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 Article ASAP

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

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

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 tbd

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.

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

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

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

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

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 On-line,

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

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.

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.

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.

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

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

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.

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, (2018). Fine tuning the extracellular environment accelerates the derivation of kidney organoids from human pluripotent stem cells Nature Materials Ahead

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.