Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))

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Global genetic interaction network of a human cell maps conserved principles and informs functional interpretation of gene co-essentiality profiles
(Elsevier B. V., 2026-04-27) Billmann, Maximilian; Costanzo, Michael; Zhang, Xiang; Hassan, Arshia Z.; Rahman, Mahfuzur; Brown, Kevin R.; Chan, Katherine S.; Tong, Amy Hin Yan; Pons Perez, Carles; Ward, Henry N.; Ross, Catherine; van Leeuwen, Jolanda; Aregger, Michael; Lawson, Keith A.; Mair, Barbara; Roth, Amy F.; Sen, Nesli E.; Forster, Duncan T.; Tan, Guihong; Mero, Patricia; Masud, Sanna N.; Lee, Yoonkyu; Aguilera-Uribe, Magali; Usaj, Matej; Almeida, Sylvia M.T.; Aulakh, Kamaldeep; Bhojoo, Urvi; Birkadze, Saba; Budijono, Nathaniel; Cai, Xunhui; Caumanns, Joseph J.; Chalmers, Jordan J.; Chandrashekhar, Megha; Chang, Daniel; Climie, Ryan; Dasgupta, Kuheli; Drazic, Adrian; Echenique, Jose I. Rojas; Gacesa, Rafael; Farias, Adrian Granda
Deciphering how genes interact within human cells is essential for understanding their functional wiring and for developing targeted therapeutic strategies. In this study, we present a genome-scale map of genetic interactions in the human haploid cell line HAP1, based on CRISPR-based perturbation of ∼4 million gene pairs. The resulting network comprises ∼89,000 high-confidence gene-gene interactions, organizing genes into hierarchical modules corresponding to protein complexes and pathways, biological processes, and cellular compartments, mirroring principles observed in yeast and highlighting the functional architecture of a human cell. This large-scale genetic network complements the DepMap gene co-essentiality network by capturing unique functional information, uncovering roles of previously uncharacterized genes, and identifying molecular determinants of cancer-cell-line-specific genetic dependencies. This study presents a general data-driven strategy for systematically exploring the roles of genes and their functional connections in human cell lines.
Oncogenic and tumor-suppressive forces converge on a progenitor niche at the benign-to-malignant transition
(Elsevier B. V., 2026-04-15) Reyes, José; Del Priore, Isabella; Chaikovsky, Andrea C.; Pasnuri, Nikhita; Elhossiny, Ahmed M.; Park, Jin; Weiler, Philipp; Krause, Tobias; Moorman, Andrew; Snopkowski, Catherine; Takizawa, Meril; Burdziak, Cassandra; Ratnayeke, Nalin; Masilionis, Ignas; Ho, Yu-Jui; Chaligné, Ronan; Romesser, Paul B.; Filliol, Aveline; Nawy, Tal; Morris, John P.; Zhao, Zhen; Pasca Di Magliano, Marina; ALONSO CURBELO, Direna; Pe’er, Dana; Lowe, Scott W.
The benign-to-malignant transition is a defining step in cancer progression. To investigate when and how malignancy initiation occurs and tissue reorganization proceeds, we combine single-cell and spatial transcriptomic profiling in mouse models of pancreatic ductal adenocarcinoma (PDAC) that capture spontaneous p53 loss. Among Kras-mutant cells, we find that oncogenic and tumor-suppressive programs, including those controlled by p53, CDKN2A, and SMAD4, are co-activated in a discrete progenitor-like population, engaging senescence-like responses. Using a framework we developed for spatial analysis, we show that a niche centered on these cells undergoes stepwise remodeling during tumor progression, mirroring invasive PDAC. Transient KRAS inhibition depletes progenitor-like cells and dismantles their niche, delaying malignancy initiation. Conversely, p53 suppression enables progenitor cell expansion, epithelial-mesenchymal reprogramming, and immune-privileged niche formation. These findings position the progenitor-like state at the convergence of cancer-driving mutations, plasticity, and tissue remodeling, revealing a critical window for intercepting malignancy.
Posttranscriptional reprogramming controls MASLD progression through chronic ER stress adaptation
(American Association for the Advancement of Science, 2026-04-03) Belloc Rocasalbas, Eulàlia; CALDERONE, VITTORIO; Naranjo-Suarez, S; Mateo Ramos, Lidia; MARTIN, J; MALIZIA, FLORENCIA; Sibilio, Annarita; Chanes Villar, Verónica; Ramirez-Pedraza, M; Delgado, ME; Drebber, U; Rheinwalt, KP; Klein, S; Brol, MJ; Schierwagen, R; Trebicka, J; Aloy Calaf, Patrick; Fernandez, M; Méndez De La Iglesia, Raúl
Metabolic dysfunction-associated steatohepatitis (MASH) and its progression to hepatocellular carcinoma remain major clinical challenges. Chronic endoplasmic reticulum (ER) stress, induced by sustained high-fat diet (HFD) intake, promotes hepatic inflammation, lipid accumulation, and hepatocellular dysfunction during MASH pathogenesis. While transcriptional responses are well characterized, the posttranscriptional mechanisms underlying hepatocyte adaptation to chronic ER stress remain poorly understood. Using an integrative approach combining transcriptomics, ribosome profiling, cytoplasmic polyadenylation analysis, and cis-regulatory mapping, we define the posttranscriptional landscape induced by chronic HFD exposure. To delineate the specific role of chronic ER stress, we use a hepatocyte-specific knockout of a key regulator of translational control under prolonged ER stress. We show that similar to 70% of HFD-induced gene expression changes are modulated at the translational level. A distinct subset of mRNAs, enriched in suboptimal codons and bearing short poly(A) tails under normal diet, becomes selectively activated upon HFD-induced poly(A) tail elongation. These transcripts, associated with cell cycle, immune response, fibrosis, and tissue remodeling, correlate with MASH severity in both murine models and human samples. Their regulation is mediated by cis-elements in the 3 ' UTR that coordinate polyadenylation and deadenylation. Loss of this adaptive response exacerbates liver damage and tumor burden in HFD-fed mice.
Age-dependent mutational loads in human tRNA genes are tumor-specific and result in chimeric tRNA sequences that could disrupt the genetic code
(Cold Spring Harbor Laboratory Press, 2026-04-15) Murillo Recio, Marina; Salvadores Ferreiro, Marina; Vaquer Picó, Aina; Tsapanou, Lina; Torres, Adrian Gabriel; Supek, Fran; Ribas De Pouplana, Lluís
Transfer RNA genes (tDNAs) are essential genomic elements that safeguard translational fidelity. Using the Telomere-to-Telomere version of the human genome we have mapped the position of human tDNAs and analyzed their individual transcriptional activities. Then we have characterized, at single base resolution, the impact of somatic mutations in human tDNAs and its relationship to the transcriptional status of each gene. We confirm that tDNAs are hotspots for somatic mutagenesis, and show that they display mutational loads that are directly proportional to their transcription rates. Highly transcribed tDNAs in tumors or healthy tissues accumulate mutations at rates up to nine-fold higher than highly transcribed protein-coding genes. Mutational loads at tDNAs are tumor-specific, and increase with patient age. Mutations at structurally conserved tRNA positions appear to be under negative selection. Anticodon nucleotides crucial for decoding frequently acquire somatic mutations, readily generating chimeric tRNA species potentially capable of systematically introducing amino acid substitutions across the proteome. Our results reveal a previously unrecognized source of somatic heterogeneity in human cancer and aging tissues that may directly impact upon translation efficiency and fidelity, and cause cell-specific proteostasis degeneration
MAdPHOS, a P‑Stereogenic Aminodiphosphane Ligand withAdamantyl Groups: Synthesis, NH/PH Tautomerism, and Rhodiumand Nickel Complexes.
(American Chemical Society, 2025-01-29) Bellido, Marina; Solé Àvila, Helena; Sidro Inglés, Martí; Grabulosa, Arnald; Verdaguer i Espaulella, Xavier; Riera i Escalé, Antoni
A novel chiral ligand, named MAdPHOS, bearing aP-stereogenic phosphane and a diadamantyl phosphane linked by aNH bridge has been synthesized. This bulky, C1-symmetric, PNPligand has been prepared from enantiopure tert-butylmethylaminophosphane and was obtained as a crystalline solid. TheNH/PH tautomerism, air-stability, and σ-donor capacity ofMAdPHOS have been assessed herein. The free ligand has beenprepared, showing much higher stability, in the solid form, than itstert-butyl analogue MaxPHOS. Both rhodium and nickel CODcomplexes have been prepared. The Rh-MAdPHOS complex hasshown outstanding enantioselectivities in the asymmetric hydrogenationof enamides.
Exposomal determinants of non-genetic plasticity in tumor initiation
(Elsevier B.V., 2025-02-28) Carra, Davide; Maas, Silvana C.E.; Seoane, Jose A.; Alonso Curbelo, Direna
The classical view of cancer as a genetically driven disease has been challenged by recent findings of oncogenic mutations in phenotypically healthy tissues, refocusing attention on non-genetic mechanisms of tumor initiation. In this context, gene–environment interactions take the stage, with recent studies showing how they unleash and redirect cellular and tissue plasticity towards protumorigenic states in response to the exposome, the ensemble of environmental factors impinging on tissue homeostasis. We conceptualize tumor-initiating plasticity as a phenotype-transforming force acting at three levels: cell-intrinsic, focusing on mutant epithelial cells’ responses to environmental variation; reprogramming of non-neoplastic cells of the host, leading to protumor micro- and macroenvironments; and microbiome ecosystem dynamics. This perspective highlights cell, tissue, and organismal plasticity mechanisms underlying tumor initiation that are shaped by the exposome, and how their functional investigation may provide new opportunities to prevent, detect, and intercept cancer-promoting plasticity.
Uncovering actionable trade-offs of antifungal resistance in a yeast pathogen
(Springer, 2026-01-12) Núñez Rodríguez, Juan Carlos; Schikora Tamarit, Miquel Àngel; Gabaldón Esteban, Toni
The increasing prevalence of antifungal resistance represents a major clinical challenge. To explore potential new therapeutic avenues, we investigated fitness trade-offs associated with azole and echinocandin resistance in Nakaseomyces glabratus (syn. Candida glabrata), a priority yeast pathogen showing growing incidence of drug and multidrug resistance. For this, we comprehensively phenotyped a large collection (n = 77) of azole- and echinocandin-resistant strains to uncover resistance-associated stress sensitivity trade-offs. Our results show that increased stress sensitivity is a common trade-off of drug resistance in this species, with 98% of resistant strains exhibiting reduced fitness under at least one of six assayed stresses. Despite the diversity of genetic backgrounds and resistance mechanisms represented by our collection, we identified consistent trends in some resistance-associated vulnerabilities. Using multivariate modeling we uncovered complex genetic interactions underlying these trade-offs. As a proof of concept for therapeutic potential, we experimentally validated the inhibitory effects of targeting some fitness trade-offs. Cyclosporin A selectively inhibited anidulafungin-resistant strains, while NaCl effectively suppressed the emergence of fluconazole resistance. This study highlights the widespread occurrence of fitness costs associated with antifungal resistance and emphasizes their potential as a novel therapeutic strategy against this growing threat.
Experimental assessment of AI-based interactome mapping
(2026-04-04) Lambourne, Luke; Yadav, Anupama; Wang, Yang; Desbuleux, Alice; Kim, Dae-Kyum; Laval, Florent; Spirohn Fitzgerald, Kerstin; Cafarelli, Tiziana; Pons, Carles; Kovács, István A.; Jailkhani, Noor; Schlabach, Sadie; De Ridder, David; Luck, Katja; Botchkarev, Vladimir V.; Debnath, Olivia; Bian, Wenting; Shen, Yun; Yang, Zhipeng; Mee, Miles W.; Helmy, Mohamed; Jacob, Yves; Lemmens, Irma; Rolland, Thomas; McClain, Gregory G.; Coté, Atina G.; Gebbia, Marinella; Kishore, Nishka; Knapp, Jennifer J.; Mellor, Joseph C.; Memisoglu, Gonen; Reimand, Jüri; Tavernier, Jan; Cusick, Michael E.; Zhong, Quan; Aloy Calaf, Patrick; Hao, Tong; Charloteaux, Benoit; Roth, Frederick P.; Rivas, Javier de las; Falter Braun, Pascal; Hill, David E.; Calderwood, Michael A.; Twizere, Jean Claude; Vidal, Marc
Genotype-phenotype relationships are mediated through intricate networks of physical and functional interactions among macromolecules. Knowledge of the interactome is vital to understand and model genetics and cellular biology. Recent advances in accurately predicting tertiary protein structures using artificial intelligence (AI) approaches such as AlphaFold1 have revived the vision that the proteinprotein interactome might be fully predictable through computational modeling of quaternary structures. Here we present a comprehensive experimental framework to systematically assess the impact of AIdriven interactome predictions for yeast2 and human3. We find that the quality of high-confidence predictions is on par with established experimental approaches. However, in proteome-wide screening, the tested AI approaches underperform in the discovery of strictly novel protein-protein interactions (PPIs) compared to experimental reference interactome maps. In particular, the yeast interactome map describe here identifies >40-fold more novel PPIs than its AI counterpart. Strikingly, AlphaFold provides structural models for a substantial number of experimentally identified PPIs miss by the virtual screens. Our results suggest that, at this stage, the main contribution of AI predictions is to provide quaternary structure models for experimentally identified PPIs.
A Plastic EMP1+ to LGR5+ Cell State Conversion as a Bypass to KRASG12D Pharmacologic Inhibition in Metastatic Colorectal Cancer
(American Association for Cancer Research, 2026-02-06) Centonze, Alessia; Roura Canalda, Adrià Jaume; Novillo Font, Meritxell; Giordano, Cristina; Hernando Momblona, Javier; Llanses Martínez, Montserrat; Prats Martínez, Paula; Sevillano Rosa, Marta; Cabot, Débora; Novell, Mireia; Pabst, Gabriel; Andersch, Florian; Cañellas Socias, Adrià; Zhang, Chong ; Giakoumakis, Nikolaos Nikiforos ; Sparks, Hugh; Dunsby, Chris; Colombelli, Julien; Fernández Barral, Asunción; Sancho Suils, Elena; Stephan-Otto Attolini, Camille; Muñoz, Alberto; Barbachano, Antonio; Martínez Quintanilla, Jordi; Palmer, Héctor G.; Zuber, Johannes; Blaj, Cristina; Sancho, Elena; Quintana, Elsa ; Cortina, Carme; Martí Renom, Marc A.; Batlle Gómez, Eduard
Inhibitors of the oncogene KRAS hold promise for treating metastatic colorectal cancer (mCRC). In this study, we show that a selective, covalent small-molecule inhibitor of the active (ON) conformation of RAS-G12D, RMC-9945, exerts durable disease control in preclinical colorectal cancer models of early liver metastasis, but its therapeutic activity was diminished in the advanced metastatic disease. RMC-9945-treated metastases underwent a transition from a poor prognosis-associated Emp1+ transcriptional state to a WNT-driven Lgr5+ stem cell-like state that withstands the absence of RAS-G12D activity. This cell state change occurred within hours of RAS(ON) inhibitor treatment through a shift in transcription factor usage that involved limited chromatin remodeling. Forced conversion of metastatic cells to the Lgr5+ state through RAS-G12D inhibition, followed by genetic ablation of this population, reduced metastatic burden and prolonged survival in a mouse mCRC model. Overall, these preclinical findings demonstrate a central role for oncogenic KRAS in governing cellular plasticity in mCRC.Significance: We show that inhibition of oncogenic KRAS in preclinical models of advanced mCRC exerts a limited benefit, primarily due to the reversion of tumor cells to a stem cell-like state. Our findings highlight the context-dependent effects of oncogenic KRAS mutations and underscore cell plasticity as a therapeutic opportunity. See related commentary by Eng and Yilmaz et al., p. 201Significance: We show that inhibition of oncogenic KRAS in preclinical models of advanced mCRC exerts a limited benefit, primarily due to the reversion of tumor cells to a stem cell-like state. Our findings highlight the context-dependent effects of oncogenic KRAS mutations and underscore cell plasticity as a therapeutic opportunity. See related commentary by Eng and Yilmaz et al., p. 201
Oligomerization enables the selective targeting of an intrinsically disordered region by a small molecule
(Elsevier, 2026-02-27) Bielskutė, Stasė ; Mateos López, Borja; Awawdy, Muhammad ; Garcia Cabau, Carla; Niskanen, Henri ; Sánchez Zarzalejo, Carolina; Bracaglia, Lorenzo ; Pierattelli, Roberta ; Felli, Isabella C. ; Frigolé Vivas, Marta ; García Arroyo, Jesús; Riera Escale, Antoni; Hnisz, Denes ; Salvatella Giralt, Xavier
Intrinsically disordered regions (IDRs) in proteins are increasingly recognized as attractive targets for therapeutic intervention. A number of small molecules interacting with IDRs have been identified, but the lack of persistent secondary and tertiary structure of these regions has led to the prevailing view that they cannot be targeted selectively. Here, we show that a small molecule targeting an IDR evaluated in a clinical trial interacts selectively with an oligomeric form of its target, which is more structured than the monomer and is stabilized by interactions involving aromatic residues in partially α- helical regions. The interaction reshapes the conformational ensemble of the target, alters the biophysical properties of its phase- separated condensates in vitro, and attenuates RNA polymerase II recruitment in cells. Our findings provide mechanistic insights into how small molecules can selectively recognize IDRs.
Proteostasis failure and mitochondrial dysfunction contribute to chromosomal instability-induced microcephaly
(Springer Nature, 2026-03-12) Gonzalez Blanco, Amanda; Acuna Higaki, Adrian Ricardo; Boettger, David; Joy, Jery; Milán Kalbfleisch, Marco
Profound cell wall remodeling in Candida parapsilosis during systemic infection confers simultaneous tolerance to echinocandins and host immunity.
(2026-02-13) Daneshnia, Farnaz; Arastehfar, Amir; Cai, Liuyang ; Gunasekaran, Deepika ; Gautam, Isha ; Perry, Austin M. ; Ghahfarokhy, Pegah Mosharaf ; Ebadati, Arefeh ; Muñoz, Julieta ; Padilla, Dorian ; Hilmioglu-Polat, Süleyha ; Mei, Shenglin ; Floyd, Daniel J. ; Schikora Tamarit, Miquel Àngel ; Fuentes Palacios, Diego; Artigues Lleixà, Maria; Walker, Louise A. ; Gonçalves, Samuel M. ; Salehi, Mostafa ; Carvalho, Agostinho ; Desai, Jigar V. ; Perlin, David S. ; Munro, Carol A. ; Hopke, Alex ; Wang, Tuo ; Gabaldón Esteban, Toni ; Fang, Wenjie ; Nobile, Clarissa J. ; Mansour, Michael K.
Antifungal tolerance can promote the emergence of resistance yet often incurs fitness costs for fungal pathogens. How tolerant populations compensate for these deficits and how they may be therapeutically targeted remain poorly under stood. Here, we investigate four sequential Candida parapsilosis isolates recovered from a patient with persistent candidemia and failure of micafungin therapy. The infection was ultimately cleared with liposomal amphotericin B (LAMB). Whole-genome sequencing (WGS) confirmed clonal relatedness and the absence of known resistance mutations. Later isolates displayed marked cell wall remodeling (CWR), characterized by increased mannan and reduced β-glucan content, as revealed by microscopy and solid-state nuclear magnetic resonance. These isolates formed thicker biofilms and displayed enhanced echinocandin tolerance but paradoxically showed increased susceptibility to amphotericin B (AMB) in vitro and during systemic infection in mice. Despite a complex mutational landscape, transcriptomic profiling across planktonic and biofilm growth showed minimal divergence from the earliest isolate. Functionally, evolved isolates suppressed M1 macrophage polarization, dampened proinflammatory cytokine production, survived better during neutrophil interactions, and transiently increased fungal burden in vivo. These findings show that host-driven CWR could promote echinocandin tolerance while simultaneously sensitizing C. parapsilosis to AMB. Our results suggest that alternating echinocandin and LAMB therapy may effectively eliminate echinocandin-tolerant fungal populations.
Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer
(American Association for Cancer Research, 2026-02-06) Gumpert, Nofar; Sagie, Shira ; Arnedo Pac, Claudia; Babu, Tomer ; Weller, Chen ; Gonzalez Perez, Abel David; Wang, Yuan ; Todó, Lucas Michel; Levy, Ronen ; Chen, Xi ; Greenberg, Polina ; Dayan-Rubinov, Maria ; Yakubovich, Elizabeta ; Wasserman-Bartov, Talya ; Zerbib, Mirie ; Gong, Jianhui ; Rebernick, Ryan J. ; Oliveira Tercero, Anna ; Agundez Muriel, Laura ; Benedek, Gil ; Kedmi, Merav ; Oren, Roni ; Ben-Dor, Shifra ; Levin, Yishai ; Troyanskaya, Olga G. ; Munzur, Aslı D. ; Wyatt, Alexander W.; Cieslik, Marcin P. ; Quigley, David A. ; Van Allen, Eliezer M. ; Anandasabapathy, Niroshana ; Mateo, Joaquin ; Yang, Xinbo ; Martínez Jiménez, Francisco ; López Bigas, Núria ; Samuels, Yardena
New approaches that generate long-lasting therapeutic responses in patients with therapy-resistant metastatic cancer are urgently needed. To address this challenge, we developed Spot Neoantigens in Metastases (SpotNeoMet), a novel data-driven pipeline that systematically identifies recurrently presented neopeptides in treatment-resistant patients. We identified seven therapy resistance mutations predicted to produce neopeptides presented by common HLAs. Using HLA immunopeptidomics, we discovered three novel neopeptides derived from androgen receptor (AR) H875Y, a common metastatic castration-resistant prostate cancer (mCRPC) mutation. We validated these neoantigens as highly immunogenic and then isolated and characterized cognate T-cell receptors (TCR) from healthy donor peripheral blood mononuclear cells. We demonstrated that AR H875Y-specific TCRs are highly specific and kill prostate cancer cells presenting AR neopeptides in vitro and in vivo. Our new pipeline identifies novel immunotherapy targets and potential treatment options for patients with mCRPC. Moreover, SpotNeoMet offers a systematic route to identify "HLA-peptide" pairs and their cognate TCRs across treatment-resistant cancers.Significance: As the emergence of resistance to targeted treatments in patients with metastatic cancer, there is an urgent need for innovative therapeutic approaches for this population. Our study provides a new analytic framework to identify neoantigens from treatment-resistant mutations and a proof-of-concept T cell-based immunotherapy treatment for mCRPC.
Molecular dynamics modelling of the interaction of a synthetic zinc-finger miniprotein with DNA
(Royal Society of Chemistry, 2023) Rodriguez, Jessica; Battistini, Federica; Learte-Aymamí, Soraya; Orozco López, Modesto; Mascareñas, José L.
We report the modelling of the DNA complex of an artificial miniprotein composed of two zinc finger modules and an AT-hook linking peptide. The computational study provides for the first time a structural view of these types of complexes, dissecting interactions that are key to modulate their stability. The relevance of these interactions was validated experimentally. These results confirm the potential of this type of computational approach for studying peptide–DNA complexes and suggest that they could be very useful for the rational design of non-natural, DNA binding miniproteins.
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.
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.
Harnessing dendritic cell metabolism for healthy ageing: reducing the risk of cardiovascular disease?
(2024-06-06) Wculek, Stefanie Kristin
Success and Limitations of Current Force Fields for the Description of RNA–Ligand Complexes
(American Chemical Society, 2025-10-31) Fernández Migens, Paula; Serrano Chacón, Israel; Orozco López, Modesto; Battistini, Federica
We present a systematic assessment of the last generation of RNA force fields to reproduce the structures and dynamics of ligand−RNA complexes. Our comprehensive analysis helped not only to define the more reliable force field to represent complex structures but also suggests details that can be improved and provide a critical analysis of the quality of experimental structures in complex systems that are expected to be very flexible and environment dependent.
Variable efficiency of nonsense-mediated mRNA decay across human tissues, tumors and individuals
(BMC, 2025-09-29) Palou Márquez, Guillermo; Supek, Fran
BackgroundNonsense-mediated mRNA decay (NMD) is a quality-control pathway that degrades mRNA bearing premature termination codons (PTCs) resulting from mutation or mis-splicing, and that additionally participates in gene regulation of unmutated transcripts. While NMD activity is known to differ between examples of PTCs, it is less well studied if human tissues differ in NMD activity, or if individuals differ.ResultsWe analyzed exomes and matched transcriptomes from Human tumors and healthy tissues to quantify individual-level NMD efficiency, and assess its variability between tissues, tumors, and individuals. This was done by monitoring mRNA levels of endogenous NMD target transcripts, and additionally supported by allele-specific expression of germline PTCs. Nervous system and reproductive system tissues have lower NMD efficiency than other tissues, such as the digestive tract. Next, there is systematic inter-individual variability in NMD efficiency, and we identify two underlying mechanisms. First, somatic copy number alterations can robustly associate with NMD efficiency, prominently the commonly-occurring gain at chromosome 1q that encompasses two core NMD genes: SMG5 and SMG7 and additional functionally interacting genes such as PMF1 and GON4L. Second, deleterious germline variants in genes such as the KDM6B chromatin modifier can associate with higher or lower NMD efficiency in individuals. Variable NMD efficiency modulates positive selection upon somatic nonsense mutations in tumor suppressor genes, and is associated with cancer patient survival and immunotherapy responses. ConclusionsNMD efficiency is variable across human tissues, and it is additionally variable across individuals and tumors thereof due to germline and somatic genetic alterations.

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