Articles publicats en revistes (Biomedicina)

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RAB5A Promotes Active Fluid Wetting by Reprogramming Breast Cancer Spheroid Mechanics
(Wiley-VCH Verlag, 2025-09-11) Barnett, Samuel F.H.; Cartagena-Rivera, Alexander X.; Selhuber-Unkel, Christine; Prevedel, Robert; Trepat Guixer, Xavier; Spatz, Joachim P.; Ivaska, Johanna; Scita, Giorgio; Cavalcanti-Adam, Elisabetta A.; Lemahieu, Grégoire; Moreno-Layseca, Paulina; Hub, Tobias; Bevilacqua, Carlo; Gómez González, Manuel; Pennarola, Federica; Colombo, Ferran; Massey, Andrew E.; Barzaghi, Leonardo; Palamidessi, Andrea; Homagk, Leon-Luca
Unjamming transitions from a solid-like to a fluid-like state are a gateway to breast epithelial cancer invasion. However, the mechanical interplay between phase transitions and dimension transitions, in particular wetting, remains elusive, despite being critical for understanding the onset of metastatic dissemination. This study shows that unjamming, mediated by the RAB5A GTPase, alters carcinoma spheroid fluidity, rigidity, and rewires adhesion mechanics to drive supracellular active wetting as a new mode of tumor expansion. Spheroid fluidification enhances the selective expression of integrin subunits and increases focal adhesion dynamics, inducing a fluid-like spreading behavior on specific matrix ligands. Notably, nanoscale regulation of integrin clustering can select for distinct phase transitions at the collective scale upon wetting. In this framework, fluidized spheroids polarize into cohesive “supracells”, and maintain a stiff peripheral actin bundle as measured by nanomechanical mapping. Furthermore, a combination of Brillouin microscopy and 2.5D traction force analysis reveals a mechanical switch within the spheroid core, characterized by significant cell softening and a reduction in compressive forces exerted on the substrate, thereby mimicking the wetting of a liquid droplet. These findings establish unjamming-driven active wetting as a key mechanism to comprehend the molecular and biophysical underpinnings of solid tumor invasion.
Pre-COPD: an evolving concept with practice potential
(Elsevier Ltd., 2025-07-31) Bui, Dinh S.; Faner, Rosa; Washko, George; Jenkins, Christine; Walters, Eugene Haydn; Dharmage, Shyamali C.
COPD is the third leading cause of death globally and remains a major public health burden. Despite its substantial impact, effective prevention remains challenging. COPD is currently defined as having FEV₁/FVC below lower limit of normal or 0.7 in a person with known risk factors. However, this formal diagnosis occurs only after significant loss of lung function and the onset of persistent symptoms. These symptoms, rather than pathophysiological changes, are what typically prompt patients to seek medical care. Even then, many are not offered spirometry, further delaying diagnosis until acute exacerbations or a level of dyspnoea that impacts daily life prompt clinical attention. By this point, more than 50% of individual’s FEV₁ has often been lost and treatment becomes largely palliative. This situation highlights a pressing need for earlier identification of lung damage associated to a later diagnosis of COPD; this is needed in its early “silent” phase, when there might be an opportunity to change the course of disease with preventive interventions.
Metabolomic signatures predict seven-year mortality in clinically stable COPD patients
(MDPI, 2025-07-02) Enríquez Rodríguez, Cesar Jesse; Agranovich, Bella; Pascual Guàrdia, Sergi; Faner, Rosa; Camps Ubach, Ramon; Castro Acosta, Ady Angélica; López Campos, José Luis; Peces Barba, Germán; Seijo Maceiras, Luis Miguel; Caguana, Oswaldo Antonio; Rodríguez Chiaradia, Diego Agustín; Barreiro, Esther; Monsó, Eduard; Cosío, Borja G.; Abramovich, Ifat; Agustí García-Navarro, Àlvar; Casadevall, Carme; Gea Guiral, Joaquim; BIOMEPOC Group
Chronic Obstructive Pulmonary Disease (COPD) is a complex condition with high mortality. Early identification of patients at increased risk of death remains a major clinical challenge. This pilot study aimed to explore whether plasma metabolomic profiling could aid in the prediction of long-term (7-year) mortality and provide insight into potential underlying mechanisms. Plasma samples from 54 randomly selected stable COPD patients were analyzed using both untargeted and semi-targeted LC-MS approaches. After excluding patients with unclear death data, non-COPD-related deaths and metabolomic outliers, 41 individuals were included in the final analysis. During follow-up, 13 patients (32%) died, and 28 survived. Univariate analysis identified 12 metabolites—mainly amino acids—that differed significantly between the two groups. Functional analysis suggested a significant disruption in energy production pathways. Predictive models developed using machine learning algorithms, consisting of either ten metabolites alone or nine metabolites plus FEV1, achieved high accuracy for 7-year mortality prediction, with the latter model performing slightly better. Internal validation was conducted using five-fold cross-validation. While exploratory, these findings support the hypothesis that early metabolic alterations, particularly in energy pathways, may contribute to long-term mortality risk in stable COPD patients, and could complement traditional prognostic markers such as FEV1.
Assessment of novel sonographic and biochemical tools for spontaneous preterm birth prediction in asymptomatic twin pregnancies
(Munksgaard, 2025-06-01) Ponce, Júlia; Cobo, Teresa; Murillo Bravo, Clara; Goncé Mellgren, Anna; Sánchez García, Ana B.; Dantas, Ana Paula; Coronado Gutiérrez, David; Crovetto, Francesca; Guirado, Laura; Bruch, Judit; Gratacós Solsona, Eduard; Palacio, Montse; Bennasar Sans, Mª del Mar
Introduction Prematurity is a major global health issue. Twin pregnancies are a group at especially high risk of preterm birth. Sonographic mid-trimester cervical length has limited accuracy in predicting preterm birth. This study aimed to evaluate the association between mid-trimester sonographic markers of early cervical remodeling and cervical inflammatory biomarkers and fetal fibronectin, alone or in combination, as predictors of preterm birth before 34+0 weeks in asymptomatic twin pregnancies. Material and Methods Prospective cohort study, including uncomplicated dichorionic or monochorionic-diamniotic twin pregnancies, recruited and assessed between 18+0 and 24+6 weeks, from a single tertiary referral center between 2020 and 2023. At inclusion, transvaginal ultrasound was performed to assess the following sonographic markers (cervical length, uterocervical angle, cervical consistency index, cervical texture) and an endocervical sample was obtained prior to ultrasound to quantify the following cervical inflammatory biomarkers (tumor necrosis factor alpha, interleukins 1b, 6, 8, 18, matrix metalloproteinase-8 and 9) and fetal fibronectin. The diagnostic performance of those sonographic and biochemical markers independently associated with spontaneous preterm birth before 34 weeks was analyzed by receiver operating characteristic curves and assessed through sensitivity and specificity analysis for several cutoffs. Results Of the 172 women included, cervical length was shorter (36 mm vs. 40 mm; p = 0.025) and uterocervical angle was wider (137° vs. 120°; p = 0.004) in the preterm group. Cervical consistency index, cervical texture score, cervical inflammatory biomarkers, and fetal fibronectin were similar among the study groups. The area under the curve to predict spontaneous preterm birth before 34+0 weeks was 0.722 (95% CI 0.577 to 0.866) for cervical length, 0.789 (95% CI 0.683 to 0.895) for uterocervical angle, and 0.852 (95% CI 0.752 to 0.952) for a combination of both. Based on the receiver operating characteristics curve cutoff, sensitivity and specificity for cervical length ≤37 mm was 55.6% and 66.3%, for an uterocervical angle ≥135° was 77.8% and 76.1%, and for both criteria present 44.4% and 93.3%, respectively. Conclusions This finding of this study suggests that the combination of cervical length and uterocervical angle in mid-trimester sonographic assessment may improve the prediction of preterm birth before 34 weeks in asymptomatic and uncomplicated twin pregnancies.
Airflow obstruction among young adults in Europe: a Chronic Airway Diseases Early Stratification (CADSET) collaboration with 48 612 individuals across eight population-based cohorts
(European Respiratory Society, 2025-11) Çolak, Yunus; Allinson, James P.; Berge, Maarten van den; Jarvis, Debbie; Langhammer, Arnulf; Breyer-Kohansal, Robab; Nwaru, Bright I.; Backman, Helena; Vonk, Judith M.; Nordestgaard, Børge G.; Lange, Peter; Aalberg Vikjord, Sigrid Anna; Breyer, Marie Kathrin; Kankaanranta, Hannu; Lindberg, Anne; Rönmark, Eva; Vanfleteren, Lowie E. G. W.; Vestbo, Jørgen; Wedzicha, Jadwiga A.; Melén, Erik; Agustí García-Navarro, Àlvar; Faner, Rosa; Afzal, Shoaib; CADSET ERS Clinical Research Collaboration
Background The extent to which airflow obstruction, a key feature of COPD, can be already present in early adulthood is unclear. We investigated the prevalence of airflow obstruction in young adults across European populations. Methods We identified 48 612 individuals aged 20–40 years across eight population-based European cohorts in the Chronic Airway Diseases Early Stratification (CADSET) collaboration and applied two commonly used definitions of airflow obstruction: pre-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.70 and below the lower limit of normal (LLN). We explored how the prevalence of airflow obstruction according to both criteria was related to age, sex and smoking. Results Airflow obstruction prevalence increased with increasing age from 2.3% in those aged 20–24.9 years to 6.3% in those aged 35–39.9 years according to FEV1/FVC <0.70, and from 7.3% to 8.3% according to FEV1/FVC
Transient platelet hyporesponsiveness in non-ischemic arrhythmogenic cardiac arrest after achieving restoration of spontaneous circulation in pigs.
(Georg Thieme Verlag, 2026-02-20) Magaldi, Marta; Giron, Gabriela O.; Radike, Monika; Ramos-Regalado, Lisaidy; Alcover, Sebastia; Otero, Sergi; Catalina, Pablo; Canovas, Maria Angeles; Vendrell, Marina; Dantas, Ana Paula; Gorog, Diana Adrienne; Padro, Teresa; Borrell, Maria; Badimon, Lina; Peray Bruel, Claudia de; Vilahur, Gemma
This study shows that variable and often attenuated platelet reactivity after CA, together with neutral OHCA outcome data argues against indiscriminate antiplatelet loading before the cause of shock is clarified. For ambiguous prehospital cardiogenic shock, initial management should prioritize early coronary angiography and comprehensive shock care, reserving full antiplatelet loading for those in whom AMI is confirmed or strongly suspected per local protocols.
Geometry-driven migration efficiency of autonomous epithelial cell clusters
(Nature Publishing Group, 2024-09-01) Vercurysse, Eléonore; Brückner, David B.; Gómez González, Manuel; Remson, Alexandre; Luciano, Marine; Kalukula, Yohalie; Rossetti, Leone; Trepat Guixer, Xavier; Hannezo, Edouard; Gabriele, Sylvain
The directed migration of epithelial cell collectives through coordinated movements plays a crucial role in various physiological processes and is increasingly understood at the level of large confluent monolayers. However, numerous processes rely on the migration of small groups of polarized epithelial clusters in complex environments, and their responses to external geometries remain poorly understood. To address this, we cultivate primary epithelial keratocyte tissues on adhesive microstripes to create autonomous epithelial clusters with well-defined geometries. We show that their migration efficiency is strongly influenced by the contact geometry and the orientation of cell–cell contacts with respect to the direction of migration. A combination of velocity and polarity alignment with contact regulation of locomotion in an active matter model captures quantitatively the experimental data. Furthermore, we predict that this combination of rules enables efficient navigation in complex geometries, which we confirm experimentally. Altogether, our findings provide a conceptual framework for extracting the interaction rules of active systems from their interaction with physical boundaries, as well as design principles for collective navigation in complex microenvironments.
Human LY9 governs CD4+ T cell IFN-γ immunity to Mycobacterium tuberculosis
(American Association for the Advancement of Science, 2025-05-30) Ogishi, Masato; Puchan, Julia; Yang, Rui; Arias, Andrés Augusto; Han, Ji Eun; Nguyen, Tina; Gutiérrez Cózar, Rebeca; Conil, Clément; Seeleuthner, Yoann; Rinchai, Darawan; Zhang, Peng; Ponsin, Khoren; Chaldebas, Matthieu; Feng, Yi; Neehus, Anna-Lena; Delmonte, Ottavia M.; Khan, Taushif; Landegren, Nils; Eriksson, Daniel; Bohlen, Jonathan; Peel, Jessica N.; Fagniez, Iris; Pelham, Simon J.; Lei, Wei-Te; Chrabieh, Maya; Laine, Candice; Ouair, Hind; Benhsaien, Ibtihal; Abid, Ahmed; Ghorfi, Ismail Abderrhamani; Souhi, Hicham; Ouazzani, Hanane; Aniss, Rafik; Riminton, D. Sean; Kämpe, Olle; Turvey, Stuart E.; Marr, Nico; Notarangelo, Luigi D.; Hatipoglu, Nevin; Bousfiha, Aziz; Ozcelik, Tayfun; El Baghdadi, Jamila; Cobat, Aurelie; Ma, Cindy S.; Abel, Laurent; Puel, Anne; Bustamante, Jacinta; Engel Rocamora, Pablo; Gros, Philippe; Tangye, Stuart G.; Sallusto, Federica; Boisson-Dupuis, Stéphanie; Casanova, Jean-Laurent
CD4+ T cells are indispensable for optimal immunity to Mycobacterium tuberculosis (M.tb), a pathogen that triggers tuberculosis (TB) in humans. M.tb-specific human CD4+ T cells are known to polarize toward an interferon-γ (IFN-γ)-producing, CCR4-CCR6+CXCR3+T-bet+RORγT+ T helper 1* cell (TH1*cell) memory phenotype. We report that autosomal recessive deficiency of the human lymphocytic surface receptor LY9 (SLAMF3 and CD229), which is found in less than 10-5 individuals in the general population, underlies TB in three unrelated patients due to selective impairment in IFN-γ production by TH1* cells. TH1* cells express higher levels of LY9 than other CD4+ T cells. Mechanistically, LY9 polarizes naïve CD4+ T cells toward memory TH1* cells by inducing T-bet via signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) and RORγT (thymus-specific retinoid-related orphan receptor γ) without SAP. LY9 costimulation enhances TCR-driven IFN-γ production of memory TH1*, but not TH1, cells in a T cell-intrinsic manner via NFAT1 (nuclear factor of activated T cells 1) and RORγT. LY9 is likely to govern an optimal TH1* cell- and IFN-γ-dependent protective immunity to M.tb in humans.
CAR-T cells targeting CCR9 and CD1a for the treatment of T cell acute lymphoblastic leukemia.
(BioMed Central, 2025-07-01) Tirado, Néstor; Fidyt, Klaudyna; Mansilla, María José; Garcia-Perez, Alba; Martínez-Moreno, Alba; Vinyoles, Meritxell; Alcain, Juan; García-Peydró, Marina; Roca-Ho, Heleia; Fernandez-Fuentes, Narcís; Guerrero-Murillo, Mercedes; Falgàs, Aïda; Velasco-Hernandez, Talia; Bueno, Clara; Panelli, Patrizio; Mulens-Arias, Vladimir; Apostolov, Apostol; Engel Rocamora, Pablo; González Navarro, Europa Azucena; Vick, Binje; Jeremias, Irmela; Caye-Eude, Aurélie; Baruchel, André; Cavé, Hélène; Genescà, Eulàlia; Ribera, Jordi; Díaz Beyà, Marina; Martínez-Sánchez, María Victoria; Fuster, José Luis; Escudero López, Adela; Minguillón, Jordi; Pérez-Martínez, Antonio; Ramírez-Orellana, Manuel; Torrebadell, Montserrat; Díaz, Víctor M.; Toribio, María L.; Sánchez-Martínez, Diego; Menéndez Buján, Pablo
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy characterized by high rates of induction failure and relapse, and effective targeted immunotherapies are lacking. Despite promising clinical progress with genome-edited CD7-directed CAR-T cells, which present significant logistical and regulatory issues, CAR-T cell therapy in T-ALL remains challenging due to the shared antigen expression between malignant and healthy T cells. This can result in CAR-T cell fratricide, T cell aplasia, and the potential for blast contamination during CAR-T cell manufacturing. Recently described CAR-T cells target non-pan-T antigens, absent on healthy T cells but expressed on specific T-ALL subsets. These antigens include CD1a (NCT05679895), which is expressed in cortical T-ALL, and CCR9. We show that CCR9 is expressed on >70% of T-ALL patients (132/180) and is maintained at relapse, with a safe expression profile in healthy hematopoietic and non-hematopoietic tissues. Further analyses showed that dual targeting of CCR9 and CD1a could benefit T-ALL patients with a greater blast coverage than single CAR-T cell treatments. We therefore developed, characterized, and preclinically validated a novel humanized CCR9-specific CAR with robust and specific antileukemic activity as a monotherapy in vitro and in vivo against cell lines, primary T-ALL samples, and patientderived xenografts. Importantly, CCR9/CD1a dual-targeting CAR-T cells showed higher efficacy than single-targeting CAR-T cells, particularly in T-ALL cases with phenotypically heterogeneous leukemic populations. Dual CD1a/CCR9 CAR-T therapy may prevent T cell aplasia and obviate the need for allogeneic transplantation and regulatory-challenging genome engineering approaches in T-ALL.
Cell Differentiation Molecules (HCDM) organization. CD Molecules Nomenclature 2025: Antibody Validation and Expression Profiling of Immune System G Protein-Coupled Receptors.
(Wiley-VCH, 2025-12-09) Fernández Calles, Javier; Kuzilkova, Daniela; Hedin, Fanny; Bakardjieva Mihaylova, Violeta; Škvárová Kramarzová, Karolina; Zelm, Menno C. van; Cosma, Antonio; Kalina, Tomas; Engel Rocamora, Pablo
Monoclonal antibodies (mAbs) targeting cell-surface molecules are pivotal in biomedical research, diagnostic applications, and biotechnology. Over the past four decades, the CD nomenclature system, established by the Human Leukocyte Differentiation Antigens Workshops and endorsed by the International Union of Immunological Societies (IUIS), has provided a standardized naming convention for both mAbs and the cell surface molecules they target. G protein-coupled receptors (GPCRs) represent the largest family of cell-surface receptors, playing essential roles in both innate and adaptive immune responses. Despite their significance, GPCRs are underrepresented in terms of well-validated mAbs available for flow cytometry and therapeutic applications. At the Eleventh HLDA Workshop (HLDA11), new CD nomenclature has been assigned to thirteen GPCR cell-surface molecules expressed on immune cells: CD198 (CCR8), CD199 (CCR9), CD372 (CCR10), CD373 (CX3CR1), CD374 (XCR1), CD375 (GPR15), CDw376 (GPR26), CD377 (SSTR3), CD378 (C3AR1), CDw379 (FPR2), CD380 (LTB4R), CDw381 (GPR183), and CDw382 (F2RL1). In this article, we introduce the newly established CD nomenclature for mAbs targeting the GPCR family. We detail the quantitative expression profiles of these molecules on various subsets of leukocytes and provide validation data for these mAbs. The implications of these expression profiles are discussed for the potential therapeutic targeting of immune-mediated diseases and cancer.
General population-based lung function trajectories over the life course: an accelerated cohort study
(Elsevier Ltd., 2025-07-01) Torrent, Maties; Vicendese, Don; Vonk, Judith M.; Vries, Maaike de; Walters, Eugene H.; Wang, Gang; Wedzicha, Jadwiga A.; Jarvis, Deborah; Faner, Rosa; Gislason, Thorarinn; Granell, Raquel; Imboden, Medea; Íñiguez, Carmen; Jeong, Ayoung; Koch, Sarah; Koppelman, Gerard H.; Leynaert, Bénédicte; Melén, Erik; Perret, Jennifer; García Aymerich, Judith; Heras, Martí de las; Carsin, Anne Elie; Accordini, Simone; Agustí García-Navarro, Àlvar; Bui, Dinh S.; Dharmage, Shyamali C.; Dodd, James W.; Eze, Ikenna; Gehring, Ulrike; Probst-Hensch, Nicole M.; Santa Marina, Loreto
Background Lung function is a key determinant of health, but current knowledge on lung function growth and decline over the life course is based on fragmented, potentially biased data. We aimed to empirically derive general population-based life course lung function trajectories, and to identify breakpoints and plateaus. Methods We created an accelerated cohort by pooling data from eight general population-based child and adult cohort studies from Europe and Australia. We included all participants with information on lung function, smoking status, BMI, and asthma diagnosis status from at least two visits. We used cross-classified three-level linear mixed models to derive sex-specific life course trajectories of FEV1, forced vital capacity (FVC), and FEV1/FVC ratio based on observations at ages 4–80 years, and Bayesian time-series decomposition to identify breakpoints and plateaus. We repeated sex-specific analyses with separate stratification for asthma status (never had asthma vs persistent asthma, where persistent was defined as the risk factor being present at all participant visits) and smoking status (never smoker vs persistent smoker). Findings The accelerated cohort included 30 438 participants born between 1901 and 2006 (15 703 [51·6%] female and 14 735 [48·4%] male; mean age 26 [SD 16] years), who provided a total of 87 666 observations (range 2–8 observations per participant). In female participants, FEV1 increased non-linearly in two phases, at a mean of 234 (95% CI 223 to 245) mL/year until age 13 (95% credible interval [CrI] 12 to 15) years, then at 99 (76 to 122) mL/year until a peak at age 20 (18 to 22) years, and subsequently decreased throughout the rest of adulthood (−26 [−27 to −25] mL/year). In male participants, the pattern was similar, with an increase in FEV1 of 271 (263 to 280) mL/year until age 16 (14 to 18) years, which slowed to 108 (93 to 124) mL/year until reaching a maximum at age 23 (21 to 25) years, decreasing thereafter (−38 [−39 to −37] mL/year), representing a later peak than in female participants. In female participants, FVC increased non-linearly in two phases, at 232 (95% CI 222 to 243) mL/year until age 14 (95% CrI 12 to 15) years, then at 77 (59 to 94) mL/year until peaking at age 20 (19 to 22) years, after which it decreased throughout the rest of adulthood (−26 [−27 to −25] mL/year). In male participants, FVC also increased in two phases, at 326 (315 to 337) mL/year until age 15 (13 to 17) years, then at 156 (144 to 168) mL/year until a peak at 23 (19 to 30) years, and subsequently declined in two phases (−22 [−29 to −14] mL/year until age 42 [38 to 50] years, then −36 [−38 to −34] mL/year thereafter). No plateau after the peak was observed for either lung function parameter in both sexes. FEV1/FVC ratio decreased throughout life from the starting age of 4 years in both sexes with some distinct patterns. Stratified analysis showed that persistent asthma (vs never had asthma) was related to an earlier FEV1 peak, lower FEV1 throughout adulthood, and lower FEV1/FVC ratio across the life course in both sexes. Persistent smoking (vs never smoking) was related to an accelerated decrease in FEV1 and FEV1/FVC ratio during adulthood in both sexes. No statistically significant plateau was observed in any lung function parameter across the strata of asthma or smoking status. Interpretation In both sexes, FEV1 and FVC increased in two phases, with a fast increase until around age 13–16 years, and then a slower increase until a peak. Neither parameter showed a plateau phase after the peak, and decreases started earlier than previously described. FEV1/FVC ratio decreased throughout life. These observations provide an essential, but previously unavailable, framework to assess and monitor lung health over the life course.
SARS-CoV-2 seroprevalence and preeclampsia markers in Mozambican pregnant women with perinatal loss.
(BioMed Central, 2024-09-19) Chileshe, Maureen; Nhampossa, Tacilta; Carrilho Carla; Mendes, Anete; Luis, Elvira; Sacarlal, Jahit; Navero Castillejos, Jessica; Morales Ruiz, Manuel; Martínez Yoldi, Miguel Julián; Ordi i Majà, Jaume; Rakislova, Natalia; Menéndez, Clara; González Álvarez, Raquel
Background SARS-CoV-2 infection during pregnancy is known to be associated with poor pregnancy outcomes, including pre-eclampsia (PE), prematurity, perinatal and maternal mortality. Data on the burden of SARS-CoV-2 infection among pregnant women and their offspring in Sub-Saharan Africa is limited. We aimed to estimate SARS-CoV-2 seroprevalence and determine PE biomarkers in Mozambican pregnant women with perinatal loss. Methods A cross-sectional study was conducted among women who had a fetal or an early neonatal death at the Maputo Central Hospital (MCH), Mozambique. Anti-SARS-CoV-2 IgG/IgM were determined in maternal and umbilical cord blood and PE biomarkers (sFlt-1 and PIGF) in maternal blood. SARS-CoV-2 RT-PCR was performed in placenta and fetal lung biopsies from participants found to be SARS-CoV-2 seropositive. Results A total of 100 COVID-19 unvaccinated women were included in the study from March 2021 to April 2022. Total SARS-CoV-2 antibodies were detected in 68 [68%; 95CI (58 – 76)] maternal and 55 [55%; 95CI (54 – 74)] cord blood samples. SARS-CoV-2 IgM was detected in 18 cord blood samples and a positive placental RT-PCR in three of these participants. The proportion of women with moderate to high sFlt-1/PIGF ratio was higher in SARS-CoV-2 seropositive women than in those seronegative (71.2% vs 28.8%, p = 0.339), although the difference was not statistically significant. Conclusions SARS-CoV-2 seroprevalence among Mozambican women with perinatal loss was high during the second pandemic year, and there was evidence of vertical transmission in stillbirths. Findings also suggest that maternal SARS-CoV-2 infection may increase the risk of developing PE.
Expansion of the neocortex and protection from neurodegeneration by in vivo transient reprogramming
(Elsevier B.V., 2024-12-05) Shen, Yi Ru; Zaballa Larrinaga, Sofía; Bech, Xavier; Sancho Balsells, Anna; Rodriguez Navarro, Irene; Cifuentes Díaz, Carmen; Seyit Bremer, Gönül; Chun, Seung Hee; Straub, Tobias; Abante Llenas, Jordi; Merino Valverde, Iñaki; Richart, Laia; Gupta, Vipul; Li, Hao Yi; Ballasch, Iván; Alcazar, Noelia; Alberch i Vié, Jordi, 1959-; Canals i Coll, Josep M.; Abad, María; Serrano, Manuel; Klein, Rüdiger; Giralt Torroella, Albert; Toro Ruiz, Daniel del
Yamanaka factors (YFs) can reverse some aging features in mammalian tissues, but their effects on the brain remain largely unexplored. Here, we induced YFs in the mouse brain in a controlled spatiotemporal manner in two different scenarios: brain development and adult stages in the context of neurodegeneration. Embryonic induction of YFs perturbed cell identity of both progenitors and neurons, but transient and low-level expression is tolerated by these cells. Under these conditions, YF induction led to progenitor expansion, an increased number of upper cortical neurons and glia, and enhanced motor and social behavior in adult mice. Additionally, controlled YF induction is tolerated by principal neurons in the adult dorsal hippocampus and prevented the development of several hallmarks of Alzheimer’s disease, including cognitive decline and altered molecular signatures, in the 5xFAD mouse model. These results highlight the powerful impact of YFs on neural proliferation and their potential use in brain disorders.
Characterisation of the gut-lung axis microbiome in clinically stable patients with chronic obstructive pulmonary disease.
(Elsevier, 2026-01-07) Viglino, Julieta; Perea Soriano, Lídia; García Nuñez, Marian; Rodrigo-Troyano, Ana; Torrego, Alfons; Domínguez Álvarez, Marisol; Villar, Judith; Carrizosa Gueri, Xènia; Quero Blanca, Sara; Gabaldón Estevan, Juan Antonio, 1973-; Willis, Jesse R.; Saus, Ester; Gea Guiral, Joaquim; Santos Pérez, Salud; Camps Massa, Paula; Agustí García-Navarro, Àlvar; Monsó, Eduard; Sibila Vidal, Oriol; Faner, Rosa
Background Airway and gut dysbiosis have been reported in Chronic Obstructive Pulmonary Disease (COPD); however, their relationship and association with clinical features remain poorly understood. We aimed to characterise the lung and gut microbiome in patients with stable COPD and controls. Methods Prospective, multicentre, longitudinal and controlled study of n = 60 stable patients with COPD and n = 30 controls. In them, we analysed 16S rRNA-seq in oropharyngeal (OP) swabs, sputum, bronchoalveolar lavage fluid (BALF) and stool. Weighted gene co-expression network analysis (WGCNA) was employed in each sample type to identify modules of co-abundant bacteria associated with clinical traits. Findings We found that the microbiome in airway and stool samples was highly dissimilar both in patients and controls, with 0.37% of this diversity associated to COPD. The microbiome taxa associated with COPD in OP swabs and sputum were highly similar, but different from BALF, suggesting that OP swabs can be a surrogate sample of sputum. Finally, using WGCNA, we identified: (a) 5 modules in OP swabs and 3 in sputum associated with FEV1, but some of them were also associated with exacerbations, dyspnoea and inhaled steroid (ICS) use; (b) In BALF 4 modules associated with FEV1 and dyspnoea, and 2 modules with ICS; and, finally, (c) in stool, 1 module related to FEV1, 1 to exacerbations and 3 with ICS. Interpretation The gut and lung microbiomes in patients with COPD are distinct, but both clinically relevant as both present bacterial associations with airflow limitation, exacerbation history, and ICS use.
Alterations of the IKZF1-IKZF2 tandem in immune cells of schizophrenia patients regulate associated phenotypes
(BioMed Central, 2024-12-18) Ballasch, Iván; López Molina, Laura; Galán Ganga, Marcos; Sancho Balsells, Anna; Rodriguez Navarro, Irene; Borràs Pernas, Sara; Rabadán Lozano, M. Ángeles; Chen, Wanqi; Pastó Pellicer, Carlota; Flotta, Francesca; Maoyu, Wang; Fernández Irigoyen, Joaquín; Santamaría Martínez, Enrique; Aguilar, Ruth; Dobaño, Carlota, 1969-; Egri, Natalia; Hernández, Carla; Alfonso, Miqueu; Juan, Manel; Alberch i Vié, Jordi, 1959-; Toro Ruiz, Daniel del; Arranz, Belén; Canals i Coll, Josep M.; Giralt Torroella, Albert
Schizophrenia is a complex multifactorial disorder and increasing evidence suggests the involvement of immune dysregulations in its pathogenesis. We observed that IKZF1 and IKZF2, classic immune-related transcription factors (TFs), were both downregulated in patients’ peripheral blood mononuclear cells (PBMCs) but not in their brain. We generated a new mutant mouse model with a reduction in Ikzf1 and Ikzf2 to study the impact of those changes. Such mice developed deficits in the three dimensions (positive–negative-cognitive) of schizophrenia-like phenotypes associated with alterations in structural synaptic plasticity. We then studied the secretomes of cultured PBMCs obtained from patients and identified potentially secreted molecules, which depended on IKZF1 and IKZF2 mRNA levels, and that in turn have an impact on neural synchrony, structural synaptic plasticity and schizophrenia-like symptoms in in vivo and in vitro models. Our results point out that IKZF1-IKZF2-dependent immune signals negatively impact on essential neural circuits involved in schizophrenia.
Human microglia-like cells differentiated from monocytes with GM-CSF and IL-34 show phagocytosis of α-synuclein aggregates and C/EBPβ-dependent proinflammatory activation
(Springer Nature, 2025-02) Llaves López, Andrea; Micoli, Elia; Belmonte Mateos, Carla; Aguilar, Gerard; Alba, Clara; Marsal, Anais; Pulido Salgado, Marta; Rabaneda Lombarte, Neus; Solà i Subirana, Carme; Serratosa i Serdà, Joan; Vidal Taboada, José Manuel; Saura Martí, Josep
Microglia, the main resident immune cells in the central nervous system, are implicated in the pathogenesis of various neurological disorders. Much of our knowledge on microglial biology was obtained using rodent microglial cultures. To understand the role of microglia in human disease, reliable in vitro models of human microglia are necessary. Monocyte-derived microglia-like cells (MDMi) are a promising approach. This study aimed to characterize MDMi cells generated from adult human monocytes using granulocyte–macrophage colony-stimulating factor and interleukin-34. To this end, 49 independent cultures of MDMI were prepared, and various methodological and functional studies were performed. We show that with this protocol, adult human monocytes develop into microglia-like cells, a coating is unnecessary, and high cell density seeding is preferable. When compared to monocytes, MDMi upregulate the expression of many, but not all, microglial markers, indicating that, although these cells display a microglia-like phenotype, they cannot be considered bona fide human microglia. At the functional level, MDMi phagocytose α-synuclein aggregates and responds to lipopolysaccharide (LPS) by nuclear translocation of the transcription factor nuclear factor-kappaB (NFkappaB) and the upregulation of proinflammatory genes. Finally, a long-lasting silencing of the transcription factor CCAAT/enhancer protein β (C/EBPβ) was achieved by small interfering RNA, resulting in the subsequent downregulation of proinflammatory genes. This supports the hypothesis that C/EBPβ plays a key role in proinflammatory gene program activation in human microglia. Altogether, this study sheds new light on the properties of MDMi cells and supports these cells as a promising in vitro model for studying adult human microglia–like cells.
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.

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