Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC))

URI permanent per a aquesta col·leccióhttps://hdl.handle.net/2445/65294

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The study of immunological markers in tuberculosis across animal models and its translation to human research
(2026-07-01) Díaz-Fernández, Sergio; Aleluia, Matilde; Saraiva, Margarida; Soldevilla, Pablo; Torrelles, Jordi B.; Sharan, Riti; Verreck, Frank A.W.; Izzo, Angelo; Vidal, Marta; Moreira, Ana C.; Pérez de Val, Bernat; Roca, Francisco Jose; Preda, Madalina; Torrents Serra, Eduard; Julián, Esther; Domínguez, José; Latorre, Irene
Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis, remains one of the major causes of death from infection worldwide, with over a million associated deaths each year. The study of biomarkers for TB is critical for advancing our understanding and management of the disease. Biomarkers, defined as measurable indicators of biological states or conditions, are invaluable for the diagnosis, prognosis and treatment monitoring of TB. Clinical studies have provided critical knowledge on the matter but are also notoriously constrained by economical, ethical and sampling limitations. The use of animal models provides a simpler, more controllable, cost-effective setting with great potential for translation to humans. They also allow the evaluation of biomarkers within the respiratory compartment, when available, which is of particular interest due to the nature of TB pathogenesis. This Review focuses on the current landscape of TB biomarker discovery in several animal models, from invertebrates to large mammals. Here we summarize the basics of host–pathogen immune interaction, describe the main methodological approaches used and highlight the most substantial findings for each animal model studied. Furthermore, we discuss the advantages, challenges and limitations associated with species-specific differences in animal models. We conclude that integrating the data obtained from animal models and human studies is absolutely required to advance the TB field to accelerate the management of this disease.
Theory of Multiscale Epithelial Mechanics under Stretch: From Active Gels to Vertex Models
(American Physical Society, 2026-04-08) Ouzeri, Adam; Kale, Sohan; Chahare, Nimesh Ramesh; Torres Sánchez, Alejandro; Santos-Olivan, Daniel; Trepat, Xavier; Arroyo Balaguer, Marino
Arroyo, Marino
Quatsome nanovesicles as antibacterial platform: Mechanistic insights into their activity against planktonic and biofilm Staphylococcus aureus
(Elsevier B.V., 2026-06-26) Korber, Mariana; Gallardo-Moreno, Amparo M; Ferrer-Tasies, Lidia; Fernandez-Calderon, Maria Coronada; Pujol-Sole, Nuria; Tomsen-Melero, Judit; Guasch, Elba; Tamurejo-Alonso, Purificacion; Mitjans, Montserrat; Vinardell, Maria Pilar; Domingo-Tafalla, Beatriu; Giannotti, Marina Inés; Rancan, Fiorenza; Schaudinn, Christoph; Veciana, Jaume; Ratera, Imma; Roldan, Monica; González-Mira, Elisabet; Gonzalez-Martin, Maria Luisa; Ventosa, Nora
The growing threat of antibiotic-resistant pathogens has intensified the demand for alternative antibacterial materials. Quatsomes-nanovesicles composed of cholesterol and quaternary ammonium surfactants (QAS)- emerge as promising candidates due to their intrinsic antimicrobial properties and tunable physicochemical characteristics. Here, we investigate the antibacterial activity of quatsomes incorporating QAS with either tetradecyl (C14) or hexadecyl (C16) alkyl chains against Staphylococcus aureus, a leading cause of hospital-acquired infections. Both quatsome types exhibited potent bactericidal activity in planktonic cultures, with C16containing formulations showing a 2.5-fold lower minimum bactericidal concentration than C14 counterparts. Confocal microscopy suggested a partial penetration of cationic quatsomes into the bacterial peptidoglycan layer, accompanied by significant increases in zeta-potential, suggesting strong electrostatic interactions without visible membrane disruption, as confirmed by scanning electron microscopy. Both formulations also demonstrated high efficacy against mature S. aureus biofilms, with no significant differences between alkyl chain lengths, indicating a mechanism primarily targeting the extracellular biofilm matrix. In addition, they showed a good antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA). A preliminary safety assessment using reconstructed human epidermis (EpiskinTM) confirmed the non-irritant nature of both formulations. These findings highlight the potential of QAS-based quatsomes as effective and biocompatible nanocarriers for topical antibacterial applications, offering a promising platform for combating antibiotic-resistant infections in both planktonic and biofilm states.
Glycogen drives the sensory activation of POMC neurons
(Nature Publishing Group, 2026-05-27) Gómez-Valadés, Alicia G.; Meseguer, David; Varela, Luis; Lienhard, Gabriele; Fernández, Uxía; Vidal Itriago, Andrés; Toledo Soler, Miriam; Eyre, Elena; Laudo, Berta; Díaz Castro, Francisco; Pozo, Macarena; Boutagouga Boudjadja, Mehdi; Fos Domènech, Júlia; García Ramón, Pau; Ferreira, Mariana; Altirriba Gutiérrez, Jordi; Beiroa, Daniel; Chen, Bandy; Rodríguez Díaz, Amanda; Milà Guasch, Maria; Chivite, Íñigo; Obri, Arnaud; Ramírez, Sara; Haddad Tovolli, Roberta; Tahiri, Iasim; Gentry, Matthew S.; Agostino, Giuseppe D'; Nogueiras, Rubén; Renier, Nicolas; Horvath, Tamas L.; Guinovart, Joan J. (Joan Josep), 1947-2025; Duran Castells, Jordi; Schneeberger, Marc; Claret i Carles, Marc
Hypothalamic POMC neurons modulate systemic energy balance and glucose homeostasis by sensing nutritional state signals. In addition to this classic regulatory mode, these neurons are also activated by the sensory perception of food. Here, we report that food-related sensory cues engage glycogen metabolism in POMC neurons. Genetic depletion of glycogen through various approaches renders POMC neurons unresponsive to food-associated sensory stimuli. This defective perception of food is linked to alterations in consummatory behaviour, hepatic adaptations and cephalic insulin release associated with a prediabetic phenotype that progresses into overweight and overt diabetes with a high-calorie diet or ageing. Collectively, our results posit glycogen as a decisive fuel resource for meeting the rapid and demanding energy requirements linked with sensory activation. Furthermore, our data delineate the biological function of food perception and provide support for the physiological relevance of neuronal glycogen.
Late-stage modification of the alkaloid toxin veratridine to photocontrol excitable tissues.
(Elsevier Masson SAS, 2026-05-25) Camerin, Luisa ; Maleeva, Galyna ; Ramírez-Abreu, Ailín; Cilleros-Mañé, Víctor; Miftari, Drilon; Batlle, Montserrat ; Matera, Carlo ; Guasch Casany, Eduard; Gorostiza, Pau
Natural products and their structural derivatives have long played a crucial role in the discovery of new medical treatments and pharmacotherapies. However, certain natural compounds, such as toxins, are classified as hazardous substances that pose risk to human health. It is desirable to modulate the activity of toxins to minimize their harmful effects and unleash their potential as selective and bioavailable drugs. Yet, the functionalization of natural products remains a challenge due to their structural complexity. Here, we present two methods for late-stage C-H nitration and subsequent derivatization of the alkaloid steroidal neurotoxin veratridine, a sodium channel opener, by introducing an azobenzene photoswitch in its structure. The resulting compound, Azoveratridine, displays aqueous solubility, reversible photoisomerization, and light-dependent activity in neurons and myocardial slices.
Association of Breathing Effort With Survival in Patients With Acute Respiratory Distress Syndrome
(Lippincott, Williams & Wilkins, 2025-10) Parrilla-Gómez, Francisco José; Castellví, Andrea; Boutonnet, Víctor; Parrilla-Gómez, Andrés; Antolín Terreros, Marta; Mestre Somoza, Cristina; Blanes Bravo, Marina; Pratsobrerroca de la Rubia, Paola; Martín-López, Eva; Marco Colás, Santiago; Festa, Olimpia; Brochard, Laurent; Goligher, Ewan; Masclans Enviz, Joan Ramon
OBJECTIVES: Invasive mechanical ventilation (IMV) is crucial for acute respiratory distress syndrome (ARDS) management, but mortality remains high. While spontaneous breathing is key to weaning, excessive respiratory effort may injure the lung and diaphragm. Most existing data on respiratory effort during IMV are based on brief periods of observation, potentially underestimating the burden of inappropriate efforts. This study aims to characterize the evolution of respiratory effort over time in ARDS patients and its relation to survival. We hypothesized that nonsurvivors would spend a greater proportion of time in the high-effort range during the active breathing phase compared with survivors. DESIGN, SETTING, AND PATIENTS: In this prospective cohort study, we continuously recorded airway pressure, flow, esophageal, and gastric pressures in ARDS patients on mechanical ventilation during 7 days after the onset of spontaneous breathing. We analyzed physiologic respiratory effort variables, focusing on the proportion of time spent within defined effort ranges, and compared these data between ICU survivors and nonsurvivors. Statistical analysis was conducted using variance weighted methods to account for variability in the number of respiratory cycles analyzed per patient. This study is registered at ClinicalTrials.gov under identifier NCT06490523. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 1,485,405 respiratory cycles were analyzed from 26 ARDS patients (19 survivors, seven nonsurvivors). Nonsurvivors spent significantly more time in high effort (12% vs. 3%; p = 0.006). In contrast, survivors spent more time in the moderate-effort range (50% vs. 5%; p < 0.001). The time spend with high dynamic transpulmonary driving pressure (> 25 cm H2O) was also significantly different between groups (32% survivors vs. 74% nonsurvivors; p = 0.001). CONCLUSIONS: Patients who die of ARDS are more likely to be exposed to high respiratory effort for prolonged periods of time compared with survivors.
Cardiac fibroblast anisotropy is determined by YAP-dependent cellular contractility and ECM production
(Elsevier B.V., 2026-10) Pereira-Sousa, Daniel; Guillamat Bassedas, Pau; Niro, Francesco; Vinarsky, Vladimir; Fernandes, Soraia; Cassani, Marco; Pagliari, Stefania; Trepat Guixer, Xavier ; Rasponi, Marco; Oliver de la Cruz, Jorge; Forte, Giancarlo
Cardiac fibroblasts (CFbs) determine the topological arrangement and the anisotropy of the heart tissue which maintains tissue integrity and function through the production and remodeling of the extracellular matrix (ECM). Under pathological conditions, CFbs can activate into myofibroblasts and promote maladaptive ECM remodeling that may lead to heart failure. Yes-Associated Protein (YAP) - a key player in cardiac fibrosis onset - has been implicated in CFb activation but its role in coordinating the supracellular organization of CFbs and in shaping the instructive properties of the ECM remains poorly understood. We addressed these questions by generating CFbs from wild-type (WT) and YAP knockout (KO) human embryonic stem cells. YAP depletion reduced the expression of cardiogenic markers and altered the transcriptomic profile of ECM- and contractility-related genes. We further demonstrated that YAP expression is required for CFbs monolayer alignment, and its absence resulted in reduced ECM deposition, decreased anisotropy, and diminished force generation. Pharmacological inhibition of cell contractility closely mirrored YAP KO phenotype, suggesting that YAP regulates both monolayer organization and ECM structure through its control over contractility. ECM cross-seeding experiments confirmed the role of ECM as a structural guide for cellular alignment. Moreover, cardiomyocytes cultured on KO CFb-derived ECM exhibited impaired sarcomere organization and altered calcium dynamics. Together, these findings demonstrate that YAP activity in CFbs governs the structural and functional properties of the ECM, influencing both fibroblast alignment and cardiomyocyte activity. Moreover, they underscore the critical role of YAP in maintaining the supracellular organization and mechanical integrity of cardiac tissue.
Nanomotor-Assisted Intravesical Chemotherapy for Bladder Tumor Reduction and Suppression of Early Tumor Regrowth
(American Chemical Society, 2026-05-06) Vilaseca, Antoni; Llop Talaverón, Josep Manuel; Sánchez-López, Sònia; Fichna, Kristin; Crespo Cuadrado, Maria; Konuparamban, Acsah; Di Carlo, Valerio; Esporrín Ubieto, David; Macías Tarrío, Irene; Jutglar Soler, Oriol; Chen, Shuqin; Gómez Martínez, María; Bakenecker, Anna C.
Nanoparticles are widely used in nanomedicine for controlled drug delivery and improved bioavailability. However, their effectiveness is often limited by passive diffusion, especially in confined, fluid-filled environments like the bladder, where rapid drug clearance and uneven distribution reduce therapeutic impact. These challenges contribute to high recurrence in bladder cancer despite intravesical chemotherapy. To address this limitation, we present urease-powered nanomotors (NM) based on mesoporous silica nanoparticles loaded with Mitomycin C (MMC), the standard chemotherapeutic for nonmuscleinvasive bladder cancer. These NM useurea present in urine to induce motion and drug dispersion. In vitro, NM showed 2.3-fold higher uptake in mouse bladder cancer cells than passive nanoparticles and achieved the efficacy of free MMC (577.5 μg/mL) at a 20-fold lower dose (30 μg/mL). In vivo, a single intravesical dose reduced tumor volumes by 83% and prevented early tumor regrowth, demonstrating the potential of NM-based delivery for bladder cancer therapy.
Massively parallel quantification of mutational impact on IAPP amyloid formation
(Springer Nature, 2026-03-17) Badia Graset, Marta; Batlle Carreras, Cristina; Bolognesi, Benedetta
Amyloid fibrils formed by the islet amyloid polypeptide cause pancreatic beta-cell damage, resulting in reduced insulin secretion and type 2 diabetes. Changes in the amino acid sequence of this peptide can influence its aggregation rate, and animals expressing variants that do not form amyloids do not develop type 2 diabetes. Conversely, specific single amino acid changes can accelerate the aggregation rate of this peptide. Here, we employ deep mutational scanning to measure the ability of 1916 islet amyloid polypeptide variants, including substitutions, insertions, truncations and deletions, to nucleate amyloids. Our results identify a continuous stretch of residues from 15 to 32 that is particularly sensitive to mutation. This region, which is likely structured in amyloids, matches the core of the early aggregated species formed by this peptide in vitro. Within this region, mutations in residues 21 to 27 have a substantial effect, suggesting tighter structural constraints. Finally, we compare the mutational atlas of the islet amyloid polypeptide to that of amyloid beta - the peptide that aggregates in Alzheimer’s disease - and find that mutations that slow down nucleation correlate between the two amyloids, but mutations that accelerate nucleation in one amyloid cannot be used to predict mutational effects in the other.
Long-Distance Charge Transport between Cytochrome c and Complex III is Mediated by Protons and Reactive Oxygen Species
(Wiley-VCH, 2025-09-12) Lagunas, Anna; Gomila, Alexandre M. J.; Nin Hill, Alba; Guerra-Castellano, Alejandra; Pérez-Mejías, Gonzalo; Samitier i Martí, Josep; Rovira i Virgili, Carme; Rosa, Miguel A. de la; Díaz Moreno, Irene; Gorostiza Langa, Pablo Ignacio
Electron transfer (ET) between redox proteins is an essential process in the respiratory and photosynthetic transport chains. While intra-protein ET is well characterized, the experimental methods to investigate inter-protein ET are limited by the presence of the solvent and by the transient nature of the protein– protein interaction and ET event, which are averaged in protein ensembles. Wiring precisely oriented redox protein partners to the nanoscale electrodes of an electrochemical scanning tunneling microscope allows recording the time- and distance-dependence of the current flowing between them. These methods have revealed that the current flowing between individual protein pairs extends beyond tunneling distances and that it is electrochemically gated. However, the corresponding mechanism and the identity of the charge carriers in aqueous solution remain to be elucidated. To determine the species involved in long-distance charge transport between the redox partner proteins Cc and Cc1 of the respiratory chain, recordings are performed as a function of pH, in heavy water solutions, and in degassed solutions. It is observed that the spatial span and electrochemical gating of long-distance currents are reduced at high pH, in heavy water, and at low oxygen concentration, showing that the currents are assisted by superoxide anions and by protons.
Optimizing Instrumental Odour Monitoring Systems in Drones by Feature Selection for Odour Detection and Odour Concentration Estimation
(Elsevier B.V., 2026-04-01) Benegiamo, Alessandro; Alonso Valdesueiro, Javier; Burgués, Javier; Vidal, Albert; Saúco, Lidia; Esclapez, María Deseada; Doñate, Silvia; Gutiérrez Gálvez, Agustín; Marco Colás, Santiago
Fugitive odour emissions from wastewater treatment plants (WWTPs) present ongoing analytical and environmental challenges. Drone-mounted Instrumental Odour Monitoring Systems (IOMS) enable real-time, spatially resolved chemical sensing; however, large sensor arrays increase calibration complexity and cost. To address this, IOMS optimization is formulated as a machine-learning feature-selection problem. A two-stage selection strategy is introduced, combining Sequential Forward Selection (SFS) and Interval Partial Least Squares (iPLS) regression to identify minimal, information-rich sensor subsets and optimal temporal measurement windows. The approach is evaluated using data from a hexacopter-borne IOMS equipped with 21 sensors operating over an active WWTP. Sensors are ranked according to their incremental contribution to odour-concentration prediction error reduction, followed by refinement of measurement intervals to capture relevant temporal dynamics. Validation on independent flight data demonstrates that a configuration comprising only three sensors with optimized time windows retains or improves predictive performance relative to the full array. For quantification, the Bland–Altman limits of agreement improve from ±7 to ±5.3 dBod, and the Pearson correlation increases from 0.80 to 0.89. For odour-detection task, a single sensor achieves an AUC of 0.95, slightly outperforming the full sensor set (AUC = 0.93). Bootstrap analysis reveals variability in feature selection, though consistent trends are observed: ammonia sensors dominate quantitative models, whereas low-temperature MOX sensors are preferred in detection. The findings demonstrate the effectiveness of feature-selection strategies in simplifying IOMS hardware while preserving chemometric performance.
Steps Toward Recapitulating Endothelium: A Perspective on the Next Generation of Hemocompatible Coatings
(Wiley-VCH, 2024-07-29) Witzdam, Lena; White, Tom; Rodriguez Emmenegger, César
Endothelium, the lining in this blood vessel, orchestrates three main critical functions such as protecting blood components, modulating of hemostasis by secreting various inhibitors, and directing clot digestion (fibrinolysis) by activating tissue plasminogen activator. No other surface can perform these tasks; thus, the contact of blood and blood-contacting medical devices inevitably leads to the activation of coagulation, often causing device failure, and thromboembolic complications. This perspective, first, discusses the biological mechanisms of activation of coagulation and highlights the efforts of advanced coatings to recapitulate one characteristic of endothelium, hereafter single functions of endothelium and noting necessity of the synergistic integration of its three main functions. Subsequently, it is emphasized that to overcome the challenges of blood compatibility an endothelium-mimicking system is needed, proposing a synergy of bottom-up synthetic biology, particularly synthetic cells, with passive- and bioactive surface coatings. Such integration holds promise for developing advanced biomaterials capable of recapitulating endothelial functions, thereby enhancing the hemocompatibility and performance of blood-contacting medical devices. The activation of coagulation on the surface of blood-contacting medical devices often leads to thromboembolic complications. A concept for the next generation of hemocompatbile surfaces inspired by endothelium is proposed. This concept not only contribute to the fundamental understanding of hemocompatibility but also offer practical implications for the design and development of biomedical devices with enhanced biocompatibility and functionality. image
Targeted Covalent Photoswitch for Two-Photon Control of Endogenous Receptors
(2026-03-19) Santini, Ramona; Malieieva, Galyna; Sortino, Rosalba; Pons Allés, Santiago; Ramos Guerra, Cristian; Matera, Carlo; Gorostiza Langa, Pablo Ignacio
The study of intact cells and their signaling circuits with light requires a stimulation strategy that is focused, deeply penetrating, and does not damage them. Implanted optic fibers, light-emitting diodes, and luminescent materials operated externally with tissue-penetrating infrared (IR) light are invasive or limited by light attenuation around the illumination point. To overcome these barriers, two-photon pharmacology takes advantage of femtosecond-pulsed IR laser light to produce deep and spatiotemporally precise cellular stimulation using specially designed photoswitchable drugs. Compounds that can be covalently tethered to the target neuroreceptor perform particularly well. However, the tethered photoswitches reported to date require mutagenesis of the target protein, which prevents the use of photopharmacology to stimulate the nervous system in wild-type animals. Here, we report the first two-photon optimized targeted covalent photoswitch (TCP2P) that combines the efficient two-photon isomerization of ortho-fluoro-substituted azobenzene with the ability to conjugate to nucleophilic residues of endogenous proteins (AMPA and kainate ionotropic glutamate receptors in neurons). TCP2P is readily obtained by click coupling of two precursor compounds prior to use, and after simple incubation, it enables controlling neuronal activity at one- and two-photon excitation up to 800 nm without genetic modifications.
Transferrin receptor 1-targeted polymersomes therapy for colorectal cancer
(Elsevier, 2025-08-30) Pina, Ariana; Mastrantuono, Elisa; Silva, Marta Marques de Almeida e; Barbieri, Valentino; Muñoz López, José María; Battaglia, Giuseppe; Graça, Luís; Matias, Diana
Colorectal cancer (CRC) ranks among the most common cancers and is the second leading cause of cancer-related</p><p>deaths. The high mortality associated with CRC is attributed mainly to difficulties in early detection and lack of effective targeted therapies. The Transferrin receptor 1 (TfR1) is particularly attractive as a therapy target given its notable overexpression in tumor cells, particularly in CRC. This study explored the potential of a polymeric nanoparticle (PSomes)-based drug delivery system targeting TfR1 to improve the precision and efficacy of CRC treatment. For this study, we used two human CRC cell lines (HT-29, and HCT116), a healthy human intestinal epithelial cell line (hIECs), and a murine CRC cell line (MC38). We engineered PSomes composed of poly (ethylene glycol) (PEG) and poly (lactic acid) (PLA), functionalized with the T7 peptide to enhance their specificity for TfR1-expressing cells. Targeting efficiency of these PSomes was assessed across all cell lines by evaluating the cellular uptake using flow cytometry. Upon establishing the optimal formulation for these NPs for TfR1-targeting, we encapsulated doxorubicin (DOX) to assess their therapeutic potential. Both in vitro and in vivo experiments demonstrated that DOX loaded TfR1-targeted PSomes delivered DOX to CRC cells, leading to efficient induction of CRC cell death, reducing tumor growth and improving survival rates, compared to the control groups. These results highlight the promise of TfR1-targeted PSomes as a precise strategy for CRCtherapy, offering enhanced treatment efficacy while reducing systemic toxicity. This novel approach could lead to more targeted and less harmful cancer treatments.
Hydrophilic Janus Micelles from an ABC Triblock Copolymer
(Wiley-VCH, 2026-02-23) Muñoz López, José María; Hu, Lei; Wang, Haomin; Tian, Xiaohe; Ruiz-Perez, Lorena; Battaglia, Giuseppe
We describe the creation of an amphiphilic triblock copolymer that drives lateral phase separation within micelle coronas. The design combines a hydrophobic poly(lactide) (PLA) core ‑forming block with two distinct hydrophilic segments: poly(ethylene glycol) (PEG) and poly( N ‑vinylpyrrolidone) (PVP). In water, the copolymer assembles into spherical micelles, confirmed by cryogenic TEM and multi ‑angle light scattering. Selective end ‑labelling of PVP with an electron ‑dense iridium complex enabled unstained TEM imaging, revealing clear contrast asymmetry that locates PVP to a single hemisphere of the corona. Complementary 2D1 H-Nuclear Overhauser Effect Spectroscopy (1 H ‑NOESY) NMR confirmed this Janus ‑type segregation of PEG and PVP. These results demonstrate how molecular architecture can encode asymmetry into soft nanostructures, offering a versatile route to polymer ‑based Janus nanoparticles with dual surface functionality and broad technological potential.
Decoding the Conformation of Polylactic Acid in Block Copolymer Micelles
(American Chemical Society, 2026-01-28) Muñoz López, José María; Tuveri, Gian Marco; Barbieri, Valentino; Basile, Marco; Cosenza, V.; Lorenz, Christian D.; Ruiz-Perez, Lorena; Battaglia, Giuseppe
Understanding how molecular features dictate the self-assembly of amphiphilic block copolymers into well-defined nanostructures is essential for the rational design of advanced soft materials. However, the large number of interdependent parameters involved, such as particle size, aggregation number, interfacial curvature, and molecular weight, makes it challenging to establish general design principles. Here we establish a scaling-based framework for PEG-<em>b</em>-PLA micelles with a fixed hydrophilic–hydrophobic ratio. Systematic variation of molecular weights enables precise control of micelle size and aggregation number, quantified by DLS, cryo-TEM, and MALS.
Structure and mechanistic basis of NrdR, a bacterial master regulator of ribonucleotide reduction
(Elsevier B.V., 2026-02-04) Pedraz López, Lucas; Szura, Arkadiusz; Schmitz, Claus; Rubio Canalejas, Alba; Martínez Mateos, Ángela; Santella, Anthony; Gomila Lluch, Gabriel; Calò, Annalisa; Solà, Maria; Torrents Serra, Eduard
Ribonucleotide reductases (RNRs) are the essential enzymes responsible for synthesizing dNTPs, the building blocks of DNA. In bacteria, the entire RNR network is controlled by the master regulator NrdR. As a regulator of an essential pathway with no eukaryotic equivalent, NrdR is a promising antimicrobial target. Recent structural studies have outlined a mechanism of action for NrdR, in which ATP and dATP induce changes in the protein quaternary structure, regulating RNR repression. However, due to a lack of functional studies linking the known structures to their biological roles, the activation mechanism of NrdR is not yet fully understood. Here, we conducted a comprehensive study of NrdR in Escherichia coli and Pseudomonas aeruginosa. We delimited the NrdR regulon, combining transcriptomics and motif-based sequence analysis. We crystallized E. coli NrdR and identified the protein-protein interfaces involved in its oligomerization, including strong interactions between NrdR dimers to form tetramers, and less stable interfaces connecting such tetramers. We examined the variability of the quaternary structures of NrdR depending on the bound nucleotides by SEC-MALS and atomic force microscopy, and correlated structure to function using point mutations, EMSAs, and in vitro transcription assays. Overall, our results demonstrate the mechanism used by NrdR to modulate its quaternary structure and activity, deciphering essential interactions between subunits, and paving the way for targeted antimicrobial therapies.
Mapping mechanical stress in curved epithelia of designed size and shape
(Nature Publishing Group, 2023-07-07) Marín Llauradó, Ariadna; Kale, Sohan; Ouzeri, Adam; Golde, Tom; Sunyer Borrell, Raimon; Torres Sánchez, Alejandro; Latorre Ibars, Ernest; Gómez González, Manuel; Roca-Cusachs Soulere, Pere; Arroyo, Marino; Trepat Guixer, Xavier
The function of organs such as lungs, kidneys and mammary glands relies on the three-dimensional geometry of their epithelium. To adopt shapes such as spheres, tubes and ellipsoids, epithelia generate mechanical stresses that are generally unknown. Here we engineer curved epithelial monolayers of controlled size and shape and map their state of stress. We design pressurized epithelia with circular, rectangular and ellipsoidal footprints. We develop a computational method, called curved monolayer stress microscopy, to map the stress tensor in these epithelia. This method establishes a correspondence between epithelial shape and mechanical stress without assumptions of material properties. In epithelia with spherical geometry we show that stress weakly increases with areal strain in a size-independent manner. In epithelia with rectangular and ellipsoidal cross-section we find pronounced stress anisotropies that impact cell alignment. Our approach enables a systematic study of how geometry and stress influence epithelial fate and function in three-dimensions.
Competition for endothelial cell polarity drives vascular morphogenesis in the mouse retina
(Elsevier, 2022-10-10) Barbacena, Pedro; Dominguez Cejudo, Maria; Fonseca, Catarina G.; Gómez González, Manuel; Faure, Laura M.; Zarkada, Georgia; Pena, Andreia; Pezzarossa, Anna; Ramalho, Daniela; Giarratano, Ylenia; Ouarné, Marie; Barata, David; Fortunato, Isabela Corina Santos; Henao Misikova, Lenka; Mauldin, Ian; Carvalho, Yulia; Trepat Guixer, Xavier; Roca-Cusachs Soulere, Pere; Eichmann, Anne; Bernabeu, Miguel O.; Franco, Claudio A.
Blood-vessel formation generates unique vascular patterns in each individual. The principles governing the apparent stochasticity of this process remain to be elucidated. Using mathematical methods, we find that the transition between two fundamental vascular morphogenetic programs—sprouting angiogenesis and vascular remodeling—is established by a shift of collective front-to-rear polarity of endothelial cells in the mouse retina. We demonstrate that the competition between biochemical (VEGFA) and mechanical (blood-flow-induced shear stress) cues controls this collective polarity shift. Shear stress increases tension at focal adhesions overriding VEGFA-driven collective polarization, which relies on tension at adherens junctions. We propose that vascular morphogenetic cues compete to regulate individual cell polarity and migration through tension shifts that translates into tissue-level emergent behaviors, ultimately leading to uniquely organized vascular patterns.
3D Micropatterned Traction Force Microscopy: A Technique to Control 3D Cell Shape While Measuring Cell-Substrate Force Transmissio
(Wiley-VCH Verlag, 2024-10-23) Faure, Laura M.; Gómez González, Manuel; Baguer, Ona; Comelles Pujadas, Jordi; Martínez, Elena; Arroyo, Marino; Trepat Guixer, Xavier; Roca-Cusachs Soulere, Pere
Cell shape and function are intimately linked, in a way that is mediated by the forces exerted between cells and their environment. The relationship between cell shape and forces has been extensively studied for cells seeded on flat 2D substrates, but not for cells in more physiological 3D settings. Here, a technique called 3D micropatterned traction force microscopy (3D-µTFM) to confine cells in 3D wells of defined shape, while simultaneously measuring the forces transmitted between cells and their microenvironment is demonstrated. This technique is based on the 3D micropatterning of polyacrylamide wells and on the calculation of 3D traction force from their deformation. With 3D-µTFM, it is shown that MCF10A breast epithelial cells exert defined, reproducible patterns of forces on their microenvironment, which can be both contractile and extensile. Cells switch from a global contractile to extensile behavior as their volume is reduced are further shown. The technique enables the quantitative study of cell mechanobiology with full access to 3D cellular forces while having accurate control over cell morphology and the mechanical conditions of the microenvironment.

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