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Year 2019


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Pérez-González, Carlos, Alert, Ricard, Blanch-Mercader, Carles, Gómez-González, Manuel, Kolodziej, Tomasz, Bazellieres, Elsa, Casademunt, Jaume, Trepat, Xavier, (2019). Active wetting of epithelial tissues Nature Physics 15, 79-88

Development, regeneration and cancer involve drastic transitions in tissue morphology. In analogy with the behaviour of inert fluids, some of these transitions have been interpreted as wetting transitions. The validity and scope of this analogy are unclear, however, because the active cellular forces that drive tissue wetting have been neither measured nor theoretically accounted for. Here we show that the transition between two-dimensional epithelial monolayers and three-dimensional spheroidal aggregates can be understood as an active wetting transition whose physics differs fundamentally from that of passive wetting phenomena. By combining an active polar fluid model with measurements of physical forces as a function of tissue size, contractility, cell–cell and cell–substrate adhesion, and substrate stiffness, we show that the wetting transition results from the competition between traction forces and contractile intercellular stresses. This competition defines a new intrinsic length scale that gives rise to a critical size for the wetting transition in tissues, a striking feature that has no counterpart in classical wetting. Finally, we show that active shape fluctuations are dynamically amplified during tissue dewetting. Overall, we conclude that tissue spreading constitutes a prominent example of active wetting—a novel physical scenario that may explain morphological transitions during tissue morphogenesis and tumour progression.


Schierwagen, Robert, Alvarez-Silva, Camila, Madsen, Mette Simone Aae, Kolbe, Carl Christian, Meyer, Carsten, Thomas, Daniel, Uschner, Frank Erhard, Magdaleno, Fernando, Jansen, Christian, Pohlmann, Alessandra, Praktiknjo, Michael, Hischebeth, Gunnar T., Molitor, Ernst, Latz, Eicke, Lelouvier, Benjamin, Trebicka, Jonel, Arumugam, Manimozhiyan, (2019). Circulating microbiome in blood of different circulatory compartments Gut In press,

Pose, Elisa, Trebicka, Jonel, Mookerjee, Rajeshwar P., Angeli, Paolo, Ginès, Pere, (2019). Statins: Old drugs as new therapy for liver diseases? Journal of Hepatology 70, (1), 194-202

In addition to lowering cholesterol levels, statins have pleiotropic effects, particularly anti-inflammatory, antiangiogenic, and antifibrotic, that may be beneficial in some chronic inflammatory conditions. Statins have only recently been investigated as a potential treatment option in chronic liver diseases because of concerns related to their safety in patients with impaired liver function. A number of experimental studies in animal models of liver diseases have shown that statins decrease hepatic inflammation, fibrogenesis and portal pressure. In addition, retrospective cohort studies in large populations of patients with cirrhosis and pre-cirrhotic conditions have shown that treatment with statins, with the purpose of decreasing high cholesterol levels, was associated with a reduced risk of disease progression, hepatic decompensation, hepatocellular carcinoma development, and death. These beneficial effects persisted after adjustment for disease severity and other potential confounders. Finally, a few randomised controlled trials have shown that treatment with simvastatin decreases portal pressure (two studies) and mortality (one study). Statin treatment was generally well tolerated but a few patients developed severe side effects, particularly rhabdomyolysis. Despite these promising beneficial effects, further randomised controlled trials in large series of patients with hard clinical endpoints should be performed before statins can be recommended for use in clinical practice.


Horteläo, Ana C., Carrascosa, Rafael, Murillo-Cremaes, Nerea, Patiño, Tania, Sánchez, Samuel, (2019). Targeting 3D bladder cancer spheroids with urease-powered nanomotors ACS Nano 13, (1), 429-439

Cancer is one of the main causes of death around the world, lacking efficient clinical treatments that generally present severe side effects. In recent years, various nanosystems have been explored to specifically target tumor tissues, enhancing the efficacy of cancer treatment and minimizing the side effects. In particular, bladder cancer is the ninth most common cancer worldwide and presents a high survival rate but serious recurrence levels, demanding an improvement in the existent therapies. Here, we present urease-powered nanomotors based on mesoporous silica nanoparticles that contain both polyethylene glycol and anti-FGFR3 antibody on their outer surface to target bladder cancer cells in the form of 3D spheroids. The autonomous motion is promoted by urea, which acts as fuel and is inherently present at high concentrations in the bladder. Antibody-modified nanomotors were able to swim in both simulated and real urine, showing a substrate-dependent enhanced diffusion. The internalization efficiency of the antibody-modified nanomotors into the spheroids in the presence of urea was significantly higher compared with antibody-modified passive particles or bare nanomotors. Furthermore, targeted nanomotors resulted in a higher suppression of spheroid proliferation compared with bare nanomotors, which could arise from the local ammonia production and the therapeutic effect of anti-FGFR3. These results hold significant potential for the development of improved targeted cancer therapy and diagnostics using biocompatible nanomotors.

Keywords: 3D cell culture, Bladder cancer, Enzymatic catalysis, Nanomachines, Nanomotors, Self-propulsion, Targeting


Patino, Tania, Porchetta, Alessandro, Jannasch, Anita, Lladó, Anna, Stumpp, Tom, Schäffer, Erik, Ricci, Francesco, Sánchez, Samuel, (2019). Self-sensing enzyme-powered micromotors equipped with pH-responsive DNA nanoswitches Nano Letters 19, (6), 3440-3447

Biocatalytic micro- and nanomotors have emerged as a new class of active matter self-propelled through enzymatic reactions. The incorporation of functional nanotools could enable the rational design of multifunctional micromotors for simultaneous real-time monitoring of their environment and activity. Herein, we report the combination of DNA nanotechnology and urease-powered micromotors as multifunctional tools able to swim, simultaneously sense the pH of their surrounding environment, and monitor their intrinsic activity. With this purpose, a FRET-labeled triplex DNA nanoswitch for pH sensing was immobilized onto the surface of mesoporous silica-based micromotors. During self-propulsion, urea decomposition and the subsequent release of ammonia led to a fast pH increase, which was detected by real-time monitoring of the FRET efficiency through confocal laser scanning microscopy at different time points (i.e., 30 s, 2 and 10 min). Furthermore, the analysis of speed, enzymatic activity, and propulsive force displayed a similar exponential decay, matching the trend observed for the FRET efficiency. These results illustrate the potential of using specific DNA nanoswitches not only for sensing the micromotors’ surrounding microenvironment but also as an indicator of the micromotor activity status, which may aid to the understanding of their performance in different media and in different applications.

Keywords: Micromotors, DNA-nanoswitch, pH detection, Self-propulsion, Nanosensors, Nanomotors


Wang, Lei, Hortelão, Ana C., Huang, Xin, Sánchez, Samuel, (2019). Lipase-powered mesoporous silica nanomotors for triglyceride degradation Angewandte Chemie International Edition 58, (24), 7992-7996

We report lipase-based nanomotors that are capable of enhanced Brownian motion over long periods of time in triglyceride solution and of degrading triglyceride droplets that mimic “blood lipids”. We achieved about 40 min of enhanced diffusion of lipase-modified mesoporous silica nanoparticles (MSNPs) through a biocatalytic reaction between lipase and its corresponding water-soluble oil substrate (triacetin) as fuel, which resulted in an enhanced diffusion coefficient (ca. 50 % increase) at low triacetin concentration (<10 mm). Lipase not only serves as the power engine but also as a highly efficient cleaner for the triglyceride droplets (e.g., tributyrin) in PBS solution, which could yield potential biomedical applications, for example, for dealing with diseases related to the accumulation of triglycerides, or for environmental remediation, for example, for the degradation of oil spills.

Keywords: Enzyme nanomotors, Lipase, Micromotors, Oil removal, Self-propulsion


Pacheco Estefan, D., Sánchez-Fibla, M., Duff, A., Principe, A., Rocamora, R., Zhang, H., Axmacher, N., Verschure, P., (2019). Coordinated representational reinstatement in the human hippocampus and lateral temporal cortex during episodic memory retrieval Nature Communications 10, (1), 2255

Theoretical models of episodic memory have proposed that retrieval depends on interactions between the hippocampus and neocortex, where hippocampal reinstatement of item-context associations drives neocortical reinstatement of item information. Here, we simultaneously recorded intracranial EEG from hippocampus and lateral temporal cortex (LTC) of epilepsy patients who performed a virtual reality spatial navigation task. We extracted stimulus-specific representations of both item and item-context associations from the time-frequency patterns of activity in hippocampus and LTC. Our results revealed a double dissociation of representational reinstatement across time and space: an early reinstatement of item-context associations in hippocampus preceded a later reinstatement of item information in LTC. Importantly, reinstatement levels in hippocampus and LTC were correlated across trials, and the quality of LTC reinstatement was predicted by the magnitude of phase synchronization between hippocampus and LTC. These findings confirm that episodic memory retrieval in humans relies on coordinated representational interactions within a hippocampal-neocortical network.


Arqué, Xavier, Romero-Rivera, Adrian, Feixas, Ferran, Patiño, Tania, Osuna, Sílvia, Sánchez, Samuel, (2019). Intrinsic enzymatic properties modulate the self-propulsion of micromotors Nature Communications 10, (1), 2826

Bio-catalytic micro- and nanomotors self-propel by the enzymatic conversion of substrates into products. Despite the advances in the field, the fundamental aspects underlying enzyme-powered self-propulsion have rarely been studied. In this work, we select four enzymes (urease, acetylcholinesterase, glucose oxidase, and aldolase) to be attached on silica microcapsules and study how their turnover number and conformational dynamics affect the self-propulsion, combining both an experimental and molecular dynamics simulations approach. Urease and acetylcholinesterase, the enzymes with higher catalytic rates, are the only enzymes capable of producing active motion. Molecular dynamics simulations reveal that urease and acetylcholinesterase display the highest degree of flexibility near the active site, which could play a role on the catalytic process. We experimentally assess this hypothesis for urease micromotors through competitive inhibition (acetohydroxamic acid) and increasing enzyme rigidity (β-mercaptoethanol). We conclude that the conformational changes are a precondition of urease catalysis, which is essential to generate self-propulsion.

Keywords: Biocatalysis, Immobilized enzymes, Molecular machines and motors


Cabré, Gisela, Garrido-Charles, Aida, Moreno, Miquel, Bosch, Miquel, Porta-de-la-Riva, Montserrat, Krieg, Michael, Gascón-Moya, Marta, Camarero, Núria, Gelabert, Ricard, Lluch, José M., Busqué, F., Hernando, Jordi, Gorostiza, Pau, Alibés, Ramon, (2019). Rationally designed azobenzene photoswitches for efficient two-photon neuronal excitation Nature Communications 10, (1), 907

Manipulation of neuronal activity using two-photon excitation of azobenzene photoswitches with near-infrared light has been recently demonstrated, but their practical use in neuronal tissue to photostimulate individual neurons with three-dimensional precision has been hampered by firstly, the low efficacy and reliability of NIR-induced azobenzene photoisomerization compared to one-photon excitation, and secondly, the short cis state lifetime of the two-photon responsive azo switches. Here we report the rational design based on theoretical calculations and the synthesis of azobenzene photoswitches endowed with both high two-photon absorption cross section and slow thermal back-isomerization. These compounds provide optimized and sustained two-photon neuronal stimulation both in light-scattering brain tissue and in Caenorhabditis elegans nematodes, displaying photoresponse intensities that are comparable to those achieved under one-photon excitation. This finding opens the way to use both genetically targeted and pharmacologically selective azobenzene photoswitches to dissect intact neuronal circuits in three dimensions.


Cutrale, Francesco, Rodriguez, Daniel, Hortigüela, Verónica, Chiu, Chi-Li, Otterstrom, Jason, Mieruszynski, Stephen, Seriola, Anna, Larrañaga, Enara, Raya, Angel, Lakadamyali, Melike, Fraser, Scott E., Martinez, Elena, Ojosnegros, Samuel, (2019). Using enhanced number and brightness to measure protein oligomerization dynamics in live cells Nature Protocols 14, 616-638

Protein dimerization and oligomerization are essential to most cellular functions, yet measurement of the size of these oligomers in live cells, especially when their size changes over time and space, remains a challenge. A commonly used approach for studying protein aggregates in cells is number and brightness (N&B), a fluorescence microscopy method that is capable of measuring the apparent average number of molecules and their oligomerization (brightness) in each pixel from a series of fluorescence microscopy images. We have recently expanded this approach in order to allow resampling of the raw data to resolve the statistical weighting of coexisting species within each pixel. This feature makes enhanced N&B (eN&B) optimal for capturing the temporal aspects of protein oligomerization when a distribution of oligomers shifts toward a larger central size over time. In this protocol, we demonstrate the application of eN&B by quantifying receptor clustering dynamics using electron-multiplying charge-coupled device (EMCCD)-based total internal reflection microscopy (TIRF) imaging. TIRF provides a superior signal-to-noise ratio, but we also provide guidelines for implementing eN&B in confocal microscopes. For each time point, eN&B requires the acquisition of 200 frames, and it takes a few seconds up to 2 min to complete a single time point. We provide an eN&B (and standard N&B) MATLAB software package amenable to any standard confocal or TIRF microscope. The software requires a high-RAM computer (64 Gb) to run and includes a photobleaching detrending algorithm, which allows extension of the live imaging for more than an hour.


Castaño, Albert G., García-Díaz, María, Torras, Núria, Altay, Gizem, Comelles, Jordi, Martínez, Elena, (2019). Dynamic photopolymerization produces complex microstructures on hydrogels in a moldless approach to generate a 3D intestinal tissue model Biofabrication 11, (2), 025007

Epithelial tissues contain three-dimensional (3D) complex microtopographies that are essential for proper performance. These microstructures provide cells with the physicochemical cues needed to guide their self-organization into functional tissue structures. However, most in vitro models do not implement these 3D architectural features. The main problem is the availability of simple fabrication techniques that can reproduce the complex geometries found in native tissues on the soft polymeric materials required as cell culture substrates. In this study reaction-diffusion mediated photolithography is used to fabricate 3D microstructures with complex geometries on poly(ethylene glycol)-based hydrogels in a single step and moldless approach. By controlling fabrication parameters such as the oxygen diffusion/depletion timescales, the distance to the light source and the exposure dose, the dimensions and geometry of the microstructures can be well-defined. In addition, copolymerization of poly(ethylene glycol) with acrylic acid improves control of the dynamic reaction-diffusion processes that govern the free-radical polymerization of highly-diluted polymeric solutions. Moreover, acrylic acid allows adjusting the density of cell adhesive ligands while preserving the mechanical properties of the hydrogels. The method proposed is a simple, single-step, and cost-effective strategy for producing models of intestinal epithelium that can be easily integrated into standard cell culture platforms.


Ortega, María A., Fernández-Garibay, Xiomara, Castaño, Albert G., De Chiara, Francesco, Hernández-Albors, Alejandro, Balaguer-Trias, Jordina, Ramón-Azcón, Javier, (2019). Muscle-on-a-chip with an on-site multiplexed biosensing system for in situ monitoring of secreted IL-6 and TNF-α Lab on a Chip Advance Article ,

Despite the increasing number of organs-on-a-chip that have been developed in the past decade, limited efforts have been made to integrate a sensing system for in situ continual measurements of biomarkers from three-dimensional (3D) tissues. Here, we present a custom-made integrated platform for muscle cell stimulation under fluidic conditions connected with a multiplexed high-sensitivity electrochemical sensing system for in situ monitoring. To demonstrate this, we use our system to measure the release levels and release time of interleukin 6 and tumor necrosis factor alpha in vitro by 3D muscle microtissue under electrical and biological stimulations. Our experimental design has enabled us to perform multiple time point measurements using functionalized screen-printed gold electrodes with sensitivity in the ng mL−1 range. This affordable setup is uniquely suited for monitoring factors released by 3D single cell types upon external stimulation for metabolic studies.


Ohui, K., Afanasenko, E., Bacher, F., Ting, R. L. X., Zafar, A., Blanco-Cabra, N., Torrents, E., Dömötör, O., May, N. V., Darvasiova, D., Enyedy, Éva A., Popovi, Reynisson, J., Rapta, P., Babak, M. V., Pastorin, G., Arion, V. B., (2019). New water-soluble copper(II) complexes with morpholine-thiosemicarbazone hybrids: Insights into the anticancer and antibacterial mode of action Journal of Medicinal Chemistry 62, (2), 512-530

Six morpholine-(iso)thiosemicarbazone hybrids HL1–HL6 and their Cu(II) complexes with good-to-moderate solubility and stability in water were synthesized and characterized. Cu(II) complexes [Cu(L1–6)Cl] (1–6) formed weak dimeric associates in the solid state, which did not remain intact in solution as evidenced by ESI-MS. The lead proligands and Cu(II) complexes displayed higher antiproliferative activity in cancer cells than triapine. In addition, complexes 2–5 were found to specifically inhibit the growth of Gram-positive bacteria Staphylococcus aureus with MIC50 values at 2–5 μg/mL. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 2 and 5, including the role of ribonucleotide reductase (RNR) inhibition, endoplasmic reticulum stress induction, and regulation of other cancer signaling pathways. Their ability to moderately inhibit R2 RNR protein in the presence of dithiothreitol is likely related to Fe chelating properties of the proligands liberated upon reduction.


Sadowska, J. M., Guillem-Marti, J., Ginebra, M. P., (2019). The influence of physicochemical properties of biomimetic hydroxyapatite on the in vitro behavior of endothelial progenitor cells and their interaction with mesenchymal stem cells Advanced Healthcare Materials 8, (2), 1801138

Calcium phosphate (CaP) substrates are successfully used as bone grafts due to their osteogenic properties. However, the influence of the physicochemical features of CaPs in angiogenesis is frequently neglected despite it being a crucial process for bone regeneration. The present work focuses on analyzing the effects of textural parameters of biomimetic calcium deficient hydroxyapatite (CDHA) and sintered beta-tricalcium phosphate (β-TCP), such as specific surface area, surface roughness, and microstructure, on the behavior of rat endothelial progenitor cells (rEPCs) and their crosstalk with rat mesenchymal stem cells (rMSCs). The higher reactivity of CDHA results in low proliferation rates in monocultured and cocultured systems. This effect is especially pronounced for rMSCs alone, and for CDHA with a fine microstructure. In terms of angiogenic and osteogenic gene expressions, the upregulation of particular genes is especially enhanced for needle-like CDHA compared to plate-like CDHA and β-TCP, suggesting the importance not only of the chemistry of the substrate, but also of its textural features. Moreover, the coculture of rEPCs and rMSCs on needle-like CDHA results in early upregulation of osteogenic modulator, i.e., protein deglycase 1 might be a possible cause of overexpression of osteogenic-related genes on the same substrate.

Keywords: Angiogenesis, Calcium phosphates, Cocultures, Osteogenesis


Mestres, G., Fernandez-Yague, M. A., Pastorino, D., Montufar, E. B., Canal, C., Manzanares-Céspedes, M. C., Ginebra, M. P., (2019). In vivo efficiency of antimicrobial inorganic bone grafts in osteomyelitis treatments Materials Science and Engineering: C 97, 84-95

The purpose of the present work was to evaluate in vivo different antimicrobial therapies to eradicate osteomyelitis created in the femoral head of New Zealand rabbits. Five phosphate-based cements were evaluated: calcium phosphate cements (CPC) and calcium phosphate foams (CPF), both in their pristine form and loaded with doxycycline hyclate, and an intrinsic antimicrobial magnesium phosphate cement (MPC; not loaded with an antibiotic). The cements were implanted in a bone previously infected with Staphylococcus aureus to discern the effects of the type of antibiotic administration (systemic vs. local), porosity (microporosity, i.e. <5 μm vs. macroporosity, i.e. >5 μm) and type of antimicrobial mechanism (release of antibiotic vs. intrinsic antimicrobial activity) on the improvement of the health state of the infected animals. A new method was developed, with a more comprehensive composite score that integrates 5 parameters of bone infection, 4 parameters of bone structural integrity and 4 parameters of bone regeneration. This method was used to evaluate the health state of the infected animals, both before and after osteomyelitis treatment. The results showed that the composite score allows to discern statistically significant differences between treatments that individual evaluations were not able to identify. Despite none of the therapies completely eradicated the infection, it was observed that macroporous materials (CPF and CPFd, the latter loaded with doxycycline hyclate) and intrinsic antimicrobial MPC allowed a better containment of the osteomyelitis. This study provides novel insights to understand the effect of different antimicrobial therapies in vivo, and a promising comprehensive methodology to evaluate the health state of the animals was developed. We expect that the implementation of such methodology could improve the criteria to select a proper antimicrobial therapy.

Keywords: Calcium phosphate cements, Calcium phosphate foams, Drug delivery, In vivo, Magnesium phosphate cements, Osteomyelitis


Martinez, Elena, St-Pierre, Jean-Philippe, Variola, Fabio, (2019). Advanced bioengineering technologies for preclinical research Advances in Physics: X 4, (1), 1622451

ABSTRACTCurrent in vitro practices must overcome important challenges to compare favorably with human studies. The limited applicability of conventional in vitro assays and strategies can be explained by the fact that standard approaches do not enable recapitulation of the complexity of human tissues and physiological functions. To address this challenge, novel bioengineering tools, techniques and technologies are rapidly emerging to advance current fundamental knowledge and innovate in vitro practices. For example, organs-on-a-chip have recently appeared as a small-scale solution to overcome the transability, financial and ethical concerns associated with animal studies in drug discovery and development. In parallel, biomimetic interfaces are increasingly recapitulating 3D structures with tissue-like dynamic properties to allow in-depth investigation of disease mechanisms. This review aims at highlighting current bioengineering approaches poised to address the shortcomings of conventional in vitro research practices towards the generation of more effective solutions for improving human health.


Mestre, Rafael, Patiño, Tania, Barceló, Xavier, Anand, Shivesh, Pérez-Jiménez, Ariadna, Sánchez, Samuel, (2019). Force modulation and adaptability of 3D-bioprinted biological actuators based on skeletal muscle tissue Advanced Materials Technologies 4, (2), 1800631

Abstract The integration of biological systems into robotic devices might provide them with capabilities acquired from natural systems and significantly boost their performance. These abilities include real-time bio-sensing, self-organization, adaptability, or self-healing. As many muscle-based bio-hybrid robots and bio-actuators arise in the literature, the question of whether these features can live up to their expectations becomes increasingly substantial. Herein, the force generation and adaptability of skeletal-muscle-based bio-actuators undergoing long-term training protocols are analyzed. The 3D-bioprinting technique is used to fabricate bio-actuators that are functional, responsive, and have highly aligned myotubes. The bio-actuators are 3D-bioprinted together with two artificial posts, allowing to use it as a force measuring platform. In addition, the force output evolution and dynamic gene expression of the bio-actuators are studied to evaluate their degree of adaptability according to training protocols of different frequencies and mechanical stiffness, finding that their force generation could be modulated to different requirements. These results shed some light into the fundamental mechanisms behind the adaptability of muscle-based bio-actuators and highlight the potential of using 3D bioprinting as a rapid and cost-effective tool for the fabrication of custom-designed soft bio-robots.


Hortigüela, Verónica, Larrañaga, Enara, Lagunas, Anna, Acosta, Gerardo A., Albericio, Fernando, Andilla, Jordi, Loza-Alvarez, Pablo, Martínez, Elena, (2019). Large-area biomolecule nanopatterns on diblock copolymer surfaces for cell adhesion studies Nanomaterials 9, (4), 579

Cell membrane receptors bind to extracellular ligands, triggering intracellular signal transduction pathways that result in specific cell function. Some receptors require to be associated forming clusters for effective signaling. Increasing evidences suggest that receptor clustering is subjected to spatially controlled ligand distribution at the nanoscale. Herein we present a method to produce in an easy, straightforward process, nanopatterns of biomolecular ligands to study ligand–receptor processes involving multivalent interactions. We based our platform in self-assembled diblock copolymers composed of poly(styrene) (PS) and poly(methyl methacrylate) (PMMA) that form PMMA nanodomains in a closed-packed hexagonal arrangement. Upon PMMA selective functionalization, biomolecular nanopatterns over large areas are produced. Nanopattern size and spacing can be controlled by the composition of the block-copolymer selected. Nanopatterns of cell adhesive peptides of different size and spacing were produced, and their impact in integrin receptor clustering and the formation of cell focal adhesions was studied. Cells on ligand nanopatterns showed an increased number of focal contacts, which were, in turn, more matured than those found in cells cultured on randomly presenting ligands. These findings suggest that our methodology is a suitable, versatile tool to study and control receptor clustering signaling and downstream cell behavior through a surface-based ligand patterning technique.


Altay, Gizem, Larrañaga, Enara, Tosi, Sébastien, Barriga, Francisco M., Batlle, Eduard, Fernández-Majada, Vanesa, Martínez, Elena, (2019). Self-organized intestinal epithelial monolayers in crypt and villus-like domains show effective barrier function Scientific Reports 9, (1), 10140

Intestinal organoids have emerged as a powerful in vitro tool for studying intestinal biology due to their resemblance to in vivo tissue at the structural and functional levels. However, their sphere-like geometry prevents access to the apical side of the epithelium, making them unsuitable for standard functional assays designed for flat cell monolayers. Here, we describe a simple method for the formation of epithelial monolayers that recapitulates the in vivo-like cell type composition and organization and that is suitable for functional tissue barrier assays. In our approach, epithelial monolayer spreading is driven by the substrate stiffness, while tissue barrier function is achieved by the basolateral delivery of medium enriched with stem cell niche and myofibroblast-derived factors. These monolayers contain major intestinal epithelial cell types organized into proliferating crypt-like domains and differentiated villus-like regions, closely resembling the in vivo cell distribution. As a unique characteristic, these epithelial monolayers form functional epithelial barriers with an accessible apical surface and physiologically relevant transepithelial electrical resistance values. Our technology offers an up-to-date and novel culture method for intestinal epithelium, providing an in vivo-like cell composition and distribution in a tissue culture format compatible with high-throughput drug absorption or microbe-epithelium interaction studies.


Manconi, M., Manca, M. L., Escribano-Ferrer, E., Coma-Cros, E. M., Biosca, A., Lantero, E., Fernàndez-Busquets, X., Fadda, A. M., Caddeo, C., (2019). Nanoformulation of curcumin-loaded eudragit-nutriosomes to counteract malaria infection by a dual strategy: Improving antioxidant intestinal activity and systemic efficacy International Journal of Pharmaceutics 556, 82-88

In this paper, nutriosomes (phospholipid vesicles associated with Nutriose® FM06) were modified to obtain new systems aimed at enhancing the efficacy of curcumin in counteracting malaria infection upon oral administration. Eudragit® L100, a pH-sensitive co-polymer, was added to these vesicles, thus obtaining eudragit-nutriosomes, to improve their in vivo performances. Liposomes without eudragit and nutriose were also prepared as a reference. Cryo-TEM images showed the formation of multicompartment vesicles, with mean diameter around 300 nm and highly negative zeta potential. Vesicles were stable in fluids mimicking the gastro-intestinal content due to the high phospholipid concentration and the presence of gastro-resistant eudragit and digestion-resistant nutriose. Eudragit-nutriosomes disclosed promising performances in vitro and in vivo: they maximized the ability of curcumin to counteract oxidative stress in intestinal cells (Caco-2), which presumably reinforced its systemic efficacy. Orally-administered curcumin-loaded eudragit-nutriosomes increased significantly the survival of malaria-infected mice relative to free curcumin-treated controls.

Keywords: Eudragit® L100, Nutriose® FM06, Nutriosomes, Curcumin, Oral administration, Malaria


de Goede, M., Dijkstra, M., Obregón, R., Ramón-Azcón, J., Martínez, E., Padilla, L., Mitjans, F., Garcia-Blanco, S. M., (2019). Al2O3 microring resonators for the detection of a cancer biomarker in undiluted urine Optics Express 27, (13), 18508-18521

Concentrations down to 3 nM of the rhS100A4 protein, associated with human tumor development, have been detected in undiluted urine using an integrated sensor based on microring resonators in the emerging Al2O3 photonic platform. The fabricated microrings were designed for operation in the C-band (λ = 1565 nm) and exhibited a high-quality factor in air of 3.2 × 105. The bulk refractive index sensitivity of the devices was ~100 nm/RIU (for TM polarization) with a limit of detection of ~10−6 RIU. A surface functionalization protocol was developed to allow for the selective binding of the monoclonal antibodies designed to capture the target biomarker to the surface of the Al2O3 microrings. The detection of rhS100A4 proteins at clinically relevant concentrations in urine is a big milestone towards the use of biosensors for the screening and early diagnosis of different cancers. Biosensors based on this microring technology can lead to portable, multiplexed and easy-to-use point of care devices.

Keywords: Distributed feedback lasers, Effective refractive index, Laser coupling, Polarization maintaining fibers, Refractive index, Scanning electron microscopy


Rafols-de-Urquia, M., Estrada, L., Estevez-Piorno, J., Sarlabous, L., Jane, R., Torres, A., (2019). Evaluation of a wearable device to determine cardiorespiratory parameters from surface diaphragm electromyography IEEE Journal of Biomedical and Health Informatics Early Access

The use of wearable devices in clinical routines could reduce healthcare costs and improve the quality of assessment in patients with chronic respiratory diseases. The purpose of this study is to evaluate the capacity of a Shimmer3 wearable device to extract reliable cardiorespiratory parameters from surface diaphragm electromyography (EMGdi). Twenty healthy volunteers underwent an incremental load respiratory test whilst EMGdi was recorded with a Shimmer3 wearable device (EMGdiW). Simultaneously, a second EMGdi (EMGdiL), inspiratory mouth pressure (Pmouth) and lead-I electrocardiogram (ECG) were recorded via a standard wired laboratory acquisition system. Different cardiorespiratory parameters were extracted from both EMGdiW and EMGdiL signals: heart rate, respiratory rate, respiratory muscle activity and mean frequency of EMGdi signals. Alongside these, similar parameters were also extracted from reference signals (Pmouth and ECG). High correlations were found between the data extracted from the EMGdiW and the reference signal data: heart rate (R = 0.947), respiratory rate (R = 0.940), respiratory muscle activity (R = 0.877), and mean frequency (R = 0.895). Moreover, similar increments in EMGdiW and EMGdiL activity were observed when Pmouth was raised, enabling the study of respiratory muscle activation. In summary, the Shimmer3 device is a promising and cost-effective solution for the ambulatory monitoring of respiratory muscle function in chronic respiratory diseases. IEEE

Keywords: Cardiorespiratory monitoring, Chronic respiratory diseases, Fixed sample entropy, Non-invasive respiratory monitoring, Surface diaphragm electromyography, Wearable wireless device


Nevola, Laura, Varese, Monica, Martín-Quirós, Andrés, Mari, Giacomo, Eckelt, Kay, Gorostiza, Pau, Giralt, Ernest, (2019). Targeted nanoswitchable inhibitors of protein-protein interactions involved in apoptosis ChemMedChem 14, 100-106

Progress in drug delivery is hampered by the lack of efficient strategies to target drugs with high specificity and precise spatiotemporal regulation. The remote control of nanoparticles and drugs with light allows controlling their action site and dosage. Peptide-based drugs are very specific, non-immunogenic and can be designed to cross the plasma membrane. In order to combine target specificity and remote control of drug action, here we describe a versatile strategy based on a generalized template to design nanoswitchable peptides that modulate protein-protein interactions with light. This approach is demonstrated to photomodulate two important targets involved in apoptosis (the interactions Bcl-xL/Bak and MDM2/p53), but can be applied to a large pool of therapeutically relevant protein-protein interactions mediated by alpha helical motifs. The template can be adjusted using readily available information about the hot spots (residues contributing most to the binding energy) at the protein-protein interface of interest.


Vidal, E., Buxadera-Palomero, J., Pierre, C., Manero, J. M., Ginebra, M. P., Cazalbou, S., Combes, C., Rupérez, E., Rodríguez, D., (2019). Single-step pulsed electrodeposition of calcium phosphate coatings on titanium for drug delivery Surface and Coatings Technology 358, 266-275

Metallic implants have some limitations related to bioactivity and bacteria colonization leading to infections. In this regard, calcium phosphate coatings can be used as carrier for drug delivery in order to improve the mentioned drawbacks. The present work proposes the introduction of an antibacterial agent in the course of a pulsed and reverse pulsed electrodeposition. Calcium phosphate coatings were prepared in 30 min using different pulse waveforms (unipolar-bipolar), current densities (2–5 mA/cm2) and temperatures (40–60 °C). Mechanical stability of the as-coated surfaces was studied in order to select the optimal electrodeposition conditions. Subsequently, selected coatings were loaded with an antiseptic agent, chlorhexidine digluconate (CHX), via a single-step co-deposition procedure. CHX concentration added to the electrolyte was adjusted to 3 mM based on the antibacterial efficacy of the loaded coatings evaluated in vitro with Staphylococcus aureus and Escherichia coli bacteria strains. Whereas the same chlorhexidine concentration was added to the electrolyte, results showed that the amount of CHX loaded was different for each condition while release kinetics was maintained. The results of this work demonstrate that a pulsed co-deposition strategy has great potential to modulate local delivery of antibacterial agents such as chlorhexidine digluconate, which may prevent early phase infections of metallic implants after insertion.

Keywords: Antibacterial agent, Calcium phosphate, Characterization, Coating, Pulse electrodeposition, Titanium


Oliveira, V. R., Uriarte, J. J., Falcones, B., Zin, W. A., Navajas, D., Farré, R., Almendros, I., (2019). Escherichia coli lipopolysaccharide induces alveolar epithelial cell stiffening Journal of Biomechanics 83, 315-318

Introduction: Application of lipopolysaccharide (LPS) is a widely employed model to mimic acute respiratory distress syndrome (ARDS). Available data regarding LPS-induced biomechanical changes on pulmonary epithelial cells are limited only to P. aeruginosa LPS. Considering that LPS from different bacteria could promote a specific mechanical response in epithelial cells, we aim to assess the effect of E. coli LPS, widely employed as a model of ARDS, in the biomechanics of alveolar epithelial cells. Methods: Young’s modulus (E) of alveolar epithelial cells (A549) was measured by atomic force microscopy every 5 min throughout 60 min of experiment after treatment with LPS from E. coli (100 μg/mL). The percentage of cells presenting actin stress fibers (F-actin staining) was also evaluated. Control cells were treated with culture medium and the values obtained were compared with LPS-treated cells for each time-point. Results: Application of LPS induced significant increase in E after 20 min (77%) till 60 min (104%) in comparison to controls. Increase in lung epithelial cell stiffness induced by LPS was associated with a higher number of cells presenting cytoskeletal remodeling. Conclusions: The observed effects of E. coli LPS on alveolar epithelial cells suggest that this widely-used LPS is able to promote a quick formation of actin stress fibers and stiffening cells, thereby facilitating the disruption of the pulmonary epithelial barrier.

Keywords: Acute respiratory distress syndrome model, Alveolar epithelium, Biomechanics, E. coli, Lipopolysaccharide


Ruzzene, G., Omelchenko, I., Schöl, E., Zakharova, A., Andrzejak, R. G. , (2019). Controlling chimera states via minimal coupling modification Chaos: An Interdisciplinary Journal of Nonlinear Science 29, (5), 051103

We propose a method to control chimera states in a ring-shaped network of nonlocally coupled phase oscillators. This method acts exclusively on the network’s connectivity. Using the idea of a pacemaker oscillator, we investigate which is the minimal action needed to control chimeras. We implement the pacemaker choosing one oscillator and making its links unidirectional. Our results show that a pacemaker induces chimeras for parameters and initial conditions for which they do not form spontaneously. Furthermore, the pacemaker attracts the incoherent part of the chimera state, thus controlling its position. Beyond that, we find that these control effects can be achieved with modifications of the network’s connectivity that are less invasive than a pacemaker, namely, the minimal action of just modifying the strength of one connection allows one to control chimeras.

Keywords: Complex networks, Oscillators, Spatiotemporal phenomena


Pellequer, J. L., Parot, P., Navajas, D., Kumar, S., Svetli, Scheuring, S., Hu, J., Li, B., Engler, A., Sousa, S., Lekka, M., Szymo, Schillers, H., Odorico, M., Lafont, F., Janel, S., Rico, F., (2019). Fifteen years of Servitude et Grandeur to the application of a biophysical technique in medicine: The tale of AFMBioMed Journal of Molecular Recognition In press

AFMBioMed is the founding name under which international conferences and summer schools are organized around the application of atomic force microscopy in life sciences and nanomedicine. From its inception at the Atomic Energy Commission in Marcoule near 2004 to its creation in 2007 and to its 10th anniversary conference in Krakow, a brief narrative history of its birth and rise will demonstrate how and what such an organization brings to laboratories and the AFM community. With the current planning of the next AFMBioMed conference in Münster in 2019, it will be 15 years of commitment to these events.

Keywords: Atomic Force Microscopy, Single molecules, Biomechanics, Force spectroscopy, High-speed AFM, Imaging, Nanoindentation, Nanomedicine, Nanotoxicology


Palacín, J., Martínez, D., Clotet, E., Pallejà, T., Burgués, J., Fonollosa, J., Pardo, A., Marco, Santiago, (2019). Application of an array of metal-oxide semiconductor gas sensors in an assistant personal robot for early gas leak detection Sensors 19, (9), 1957

This paper proposes the application of a low-cost gas sensor array in an assistant personal robot (APR) in order to extend the capabilities of the mobile robot as an early gas leak detector for safety purposes. The gas sensor array is composed of 16 low-cost metal-oxide (MOX) gas sensors, which are continuously in operation. The mobile robot was modified to keep the gas sensor array always switched on, even in the case of battery recharge. The gas sensor array provides 16 individual gas measurements and one output that is a cumulative summary of all measurements, used as an overall indicator of a gas concentration change. The results of preliminary experiments were used to train a partial least squares discriminant analysis (PLS-DA) classifier with air, ethanol, and acetone as output classes. Then, the mobile robot gas leak detection capabilities were experimentally evaluated in a public facility, by forcing the evaporation of (1) ethanol, (2) acetone, and (3) ethanol and acetone at different locations. The positive results obtained in different operation conditions over the course of one month confirmed the early detection capabilities of the proposed mobile system. For example, the APR was able to detect a gas leak produced inside a closed room from the external corridor due to small leakages under the door induced by the forced ventilation system of the building.

Keywords: Metal-oxide semiconductor, Gas sensor, Gas leak detection, Assistant personal robot, Mobile robot


Montero, Joan, (2019). The attack of the “seeding” clones Science Translational Medicine 11, (483), eaax0872

Tumor clone tracking in breast cancer xenografts identifies a small subset of circulating tumor cells as “seeders” associated with metastasis.


Grechuta, K., Rubio Ballester, B., Espín Munne, R., Usabiaga Bernal, T., Molina Hervás, B., Mohr, B., Pulvermüller, F., San Segundo, R., Verschure, P., (2019). Augmented dyadic therapy boosts recovery of language function in patients with nonfluent aphasia Stroke 50, (5), 1270-1274

Background and Purpose- Evidence suggests that therapy can be effective in recovering from aphasia, provided that it consists of socially embedded, intensive training of behaviorally relevant tasks. However, the resources of healthcare systems are often too limited to provide such treatment at sufficient dosage. Hence, there is a need for evidence-based, cost-effective rehabilitation methods. Here, we asked whether virtual reality-based treatment grounded in the principles of use-dependent learning, behavioral relevance, and intensity positively impacts recovery from nonfluent aphasia. Methods- Seventeen patients with chronic nonfluent aphasia underwent intensive therapy in a randomized, controlled, parallel-group trial. Participants were assigned to the control group (N=8) receiving standard treatment or to the experimental group (N=9) receiving augmented embodied therapy with the Rehabilitation Gaming System for aphasia. All Rehabilitation Gaming System for aphasia sessions were supervised by an assistant who monitored the patients but did not offer any elements of standard therapy. Both interventions were matched for intensity and materials. Results- Our results revealed that at the end of the treatment both groups significantly improved on the primary outcome measure (Boston Diagnostic Aphasia Examination: control group, P=0.04; experimental group, P=0.01), and the secondary outcome measure (lexical access-vocabulary test: control group, P=0.01; experimental group, P=0.007). However, only the Rehabilitation Gaming System for aphasia group improved on the Communicative Aphasia Log ( P=0.01). The follow-up assessment (week 16) demonstrated that while both groups retained vocabulary-related changes (control group, P=0.01; experimental group, P=0.007), only the Rehabilitation Gaming System for aphasia group showed therapy-induced improvements in language ( P=0.01) and communication ( P=0.05). Conclusions- Our results demonstrate the effectiveness of Rehabilitation Gaming System for aphasia for improving language and communication in patients with chronic aphasia suggesting that current challenges faced by the healthcare system in the treatment of stroke might be effectively addressed by augmenting traditional therapy with computer-based methods. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02928822.

Keywords: Aphasia, Embodied training, Neurological rehabilitation, Virtual reality


Blithikioti, C., Miquel, L., Batalla, A., Rubio, B., Maffei, G., Herreros, I., Gual, A., Verschure, P., Balcells-Oliveró, M., (2019). Cerebellar alterations in cannabis users: A systematic review Addiction Biology Online Version of Record before inclusion in an issue

Cannabis is the most used illicit substance in the world. As many countries are moving towards decriminalization, it is crucial to determine whether and how cannabis use affects human brain and behavior. The role of the cerebellum in cognition, emotion, learning, and addiction is increasingly recognized. Because of its high density in CB1 receptors, it is expected to be highly affected by cannabis use. The aim of this systematic review is to investigate how cannabis use affects cerebellar structure and function, as well as cerebellar‐dependent behavioral tasks. Three databases were searched for peer‐reviewed literature published until March 2018. We included studies that focused on cannabis effects on cerebellar structure, function, or cerebellar‐dependent behavioral tasks. A total of 348 unique records were screened, and 40 studies were included in the qualitative synthesis. The most consistent findings include (1) increases in cerebellar gray matter volume after chronic cannabis use, (2) alteration of cerebellar resting state activity after acute or chronic use, and (3) deficits in memory, decision making, and associative learning. Age of onset and higher exposure to cannabis use were frequently associated with increased cannabis‐induced alterations. Chronic cannabis use is associated with alterations in cerebellar structure and function, as well as with deficits in behavioral paradigms that involve the cerebellum (eg, eyeblink conditioning, memory, and decision making). Future studies should consider tobacco as confounding factor and use standardized methods for assessing cannabis use. Paradigms exploring the functional activity of the cerebellum may prove useful as monitoring tools of cannabis‐induced impairment.

Keywords: Behavior, Cannabis use, Cerebellum, Cognitive function, Structure


Ballester, B. R., Maier, M., Duff, A., Cameirão, M., Bermúdez, S., Duarte, E., Cuxart, A., Rodríguez, S., San Segundo Mozo, R. M., Verschure, P., (2019). A critical time window for recovery extends beyond one-year post-stroke Journal of neurophysiology 122, (1), 350-357

The impact of rehabilitation on post-stroke motor recovery and its dependency on the patient's chronicity remain unclear. The field has widely accepted the notion of a proportional recovery rule with a "critical window for recovery" within the first 3-6 mo poststroke. This hypothesis justifies the general cessation of physical therapy at chronic stages. However, the limits of this critical window have, so far, been poorly defined. In this analysis, we address this question, and we further explore the temporal structure of motor recovery using individual patient data from a homogeneous sample of 219 individuals with mild to moderate upper-limb hemiparesis. We observed that improvement in body function and structure was possible even at late chronic stages. A bootstrapping analysis revealed a gradient of enhanced sensitivity to treatment that extended beyond 12 mo poststroke. Clinical guidelines for rehabilitation should be revised in the context of this temporal structure. NEW & NOTEWORTHY Previous studies in humans suggest that there is a 3- to 6-mo "critical window" of heightened neuroplasticity poststroke. We analyze the temporal structure of recovery in patients with hemiparesis and uncover a precise gradient of enhanced sensitivity to treatment that expands far beyond the limits of the so-called critical window. These findings highlight the need for providing therapy to patients at the chronic and late chronic stages.

Keywords: Motor recovery, Neuroplasticity, Neurorehabilitation, Stroke recovery, Virtual reality


Malandrino, Andrea, Trepat, Xavier, Kamm, Roger D., Mak, Michael, (2019). Dynamic filopodial forces induce accumulation, damage, and plastic remodeling of 3D extracellular matrices PLoS Computational Biology PLOS Computational Biology , 15, (4), e1006684

The mechanical properties of the extracellular matrix (ECM)–a complex, 3D, fibrillar scaffold of cells in physiological environments–modulate cell behavior and can drive tissue morphogenesis, regeneration, and disease progression. For simplicity, it is often convenient to assume these properties to be time-invariant. In living systems, however, cells dynamically remodel the ECM and create time-dependent local microenvironments. Here, we show how cell-generated contractile forces produce substantial irreversible changes to the density and architecture of physiologically relevant ECMs–collagen I and fibrin–in a matter of minutes. We measure the 3D deformation profiles of the ECM surrounding cancer and endothelial cells during stages when force generation is active or inactive. We further correlate these ECM measurements to both discrete fiber simulations that incorporate fiber crosslink unbinding kinetics and continuum-scale simulations that account for viscoplastic and damage features. Our findings further confirm that plasticity, as a mechanical law to capture remodeling in these networks, is fundamentally tied to material damage via force-driven unbinding of fiber crosslinks. These results characterize in a multiscale manner the dynamic nature of the mechanical environment of physiologically mimicking cell-in-gel systems.

Keywords: Collagens, Fibrin, Extracellular matrix, Cross-linking, Cell physiology, Deformation, Fluorescence imaging, Cell biology


Maier, Martina, Rubio Ballester, Belén, Duff, Armin, Duarte Oller, Esther, Verschure, P., (2019). Effect of specific over nonspecific VR-based rehabilitation on poststroke motor recovery: A systematic meta-analysis Neurorehabilitation and Neural Repair 33, (2), 112-129

Background. Despite the rise of virtual reality (VR)-based interventions in stroke rehabilitation over the past decade, no consensus has been reached on its efficacy. This ostensibly puzzling outcome might not be that surprising given that VR is intrinsically neutral to its use—that is, an intervention is effective because of its ability to mobilize recovery mechanisms, not its technology. As VR systems specifically built for rehabilitation might capitalize better on the advantages of technology to implement neuroscientifically grounded protocols, they might be more effective than those designed for recreational gaming. Objective. We evaluate the efficacy of specific VR (SVR) and nonspecific VR (NSVR) systems for rehabilitating upper-limb function and activity after stroke. Methods. We conducted a systematic search for randomized controlled trials with adult stroke patients to analyze the effect of SVR or NSVR systems versus conventional therapy (CT). Results. We identified 30 studies including 1473 patients. SVR showed a significant impact on body function (standardized mean difference [SMD] = 0.23; 95% CI = 0.10 to 0.36; P = .0007) versus CT, whereas NSVR did not (SMD = 0.16; 95% CI = −0.14 to 0.47; P = .30). This result was replicated in activity measures. Conclusions. Our results suggest that SVR systems are more beneficial than CT for upper-limb recovery, whereas NSVR systems are not. Additionally, we identified 6 principles of neurorehabilitation that are shared across SVR systems and are possibly responsible for their positive effect. These findings may disambiguate the contradictory results found in the current literature.

Keywords: Stroke, Paresis, Virtual reality, Rehabilitation, Occupational therapy, Review


Lopez-Martinez, Montserrat, López-Ortiz, Manuel, Antinori, Maria Elena, Wientjes, Emilie, Nin-Hill, Alba, Rovira, Carme, Croce, Roberta, Díez-Pérez, Ismael, Gorostiza, Pau, (2019). Electrochemically gated long distance charge transport in photosystem I Angewandte Chemie International Edition Accepter Article

The transport of electrons along photosynthetic and respiratory chains involves a series of enzymatic reactions that are coupled through redox mediators, including proteins and small molecules. The use of native and synthetic redox probes is key to understand charge transport mechanisms, and to design bioelectronic sensors and solar energy conversion devices. However, redox probes have limited tunability to exchange charge at the desired electrochemical potentials (energy levels) and at different protein sites. Here, we take advantage of electrochemical scanning tunneling microscopy (ECSTM) to control the Fermi level and nanometric position of the ECSTM probe in order to study electron transport in individual photosystem I (PSI) complexes. Current-distance measurements at different potentiostatic conditions indicate that PSI supports long-distance transport that is electrochemically gated near the redox potential of P700, with current extending farther under hole injection conditions.

Keywords: Current decay, ECSTM, Electrochemical gate, Electron transfer, Photosynthesis


Sarlabous, L., Estrada, L., Cerezo-Hernández, A., Leest, Sietske V. D., Torres, A., Jané, R., Duiverman, M., Garde, Ainara, (2019). Electromyography-based respiratory onset detection in COPD patients on non-invasive mechanical ventilation Entropy 21, (3), 258

To optimize long-term nocturnal non-invasive ventilation in patients with chronic obstructive pulmonary disease, surface diaphragm electromyography (EMGdi) might be helpful to detect patient-ventilator asynchrony. However, visual analysis is labor-intensive and EMGdi is heavily corrupted by electrocardiographic (ECG) activity. Therefore, we developed an automatic method to detect inspiratory onset from EMGdi envelope using fixed sample entropy (fSE) and a dynamic threshold based on kernel density estimation (KDE). Moreover, we combined fSE with adaptive filtering techniques to reduce ECG interference and improve onset detection. The performance of EMGdi envelopes extracted by applying fSE and fSE with adaptive filtering was compared to the root mean square (RMS)-based envelope provided by the EMG acquisition device. Automatic onset detection accuracy, using these three envelopes, was evaluated through the root mean square error (RMSE) between the automatic and mean visual onsets (made by two observers). The fSE-based method provided lower RMSE, which was reduced from 298 ms to 264 ms when combined with adaptive filtering, compared to 301 ms provided by the RMS-based method. The RMSE was negatively correlated with the proposed EMGdi quality indices. Following further validation, fSE with KDE, combined with adaptive filtering when dealing with low quality EMGdi, indicates promise for detecting the neural onset of respiratory drive.

Keywords: Fixed sample entropy, Adaptive filtering, Root mean square, Diaphragm electromyography, Non-invasive mechanical ventilation, Chronic obstructive pulmonary disease


Garreta, Elena, Prado, Patricia, Tarantino, Carolina, Oria, Roger, Fanlo, Lucia, Martí, Elisa, Zalvidea, Dobryna, Trepat, Xavier, Roca-Cusachs, Pere, Gavaldà -Navarro, Aleix, Cozzuto, Luca, Campistol, Josep M., Izpisúa Belmonte, Juan Carlos, Hurtado del Pozo, Carmen, Montserrat, Nuria, (2019). Fine tuning the extracellular environment accelerates the derivation of kidney organoids from human pluripotent stem cells Nature Materials 18, 397-405

The generation of organoids is one of the biggest scientific advances in regenerative medicine. Here, by lengthening the time that human pluripotent stem cells (hPSCs) were exposed to a three-dimensional microenvironment, and by applying defined renal inductive signals, we generated kidney organoids that transcriptomically matched second-trimester human fetal kidneys. We validated these results using ex vivo and in vitro assays that model renal development. Furthermore, we developed a transplantation method that utilizes the chick chorioallantoic membrane. This approach created a soft in vivo microenvironment that promoted the growth and differentiation of implanted kidney organoids, as well as providing a vascular component. The stiffness of the in ovo chorioallantoic membrane microenvironment was recapitulated in vitro by fabricating compliant hydrogels. These biomaterials promoted the efficient generation of renal vesicles and nephron structures, demonstrating that a soft environment accelerates the differentiation of hPSC-derived kidney organoids.


Checa, M., Millan-Solsona, R., Gomila, G., (2019). Frequency-dependent force between ac-voltage-biased plates in electrolyte solutions Physical Review E 100, (2), 022604

We analyze the frequency dependence of the force between ac-voltage-biased plates in electrolyte solutions. To this end we solve analytically the Poisson-Nernst-Planck transport model in the dilute concentration and low voltage regime for a 1:1 symmetric electrolyte with blocking electrodes under a dc+ac applied voltage. The total force, which is the resultant of the electric and osmotic forces, shows a complex dependence on plate separation, frequency, ion concentration, and compact layer properties, different from that predicted from electrostatic current models or equivalent circuit models, due to the relevance of the osmotic force contribution in almost the whole range of frequencies. For the total dc force, we show that it decays at fixed ion concentration, linearly with plate separation for separations larger than a few times the Debye screening length. This linear dependence is due to the assumption about the conservation of the number of ions in the system. Moreover, the 1ω and 2ω ac harmonics of the total force show a broad peak at intermediate frequencies; it is centered at about the inverse of the charging time of the double layer capacitance, and covers the frequency range between the inverse of the diffusion time and the inverse of the electrolyte dielectric relaxation time. Finally, the 1ω ac harmonic component attains its high frequency asymptotic value at frequencies much higher than the inverse of the electrolyte dielectric relaxation time due to the very slow relaxation of the osmotic 1ω harmonic component at high frequencies. The derived analytical expressions for the total force remain valid up to voltages of the order of the thermal voltage, as has been assessed by means of numerical calculations. The numerical calculations are also used to explore the onset of higher force harmonics for larger applied voltages. Understanding the frequency dependence of the force acting on voltage-biased plates in electrolyte solutions can be of relevance for electrical actuation strategies in microelectromechanical systems and for the interpretation of some emerging electric scanning probe force microscopy techniques operating in electrolyte solutions.

Keywords: Electrochemistry, Statistical physics


Sánchez-Fibla, M., Forestier, S., Moulin-Frier, C., Puigbò, J. Y., Verschure, P., (2019). From motor to visually guided bimanual affordance learning Adaptive Behavior Article first published online

The mechanisms of how the brain orchestrates multi-limb joint action have yet to be elucidated and few computational sensorimotor (SM) learning approaches have dealt with the problem of acquiring bimanual affordances. We propose a series of bidirectional (forward/inverse) SM maps and its associated learning processes that generalize from uni- to bimanual interaction (and affordances) naturally, reinforcing the motor equivalence property. The SM maps range from a SM nature to a solely sensory one: full body control, delta SM control (through small action changes), delta sensory co-variation (how body-related perceptual cues covariate with object-related ones). We make several contributions on how these SM maps are learned: (1) Context and Behavior-Based Babbling: generalizing goal babbling to the interleaving of absolute and local goals including guidance of reflexive behaviors; (2) Event-Based Learning: learning steps are driven by visual, haptic events; and (3) Affordance Gradients: the vectorial field gradients in which an object can be manipulated. Our modeling of bimanual affordances is in line with current robotic research in forward visuomotor mappings and visual servoing, enforces the motor equivalence property, and is also consistent with neurophysiological findings like the multiplicative encoding scheme.

Keywords: Affordances, Bimanual affordances, Goal babbling, Interlimb coordination, Motor equivalence, Sensorimotor learning


Bloise, Ermelinda, Di Bello, Maria Pia, Mele, Giuseppe, Rizzello, Loris, (2019). A green method for the production of an efficient bioimaging nanotool Nanoscale Advances RSC

The possibility of exploring basic biological phenomena requires the development of new and efficient bio-imaging tools. These should ideally combine the feasibility of production (potentially through the use of green chemistry) together with high targeting efficiency, low cytotoxicity, and optimal contrast characteristics. In this work, we developed nanovesicles based on cardanol, a natural and renewable byproduct of the cashew industry, and a fluorescent reporter was encapsulated in them through an environment-friendly synthesis method. In vitro investigations demonstrated that the cardanol nanovesicles are efficiently taken-up by both professional and non-professional phagocytic cells, which have been modeled in our approach by macrophages and HeLa cells, respectively. Co-localization studies show high affinity of the nanovesicles towards the cell plasma membrane. Moreover, metabolic assays confirmed that these nanostructures are biocompatible in a specific concentration range, and do not promote inflammation response in human macrophages. Stability studies carried out at different temperatures showed that the nanovesicles are stable at both 37 °C and 20 °C, while the formation of aggregates occurs when the nanodispersion is incubated at 4 °C. The results demonstrate the high potential of fluorescent cardanol nanovesicles as a green bioimaging tool, especially for investigating cell membrane dynamics.


Leguia, Marc G., Martínez, Cristina G. B., Malvestio, Irene, Campo, Adrià  Tauste, Rocamora, Rodrigo, Levnaji, Andrzejak, Ralph G., (2019). Inferring directed networks using a rank-based connectivity measure Physical Review E 99, (1), 012319

Inferring the topology of a network using the knowledge of the signals of each of the interacting units is key to understanding real-world systems. One way to address this problem is using data-driven methods like cross-correlation or mutual information. However, these measures lack the ability to distinguish the direction of coupling. Here, we use a rank-based nonlinear interdependence measure originally developed for pairs of signals. This measure not only allows one to measure the strength but also the direction of the coupling. Our results for a system of coupled Lorenz dynamics show that we are able to consistently infer the underlying network for a subrange of the coupling strength and link density. Furthermore, we report that the addition of dynamical noise can benefit the reconstruction. Finally, we show an application to multichannel electroencephalographic recordings from an epilepsy patient.


Kechagia, Jenny Z., Ivaska, Johanna, Roca-Cusachs, Pere, (2019). Integrins as biomechanical sensors of the microenvironment Nature Reviews Molecular Cell Biology 20, (8), 457-473

Integrins, and integrin-mediated adhesions, have long been recognized to provide the main molecular link attaching cells to the extracellular matrix (ECM) and to serve as bidirectional hubs transmitting signals between cells and their environment. Recent evidence has shown that their combined biochemical and mechanical properties also allow integrins to sense, respond to and interact with ECM of differing properties with exquisite specificity. Here, we review this work first by providing an overview of how integrin function is regulated from both a biochemical and a mechanical perspective, affecting integrin cell-surface availability, binding properties, activation or clustering. Then, we address how this biomechanical regulation allows integrins to respond to different ECM physicochemical properties and signals, such as rigidity, composition and spatial distribution. Finally, we discuss the importance of this sensing for major cell functions by taking cell migration and cancer as examples.

Keywords: Cell migration, Extracellular matrix, Integrins, Mechanotransduction, Single-molecule biophysics


Chen, Tianchi, Callan-Jones, Andrew, Fedorov, Eduard, Ravasio, Andrea, Brugués, Agustí, Ong, Hui Ting, Toyama, Yusuke, Low, Boon Chuan, Trepat, Xavier, Shemesh, Tom, Voituriez, Raphaël, Ladoux, Benoît, (2019). Large-scale curvature sensing by directional actin flow drives cellular migration mode switching Nature Physics 15, (4), 393-402

Cell migration over heterogeneous substrates during wound healing or morphogenetic processes leads to shape changes driven by different organizations of the actin cytoskeleton and by functional changes including lamellipodial protrusions and contractile actin cables. Cells distinguish between cell-sized positive and negative curvatures in their physical environment by forming protrusions at positive curvatures and actin cables at negative curvatures; however, the cellular mechanisms remain unclear. Here, we report that concave edges promote polarized actin structures with actin flow directed towards the cell edge, in contrast to well-documented retrograde flow at convex edges. Anterograde flow and contractility induce a tension anisotropy gradient. A polarized actin network is formed, accompanied by a local polymerization–depolymerization gradient, together with leading-edge contractile actin cables in the front. These cables extend onto non-adherent regions while still maintaining contact with the substrate through focal adhesions. The contraction and dynamic reorganization of this actin structure allows forward movements enabling cell migration over non-adherent regions on the substrate. These versatile functional structures may help cells sense and navigate their environment by adapting to external geometric and mechanical cues.

Keywords: Biopolymers in vivo, Cellular motility


Casanellas, Ignasi, Lagunas, Anna, Vida, Yolanda, Pérez-Inestrosa, Ezequiel, Andrades, José A., Becerra, José, Samitier, Josep, (2019). Matrix nanopatterning regulates mesenchymal differentiation through focal adhesion size and distribution according to cell fate Biomimetics 4, (2), 43

Extracellular matrix remodeling plays a pivotal role during mesenchyme patterning into different lineages. Tension exerted from cell membrane receptors bound to extracellular matrix ligands is transmitted by the cytoskeleton to the cell nucleus inducing gene expression. Here, we used dendrimer-based arginine–glycine–aspartic acid (RGD) uneven nanopatterns, which allow the control of local surface adhesiveness at the nanoscale, to unveil the adhesive requirements of mesenchymal tenogenic and osteogenic commitments. Cell response was found to depend on the tension resulting from cell–substrate interactions, which affects nuclear morphology and is regulated by focal adhesion size and distribution.

Keywords: Arginine–glycine–aspartic acid (RGD), Nanopattern, Mesenchymal stem cells, Tenogenesis, Osteogenesis, Cell nuclei, Focal adhesions


Infante, Elvira, Stannard, Andrew, Board, Stephanie J., Rico-Lastres, Palma, Rostkova, Elena, Beedle, Amy E. M., Lezamiz, Ainhoa, Wang, Yong Jian, Gulaidi Breen, Samuel, Panagaki, Fani, Sundar Rajan, Vinoth, Shanahan, Catherine, Roca-Cusachs, Pere, Garcia-Manyes, Sergi, (2019). The mechanical stability of proteins regulates their translocation rate into the cell nucleus Nature Physics Epub ahead of print

A cell’s ability to react to mechanical stimuli is known to be affected by the transport of transcription factors, the proteins responsible for regulating transcription of DNA into RNA, across the membrane enveloping its nucleus. Yet the molecular mechanisms by which mechanical cues control this process remain unclear. Here we show that one such protein, myocardin-related transcription factor A (MRTFA), is imported into the nucleus at a rate that is inversely correlated with its nanomechanical stability, but independent of its thermodynamic stability. Attaching mechanically stable proteins to MRTFA results in reduced gene expression and the subsequent slowing down of cell migration. We conclude that the mechanical unfolding of proteins regulates their nuclear translocation rate, and highlight the role of the nuclear pore complex as a selective mechanosensor that is capable of detecting forces as low as 10 pN. The modulation of the mechanical stability of transcription factors may represent a general strategy for the control of gene expression.

Keywords: Biological physics, Biophysics, Chemistry, Nanoscience and technology


Williams, Charlotte Katherine, Zhu, Yunqing, Poma, Alessandro, Rizzello, Loris, Gouveia, Virginia, Ruiz Perez, Lorena, Battaglia, Guiseppe, (2019). Metabolic-active fully hydrolysable polymersomes Angewandte Chemie International Edition Accepted Article

The synthesis and aqueous self-assembly of a new class of amphiphilic aliphatic polyesters are presented. These AB block polyesters comprise polycaprolactone (hydrophobe) and an alternating polyester from succinic acid and an ether substituted epoxide (hydrophile). They self-assemble into biodegradable polymersomes capable of entering cells. Their degradation products are bioactive giving rise to differentiated cellular responses inducing stromal cell proliferation and macrophage apoptosis. Both effects emerge only when the copolymers enter cells as polymersomes and their magnitudes are size dependent.


Riefolo, F., Matera, C., Garrido-Charles, A., Gomila, A., Sortino, R., Agnetta, L., Claro, E., Masgrau, R., Holzgrabe, U., Batlle, M., Decker, M., Guasch, E., Gorostiza, P., (2019). Optical control of cardiac function with a photoswitchable muscarinic agonist Journal of the American Chemical Society 141, (18), 7628-7636

Light-triggered reversible modulation of physiological functions offers the promise of enabling on-demand spatiotemporally controlled therapeutic interventions. Optogenetics has been successfully implemented in the heart, but significant barriers to its use in the clinic remain, such as the need for genetic transfection. Herein, we present a method to modulate cardiac function with light through a photoswitchable compound and without genetic manipulation. The molecule, named PAI, was designed by introduction of a photoswitch into the molecular structure of an M2 mAChR agonist. In vitro assays revealed that PAI enables light-dependent activation of M2 mAChRs. To validate the method, we show that PAI photoisomers display different cardiac effects in a mammalian animal model, and demonstrate reversible, real-time photocontrol of cardiac function in translucent wildtype tadpoles. PAI can also effectively activate M2 receptors using two-photon excitation with near-infrared light, which overcomes the scattering and low penetration of short-wave-length illumination, and offers new opportunities for intravital imaging and control of cardiac function.


Hervera, Arnau, Santos, Celio X., De Virgiliis, Francesco, Shah, Ajay M., Di Giovanni, Simone, (2019). Paracrine mechanisms of redox signalling for postmitotic cell and tissue regeneration Trends in Cell Biology 29, (6), 514-530

Adult postmitotic mammalian cells, including neurons and cardiomyocytes, have a limited capacity to regenerate after injury. Therefore, an understanding of the molecular mechanisms underlying their regenerative ability is critical to advance tissue repair therapies. Recent studies highlight how redox signalling via paracrine cell-to-cell communication may act as a central mechanism coupling tissue injury with regeneration. Post-injury redox paracrine signalling can act by diffusion to nearby cells, through mitochondria or within extracellular vesicles, affecting specific intracellular targets such as kinases, phosphatases, and transcription factors, which in turn trigger a regenerative response. Here, we review redox paracrine signalling mechanisms in postmitotic tissue regeneration and discuss current challenges and future directions.


Lozano-García, M., Estrada, L., Jané, R., (2019). Performance evaluation of fixed sample entropy in myographic signals for inspiratory muscle activity estimation Entropy 21, (2), 183

Fixed sample entropy (fSampEn) has been successfully applied to myographic signals for inspiratory muscle activity estimation, attenuating interference from cardiac activity. However, several values have been suggested for fSampEn parameters depending on the application, and there is no consensus standard for optimum values. This study aimed to perform a thorough evaluation of the performance of the most relevant fSampEn parameters in myographic respiratory signals, and to propose, for the first time, a set of optimal general fSampEn parameters for a proper estimation of inspiratory muscle activity. Different combinations of fSampEn parameters were used to calculate fSampEn in both non-invasive and the gold standard invasive myographic respiratory signals. All signals were recorded in a heterogeneous population of healthy subjects and chronic obstructive pulmonary disease patients during loaded breathing, thus allowing the performance of fSampEn to be evaluated for a variety of inspiratory muscle activation levels. The performance of fSampEn was assessed by means of the cross-covariance of fSampEn time-series and both mouth and transdiaphragmatic pressures generated by inspiratory muscles. A set of optimal general fSampEn parameters was proposed, allowing fSampEn of different subjects to be compared and contributing to improving the assessment of inspiratory muscle activity in health and disease.

Keywords: Electromyography, Fixed sample entropy, Mechanomyography, Non-invasive physiological measurements, Oesophageal electromyography, Respiratory muscle


Roux, Anabel-Lise Lee, Quiroga, Xarxa, Walani, Nikhil, Arroyo, Marino, Roca-Cusachs, Pere, (2019). The plasma membrane as a mechanochemical transducer Philosophical Transactions of the Royal Society B: Biological Sciences 374, (1779), 20180221

Cells are constantly submitted to external mechanical stresses, which they must withstand and respond to. By forming a physical boundary between cells and their environment that is also a biochemical platform, the plasma membrane (PM) is a key interface mediating both cellular response to mechanical stimuli, and subsequent biochemical responses. Here, we review the role of the PM as a mechanosensing structure. We first analyse how the PM responds to mechanical stresses, and then discuss how this mechanical response triggers downstream biochemical responses. The molecular players involved in PM mechanochemical transduction include sensors of membrane unfolding, membrane tension, membrane curvature or membrane domain rearrangement. These sensors trigger signalling cascades fundamental both in healthy scenarios and in diseases such as cancer, which cells harness to maintain integrity, keep or restore homeostasis and adapt to their external environment.

Keywords: Plasma membrane, Mechanotransduction, Membrane tension, Mechanosensor


Rubio Ballester, Belen, Duff, Armin, Maier, Martina, Cameirao, Monica, Bermudez, Sergi, Duarte, Esther, Cuxart, Ampar, Rodriguez, Susana, Verschure, Paul F. M. J., (2019). Revealing an extended critical window of recovery post-stroke bioRxiv (pre-print server) , 458745

The impact of rehabilitation on post-stroke motor recovery and its dependency on the patient's chronicity remain unclear. The existence and regularity of a, so called, proportional recovery rule across a range of functional deficits and therapies supports the notion that functional interventions have little or no impact beyond spontaneous recovery rates in a 'critical window of recovery' which lasts from 3 to 6 months post-stroke. In this meta-analysis, we apply a bootstrap analysis method to assess the overall impact of a specific VR-based rehabilitation protocol for the upper extremities on a homogeneous sample of 219 individuals with hemiparesis at various stages post stroke. Our analysis uncovers a precise gradient of sensitivity to treatment that expands more than one year beyond the limits of the so-called 'critical window of recovery'. These findings redefine the limits of the so-called 'critical window of recovery' and suggest that stroke-derived plasticity mechanisms do facilitate functional recovery even at the chronic and late chronic stage.


Pittolo, Silvia, Lee, Hyojung, Lladó, Anna, Tosi, Sébastien, Bosch, Miquel, Bardia, Lídia, Gómez-Santacana, Xavier, Llebaria, Amadeu, Soriano, Eduardo, Colombelli, Julien, Poskanzer, Kira E., Perea, Gertrudis, Gorostiza, Pau, (2019). Reversible silencing of endogenous receptors in intact brain tissue using two-photon pharmacology Proceedings of the National Academy of Sciences of the United States of America Epub ahead of print

The physiological activity of proteins is often studied with loss-of-function genetic approaches, but the corresponding phenotypes develop slowly and can be confounding. Photopharmacology allows direct, fast, and reversible control of endogenous protein activity, with spatiotemporal resolution set by the illumination method. Here, we combine a photoswitchable allosteric modulator (alloswitch) and 2-photon excitation using pulsed near-infrared lasers to reversibly silence metabotropic glutamate 5 (mGlu5) receptor activity in intact brain tissue. Endogenous receptors can be photoactivated in neurons and astrocytes with pharmacological selectivity and with an axial resolution between 5 and 10 µm. Thus, 2-photon pharmacology using alloswitch allows investigating mGlu5-dependent processes in wild-type animals, including synaptic formation and plasticity, and signaling pathways from intracellular organelles.

Keywords: Photopharmacology, Photoactivation, Pharmacological selectivity, Functional silencing, 2-photon pharmacology


Grechuta, Klaudia, Ulysse, Laura, Rubio Ballester, Belen, Verschure, Paul, (2019). Self beyond the body: task-relevant distal cues modulate performance and body ownership bioRxiv (pre-print server) , 361022

The understanding of Body Ownership (BO) largely relies on the Rubber Hand Illusion (RHI) where synchronous stroking of real and Rubber Hands (RH) leads to an illusion of ownership of RH provided physical, anatomical, postural and spatial plausibility of the two body-parts. RHI also occurs during visuomotor synchrony, in particular, when the visual feedback of virtual arm movements follows the trajectory of the instantiated motor command. Hence BO seems to result from a bottom-up integration of afferent and efferent proximal multisensory evidence, and top-down prediction of both externally and self-generated signals, which occurs when the predictions about upcoming sensory signals are accurate. In motor control, the differential processing of predicted and actual sensory consequences of self-generated actions is addressed by, the so-called, Forward Model (FM). Based on an efference copy or corollary discharge, FM issues predictions about the sensory consequences of motor commands and compares them with the actual outcome. The discrepancies (Sensory Prediction Errors, SPEs) are used to correct the action on the consecutive trial and provide new estimates of the current state of the body and the environment. Here, we propose that BO might be computed by FMs, and therefore, it might depend on their consistency, specifically, in contexts where the sensory feedback is self-generated. Crucially, to reduce SPE, FMs integrate both proximal (proprioceptive) and distal (vision, audition) sensory cues relevant to the task. Thus, if BO depends on the consistency of FMs, it would be compromised by the incongruency of not only proximal but also distal cues. To test our hypothesis, we devised an embodied VR-based task where action outcomes were signaled by distinct auditory cues. By manipulating the cues with respect to their spatiotemporal congruency and valence, we show that distal feedback which violates predictions about action outcomes compromises both BO and performance. These results demonstrate that BO is influenced by not only efferent and afferent cues which pertain to the body itself but also those arising outside of the body and suggest that in goal-oriented tasks BO might result from a computation of FM.


Burgués, Javier, Hernández, Victor, Lilienthal, Achim J., Marco, Santiago, (2019). Smelling nano aerial vehicle for gas source localization and mapping Sensors 19, (3), 478

This paper describes the development and validation of the currently smallest aerial platform with olfaction capabilities. The developed Smelling Nano Aerial Vehicle (SNAV) is based on a lightweight commercial nano-quadcopter (27 g) equipped with a custom gas sensing board that can host up to two in situ metal oxide semiconductor (MOX) gas sensors. Due to its small form-factor, the SNAV is not a hazard for humans, enabling its use in public areas or inside buildings. It can autonomously carry out gas sensing missions of hazardous environments inaccessible to terrestrial robots and bigger drones, for example searching for victims and hazardous gas leaks inside pockets that form within the wreckage of collapsed buildings in the aftermath of an earthquake or explosion. The first contribution of this work is assessing the impact of the nano-propellers on the MOX sensor signals at different distances to a gas source. A second contribution is adapting the ‘bout’ detection algorithm, proposed by Schmuker et al. (2016) to extract specific features from the derivative of the MOX sensor response, for real-time operation. The third and main contribution is the experimental validation of the SNAV for gas source localization (GSL) and mapping in a large indoor environment (160 m2) with a gas source placed in challenging positions for the drone, for example hidden in the ceiling of the room or inside a power outlet box. Two GSL strategies are compared, one based on the instantaneous gas sensor response and the other one based on the bout frequency. From the measurements collected (in motion) along a predefined sweeping path we built (in less than 3 min) a 3D map of the gas distribution and identified the most likely source location. Using the bout frequency yielded on average a higher localization accuracy than using the instantaneous gas sensor response (1.38 m versus 2.05 m error), however accurate tuning of an additional parameter (the noise threshold) is required in the former case. The main conclusion of this paper is that a nano-drone has the potential to perform gas sensing tasks in complex environments.

Keywords: Robotics, Signal processing, Electronics, Gas source localization, Gas distribution mapping, Gas sensors, Drone, UAV, MOX sensor, Quadcopter


Cabré, Gisela, Garrido-Charles, Aida, González-Lafont, Àngels, Moormann, Widukind, Langbehn, Daniel, Egea, David, Lluch, José M., Herges, Rainer, Alibés, Ramon, Busqué, Félix, Gorostiza, Pau, Hernando, Jordi, (2019). Synthetic photoswitchable neurotransmitters based on bridged azobenzenes Organic Letters Article ASAP

Photoswitchable neurotransmitters of ionotropic kainate receptors were synthesized by tethering a glutamate moiety to disubstituted C2-bridged azobenzenes, which were prepared through a novel methodology that allows access to diazocines with higher yields and versatility. Because of the singular properties of these photochromes, photoisomerizable compounds were obtained with larger thermal stability for their inert cis isomer than for their biologically activity trans state. This enabled selective neuronal firing upon irradiation without background activity in the dark.


De Matteis, Valeria, Cascione, Mariafrancesca, Toma, Chiara Cristina, Pellegrino, Paolo, Rizzello, Loris, Rinaldi, Rosaria, (2019). Tailoring cell morphomechanical perturbations through metal oxide nanoparticles Nanoscale Research Letters 14, (1), 109

The nowadays growing use of nanoparticles (NPs) in commercial products does not match a comprehensive understanding of their potential harmfulness. More in vitro investigations are required to address how the physicochemical properties of NPs guide their engulfment within cells and their intracellular trafficking, fate, and toxicity. These nano-bio interactions have not been extensively addressed yet, especially from a mechanical viewpoint. Cell mechanic is a critical indicator of cell health because it regulates processes like cell migration, tissue integrity, and differentiation via cytoskeleton rearrangements. Here, we investigated in vitro the elasticity perturbation of Caco-2 and A549 cell lines, in terms of Young’s modulus modification induced by SiO2NPS and TiO2NPS. TiO2NPs demonstrated stronger effects on cell elasticity compared to SiO2NPs, as they induced significant morphological and morphometric changes in actin network. TiO2NPS increased the elasticity in Caco-2 cells, while opposite effects have been observed on A549 cells. These results demonstrate the existence of a correlation between the alteration of cell elasticity and NPs toxicity that depends, in turn, on the NPs physicochemical properties and the specific cell tested.


Uroz, Marina, Garcia-Puig, Anna, Tekeli, Isil, Elosegui-Artola, Alberto, Abenza, Juan F., Marín-Llauradó, Ariadna, Pujals, Silvia, Conte, Vito, Albertazzi, Lorenzo, Roca-Cusachs, Pere, Raya, Ángel, Trepat, Xavier, (2019). Traction forces at the cytokinetic ring regulate cell division and polyploidy in the migrating zebrafish epicardium Nature Materials

Epithelial repair and regeneration are driven by collective cell migration and division. Both cellular functions involve tightly controlled mechanical events, but how physical forces regulate cell division in migrating epithelia is largely unknown. Here we show that cells dividing in the migrating zebrafish epicardium exert large cell–extracellular matrix (ECM) forces during cytokinesis. These forces point towards the division axis and are exerted through focal adhesions that connect the cytokinetic ring to the underlying ECM. When subjected to high loading rates, these cytokinetic focal adhesions prevent closure of the contractile ring, leading to multi-nucleation through cytokinetic failure. By combining a clutch model with experiments on substrates of different rigidity, ECM composition and ligand density, we show that failed cytokinesis is triggered by adhesion reinforcement downstream of increased myosin density. The mechanical interaction between the cytokinetic ring and the ECM thus provides a mechanism for the regulation of cell division and polyploidy that may have implications in regeneration and cancer.


Roki, N., Tsinas, Z., Solomon, M., Bowers, J., Getts, R. C., Muro, S., (2019). Unprecedently high targeting specificity toward lung ICAM-1 using 3DNA nanocarriers Journal of Controlled Release 305, 41-49

DNA nanostructures hold great potential for drug delivery. However, their specific targeting is often compromised by recognition by scavenger receptors involved in clearance. In our previous study in cell culture, we showed targeting specificity of a 180 nm, 4-layer DNA-built nanocarrier called 3DNA coupled with antibodies against intercellular adhesion molecule-1 (ICAM-1), a glycoprotein overexpressed in the lungs in many diseases. Here, we examined the biodistribution of various 3DNA formulations in mice. A formulation consisted of 3DNA whose outer-layer arms were hybridized to secondary antibody-oligonucleotide conjugates. Anchoring IgG on this formulation reduced circulation and kidney accumulation vs. non-anchored IgG, while increasing liver and spleen clearance, as expected for a nanocarrier. Anchoring anti-ICAM changed the biodistribution of this antibody similarly, yet this formulation specifically accumulated in the lungs, the main ICAM-1 target. Since lung targeting was modest (2-fold specificity index over IgG formulation), we pursued a second preparation involving direct hybridization of primary antibody-oligonucleotide conjugates to 3DNA. This formulation had prolonged stability in serum and showed a dramatic increase in lung distribution: the specificity index was 424-fold above a matching IgG formulation, 144-fold more specific than observed for PLGA nanoparticles of similar size, polydispersity, ζ-potential and antibody valency, and its lung accumulation increased with the number of anti-ICAM molecules per particle. Immunohistochemistry showed that anti-ICAM and 3DNA components colocalized in the lungs, specifically associating with endothelial markers, without apparent histological changes. The degree of in vivo targeting for anti-ICAM/3DNA-nanocarriers is unprecedented, for which this platform technology holds great potential to develop future therapeutic applications.

Keywords: 3DNA, DNA nanostructure, Drug nanocarrier, Endothelial and lung targeting, ICAM-1, In vivo biodistribution


Mas, S., Torro, A., Bec, N., Fernández, L., Erschov, G., Gongora, C., Larroque, C., Martineau, P., de Juan, A., Marco, S., (2019). Use of physiological information based on grayscale images to improve mass spectrometry imaging data analysis from biological tissues Analytica Chimica Acta In Press, Accepted Manuscript

The characterization of cancer tissues by matrix-assisted laser desorption ionization-mass spectrometry images (MALDI-MSI) is of great interest because of the power of MALDI-MS to understand the composition of biological samples and the imaging side that allows for setting spatial boundaries among tissues of different nature based on their compositional differences. In tissue-based cancer research, information on the spatial location of necrotic/tumoral cell populations can be approximately known from grayscale images of the scanned tissue slices. This study proposes as a major novelty the introduction of this physiologically-based information to help in the performance of unmixing methods, oriented to extract the MS signatures and distribution maps of the different tissues present in biological samples. Specifically, the information gathered from grayscale images will be used as a local rank constraint in Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) for the analysis of MALDI-MSI of cancer tissues. The use of this constraint, setting absence of certain kind of tissues only in clear zones of the image, will help to improve the performance of MCR-ALS and to provide a more reliable definition of the chemical MS fingerprint and location of the tissues of interest. The general strategy to address the analysis of MALDI-MSI of cancer tissues will involve the study of the MCR-ALS results and the posterior use of MCR-ALS scores as dimensionality reduction for image segmentation based on K-means clustering. The resolution method will provide the MS signatures and their distribution maps for each tissue in the sample. Then, the resolved distribution maps for each biological component (MCR scores) will be submitted as initial information to K-means clustering for image segmentation to obtain information on the boundaries of the different tissular regions in the samples studied. MCR-ALS prior to K-means not only provides the desired dimensionality reduction, but additionally resolved non-biological signal contributions are not used and the weight given to the different biological components in the segmentation process can be modulated by suitable preprocessing methods.

Keywords: MCR-ALS, K-means, Local rank constraints, MALDI-MSI, Grayscale images


Feitosa, J. A., Stefano Filho, C. A., Casseb, R. F., Camargo, A., Martins, B. S. G., Ballester, B. R., Omedas, P., Verschure, P., Oberg, T. D., Min, L. L., Castellano, G., (2019). Complex network changes during a virtual reality rehabilitation protocol following stroke: A case study NER 2019 9th International IEEE/EMBS Conference on Neural Engineering , IEEE (San Francisco, USA) , 891-894

Stroke is one of the main causes of disabilities caused by injuries to the human central nervous system, yielding a wide range of mild to severe impairments that can compromise sensorimotor and cognitive functions. Although rehabilitation protocols may improve function of stroke survivors, patients often reach plateaus while undergoing therapy. Recently, virtual reality (VR) technologies have been paired with traditional rehabilitation aiming to improve function recovery after stroke. Aiming to better understand structural brain changes due to VR rehabilitation protocols, we modeled the brain as a graph and extracted three measures representing the network's topology: degree, clustering coefficient and betweenness centrality (BC). In this single case study, our results indicate that all metrics increased on the ipsilesional hemisphere, while remaining about the same at the contrale-sional site. Particularly, the number of functional connections increased in the lesion area overtime. In addition, the BC displayed the highest variations, and in brain regions related to the patient's cognitive and motor impairments; hence, we argue that this measure could be regarded as an indicative for brain plasticity mechanisms.


Vouloutsi, V., Grechuta, K., Verschure, P., (2019). Evaluation of the facial expressions of a humanoid robot Biomimetic and Biohybrid Systems 8th International Conference, Living Machines 2019 (Lecture Notes in Computer Science) , Springer International Publishing (Nara, Japan) 11556, 365-368

Facial expressions are salient social features that crucial in communication, and humans are capable of reading the messages faces convey and the emotions they display. Robots that interact with humans will need to employ similar communication channels for successful interactions. Here, we focus on the readability of the facial expressions of a humanoid robot. We conducted an online survey where participants evaluated emotional stimuli and assessed the robot’s expressions. Results suggest that the robot’s facial expressions are correctly recognised and the appraisal of the robots expressive elements are consistent with the literature.

Keywords: Emotion recognition, Facial expressions, Human-robot interaction


Gumí-Audenis, B., Giannotti, M. I., (2019). Structural and mechanical characterization of supported model membranes by AFM Biomimetic Lipid Membranes: Fundamentals, Applications, and Commercialization (ed. Kök, Fatma N., Arslan Yildiz, Ahu, Inci, Fatih), Springer International Publishing (Cham, Germany) , 1-27

Several cellular processes, including adhesion, signaling and transcription, endocytosis, and membrane resealing, among others, involve conformational changes such as bending, vesiculation, and tubulation. These mechanisms generally involve membrane separation from the cytoskeleton as well as strong bending, for which the membrane chemical composition and physicochemical properties, often highly localized and dynamic, are key players. The mechanical role of the lipid membrane in force triggered (or sensing) mechanisms in cells is important, and understanding the lipid bilayers’ physical and mechanical properties is essential to comprehend their contribution to the overall membrane. Atomic force microscopy (AFM)-based experimental approaches have been to date very valuable to deepen into these aspects. As a stand-alone, high-resolution imaging technique and force transducer with the possibility to operate in aqueous environment, it defies most other surface instrumentation in ease of use, sensitivity and versatility. In this chapter, we introduce the different AFM-based methods to assess topological and nanomechanical information on model membranes, specifically to supported lipid bilayers (SLBs), including several examples ranging from pure phospholipid homogeneous bilayers to multicomponent and phase-separated SLBs, increasing the bilayer complexity, in the direction of mimicking biological membranes.

Keywords: Atomic force microscopy, Force spectroscopy, Model membranes, Nanomechanics, Supported lipid bilayers