF contributes to tumor progression through coordinated regulation of autophagy and EV-mediated signaling. Collectively, our results identify MITF as a key regulator of GIST biology, highlighting its potential as a therapeutic target to limit tumor growth and metastasis.
Obese Asthma Syndrome: Multiple Inflammatory Patterns and A Key Solution
(Esmon Publicidad S.A., 2025-12-01) Bantulà, Marina; Picado Vallés, César; García, A.; Arismendi, Ebymar
Obesity frequently complicates the pathobiology, diagnosis, and management of asthma. Traditionally, obese asthma patients have been classified as presenting either early-onset obese asthma, characterized by atopy and type 2 inflammation, or late-onset, noneosinophilic, obese asthma
Variability vs. phenotype: Multimodal analysis of Dravet syndrome brain organoids powered by deep learning
(Elsevier, 2025-11-21) Lao, Oscar; Acosta, Sandra; Turpin, Isabel; Modrego, Adriana; Martí Sarrias, Andrea; Ortega Gascó, Alba; Haeb, Anna-Christina; García González, Laura; Soriano i Fradera, Jordi; Ruiz, Núria; Peñuelas Haro, Irene; Espinet, Elisa; Tornero, Daniel
Dravet syndrome (DS) is a developmental epileptic encephalopathy (DEE) driven by pathogenic variants in the SCN1A gene. Brain organoids (BOs) have emerged as reliable models for neurodevelopmental genetic disorders, reproducing human brain developmental milestones and rising as a promising drug testing tool. Here, we determined the underlying molecular DS pathophysiology affecting neuronal connectivity, revealing an early onset excitatory-inhibitory imbalance in maturing DS organoid circuitry. However, neuronal circuitry modeling in BOs remains hampered by the notorious inter- and intra-organoid variability. Thus, leveraging deep learning (DL), we developed ImPheNet, a predictive tool grounded in BO live imaging datasets, to overcome the limitations of the intrinsic BOs variability. ImPheNet accurately classified healthy and DS phenotypes at early onset stages, revealing differences between genotypes and upon antiseizure drug exposure. Altogether, our DL-predictive live imaging strategy, ImPheNet, emerges as a powerful tool to accelerate DEEs research and advance toward treatment discovery in a time- and cost-efficient manner.
Neuropilin-2 upregulation by stromal TGFβ1 induces lung disseminated tumor cells dormancy escape and promotes metastasis outgrowth
(Elsevier, 2025-10-01) Recalde Percaz, Leire; de la Guía López, Inés; Linzoain-Agos, Paula; Noguera Castells, Aleix; Rodrigo-Faus, María; Jauregui, Patricia; López Plana, Anna; Fernández Nogueira, Patricia; Iniesta-González, Minerva; Cueto-Remacha, Mateo; Manzano, Sara; Alonso, Rodrigo; Moragas, Núria; Baquero, Cristina; Palao, Nerea; Dalla, Erica; Avilés Jurado, Francesc Xavier; Vilaseca González, Isabel; Leon Vintro, Xavier; Camacho, Mercedes; Fuster Orellana, Gemma; Alcaraz Casademunt, Jordi; Aguirre-Ghiso, Julio; Gascón, Pere; Porras, Almudena; Gutiérrez-Uzquiza, Álvaro; Carbó Carbó, Neus; Bragado Domingo, Paloma
Metastasis is the main cause of death from solid tumors. Therefore, identifying the mechanisms that govern metastatic growth poses a major biomedical challenge. Tumor microenvironment signals regulate the fate and survival of disseminated tumor cells (DTCs) in secondary organs. However, very little is known about the role of nervous system mediators in this process. We have previously reported that neuropilin-2 (NRP2) expression in breast cancer correlates with poor prognosis. Here, we show that NRP2 positively regulates the proliferation, invasion, and survival of breast and head and neck cancer cells in vitro. NRP2 deletion in tumor cells inhibits tumor growth in vivo and decreases the number and size of lung metastases by promoting lung DTCs quiescence. NRP2 deletion upregulates dormancy and cell cycle regulators expression and promotes DTCs reprograming into quiescence. Moreover, lung fibroblasts and macrophages induce NRP2 upregulation in DTCs through the secretion of TGFβ1. NRP2 facilitates lung DTC interaction with the extracellular matrix and promotes lung DTCs activation and metastasis. Therefore, we conclude that the TGFβ1-NRP2 axis is a new key dormancy-awakening inducer that promotes DTCs proliferation and lung metastasis development.
Mediterranean Diet Pattern: Potential Impact on the Different Altered Pathways Related to Cardiovascular Risk in Advanced Chronic Kidney Disease
(MDPI, 2024-10-31) Rovira, Jordi; Ramírez Bajo, María José; Bañón Maneus, Elisenda; Ventura Aguiar, Pedro; Arias Guillén, Marta; Romano Andrioni, Bárbara; Ojeda, Raquel; Revuelta, Ignacio; García Calderó, Héctor; Barberà i Mir, Joan Albert; Dantas, Ana Paula; Diaz Ricart, M. Isabel; Crispi Brillas, Fàtima; García Pagán, Juan Carlos; Campistol Plana, Josep M.; Diekmann, Fritz
Background: Cardiovascular disease (CVD) remains the most common cause of mortality in chronic kidney disease (CKD) patients. Several studies suggest that the Mediterranean diet reduces the risk of CVD due to its influence on endothelial function, inflammation, lipid profile, and blood pressure. Integrating metabolomic and proteomic analyses of CKD could provide insights into the pathways involved in uremia-induced CVD and those pathways modifiable by the Mediterranean diet. Methods: We performed metabolomic and proteomic analyses on serum samples from 19 patients with advanced CKD (aCKD) and 27 healthy volunteers. The metabolites were quantified using four different approaches, based on their properties. Proteomic analysis was performed after depletion of seven abundant serum proteins (Albumin, IgG, antitrypsin, IgA, transferrin, haptoglobin, and fibrinogen). Integrative analysis was performed using MetaboAnalyst 4.0 and STRING 11.0 software to identify the dysregulated pathways and biomarkers. Results: A total of 135 metabolites and 75 proteins were differentially expressed in aCKD patients, compared to the controls. Pathway enrichment analysis showed significant alterations in the innate immune system pathways, including complement, coagulation, and neutrophil degranulation, along with disrupted linoleic acid and cholesterol metabolism. Additionally, certain key metabolites and proteins were altered in aCKD patients, such as glutathione peroxidase 3, carnitine, homocitrulline, 3-methylhistidine, and several amino acids and derivatives. Conclusions: Our findings reveal significant dysregulation of the serum metabolome and proteome in aCKD, particularly in those pathways associated with endothelial dysfunction and CVD. These results suggest that CVD prevention in CKD may benefit from a multifaceted approach, including dietary interventions such as the Mediterranean diet.

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