Publications

Year 2020


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Kyndiah, A., Leonardi, F., Tarantino, C., Cramer, T., Millan-Solsona, R., Garreta, E., Montserrat, N., Mas-Torrent, M., Gomila, G., (2020). Bioelectronic recordings of cardiomyocytes with accumulation mode electrolyte gated organic field effect transistors Biosensors and Bioelectronics 150, 111844

Organic electronic materials offer an untapped potential for novel tools for low-invasive electrophysiological recording and stimulation devices. Such materials combine semiconducting properties with tailored surface chemistry, elastic mechanical properties and chemical stability in water. In this work, we investigate solution processed Electrolyte Gated Organic Field Effect Transistors (EGOFETs) based on a small molecule semiconductor. We demonstrate that EGOFETs based on a blend of soluble organic semiconductor 2,8-Difluoro-5,11-bis(triethylsilylethynyl)anthradithiophene (diF-TES-ADT) combined with an insulating polymer show excellent sensitivity and long-term recording under electrophysiological applications. Our devices can stably record the extracellular potential of human pluripotent stem cell derived cardiomyocyte cells (hPSCs-CMs) for several weeks. In addition, cytotoxicity tests of pharmaceutical drugs, such as Norepinephrine and Verapamil was achieved with excellent sensitivity. This work demonstrates that organic transistors based on organic blends are excellent bioelectronics transducer for extracellular electrical recording of excitable cells and tissues thus providing a valid alternative to electrochemical transistors.

Keywords: Bioelectronics, Cardiac cells, Organic electronics, Organic field effect transistors, Organic semiconducting blend


Maier, Martina, Ballester, Belén Rubio, Leiva Bañuelos, Nuria, Duarte Oller, Esther, Verschure, P., (2020). Adaptive conjunctive cognitive training (ACCT) in virtual reality for chronic stroke patients: a randomized controlled pilot trial Journal of NeuroEngineering and Rehabilitation 17, (1), 42

Current evidence for the effectiveness of post-stroke cognitive rehabilitation is weak, possibly due to two reasons. First, patients typically express cognitive deficits in several domains. Therapies focusing on specific cognitive deficits might not address their interrelated neurological nature. Second, co-occurring psychological problems are often neglected or not diagnosed, although post-stroke depression is common and related to cognitive deficits. This pilot trial aims to test a rehabilitation program in virtual reality that trains various cognitive domains in conjunction, by adapting to the patient’s disability and while investigating the influence of comorbidities.


Vilanova, E., Ciodaro, P. J., Bezerra, F. F., Santos, G. R. C., Valle-Delgado, J. J., Anselmetti, D., Fernàndez-Busquets, X., Mourão, P. A. S., (2020). Adhesion of freshwater sponge cells mediated by carbohydrate-carbohydrate interactions requires low environmental calcium Glycobiology 30, (9), 710-721

Marine ancestors of freshwater sponges had to undergo a series of physiological adaptations to colonize harsh and heterogeneous limnic environments. Besides reduced salinity, river-lake systems also have calcium concentrations far lower than seawater. Cell adhesion in sponges is mediated by calcium-dependent multivalent self-interactions of sulfated polysaccharide components of membrane-bound proteoglycans named aggregation factors. Cells of marine sponges require seawater average calcium concentration (10 mM) to sustain adhesion promoted by aggregation factors. We demonstrate here that the freshwater sponge Spongilla alba can thrive in a calcium-poor aquatic environment and that their cells are able to aggregate and form primmorphs with calcium concentrations 40-fold lower than that required by marine sponges cells. We also find that their gemmules need calcium and other micronutrients to hatch and generate new sponges. The sulfated polysaccharide purified from S. alba has sulfate content and molecular size notably lower than those from marine sponges. Nuclear magnetic resonance analyses indicated that it is composed of a central backbone of non- and 2-sulfated α- and β-glucose units decorated with branches of α-glucose. Assessments with atomic force microscopy/single-molecule force spectroscopy show that S. alba glucan requires 10-fold less calcium than sulfated polysaccharides from marine sponges to self-interact efficiently. Such an ability to retain multicellular morphology with low environmental calcium must have been a crucial evolutionary step for freshwater sponges to successfully colonize inland waters.

Keywords: Carbohydrate interactions, Evolutionary adaptation, Porifera, Proteoglycans, Sulfated polysaccharides


Aeridou, E., Díaz Díaz, D., Alemán, C., Pérez-Madrigal, M. M., (2020). Advanced functional hydrogel biomaterials based on dynamic B-O bonds and polysaccharide building blocks Biomacromolecules 21, (10), 3984-3996

Dynamic covalent chemistry applied to polymers has attracted significant attention over the past decade. Within this area, this review highlights the recent research on polysaccharide-based hydrogels cross-linked by boronic acid moieties, illustrating its versatility and relevance in biomaterials science to design self-healing, multiple stimuli-responsive, and adaptive biointerfaces and advanced functional devices.


Allaw, M., Manca, M. L., Caddeo, C., Recio, M. C., Pérez-Brocal, V., Moya, A., Fernàndez-Busquets, X., Manconi, M., (2020). Advanced strategy to exploit wine-making waste by manufacturing antioxidant and prebiotic fibre-enriched vesicles for intestinal health Colloids and Surfaces B: Biointerfaces 193, 111146

Grape extract-loaded fibre-enriched vesicles, nutriosomes, were prepared by combining antioxidant extracts obtained from grape pomaces and a prebiotic, soluble fibre (Nutriose®FM06). The nutriosomes were small in size (from ∼140 to 260 nm), homogeneous (polydispersity index < 0.2) and highly negative (∼ −79 mV). The vesicles were highly stable during 12 months of storage at 25 °C. When diluted with warmed (37 °C) acidic medium (pH 1.2) of high ionic strength, the vesicles only displayed an increase of the mean diameter and a low release of the extract, which were dependent on Nutriose concentration. The formulations were highly biocompatible and able to protect intestinal cells (Caco-2) from oxidative stress damage. In vivo results underlined that the composition of mouse microbiota was not affected by the vesicular formulations. Overall results support the potential application of grape nutriosomes as an alternative strategy for the protection of the intestinal tract.

Keywords: Antioxidant activity, Grape pomace, Gut microbiota, In vivo studies, Intestinal cells, Nutriosomes, Phospholipid vesicles, Prebiotic activity


Zanuy, D., Puiggalí-Jou, A., Conflitti, P., Bocchinfuso, G., Palleschi, A., Alemán, C., (2020). Aggregation propensity of therapeutic fibrin-homing pentapeptides: Insights from experiments and molecular dynamics simulations Soft Matter 16, (44), 10169-10179

CREKA (Cys–Arg–Glu–Lys–Ala) and its engineered analogue CRMeEKA, in which Glu has been replaced by N-methyl-Glu to provide resistance against proteolysis, are emerging pentapeptides that were specifically designed to bind fibrin–fibronectin complexes accumulated in the walls of tumour vessels. However, many of the intrinsic properties of CREKA and CRMeEKA, which are probably responsible for their different behaviour when combined with other materials (such as polymers) for diagnosis and therapeutics, remain unknown yet. The intrinsic tendency of these pentapeptides to form aggregates has been analysed by combining experimental techniques and atomistic Molecular Dynamics (MD) simulations. Dynamic light scattering assays show the formation of nanoaggregates that increase in size with the peptide concentration, even though aggregation occurs sooner for CRMeEKA, independently of the peptide concentration. FTIR and circular dichroism spectroscopy studies suggest that aggregated pentapeptides do not adopt any secondary structure. Atomistic MD trajectories show that CREKA aggregates faster and forms bigger molecular clusters than CRMeEKA. This behaviour has been explained by stability of the conformations adopted by un-associated peptide strands. While CREKA molecules organize by forming intramolecular backbone – side chain hydrogen bonds, CRMeEKA peptides display main chain – main chain hydrogen bonds closing very stable γ- or β-turns. Besides, energetic analyses reveal that CRMeEKA strands are better solvated in water than CREKA ones, independent of whether they are assembled or un-associated.


Queck, A., Fink, A. F., Sirait-Fischer, E., Rüschenbaum, S., Thomas, D., Snodgrass, R. G., Geisslinger, G., Baba, H. A., Trebicka, J., Zeuzem, S., Weigert, A., Lange, C. M., Brüne, B., (2020). Alox12/15 deficiency exacerbates, while lipoxin A4 ameliorates hepatic inflammation in murine alcoholic hepatitis Frontiers in Immunology 11, 1447

Alcoholism is one of the leading and increasingly prevalent reasons of liver associated morbidity and mortality worldwide. Alcoholic hepatitis (AH) constitutes a severe disease with currently no satisfying treatment options. Lipoxin A4 (LXA4), a 15-lipoxygenase (ALOX15)-dependent lipid mediator involved in resolution of inflammation, showed promising pre-clinical results in the therapy of several inflammatory diseases. Since inflammation is a main driver of disease progression in alcoholic hepatitis, we investigated the impact of endogenous ALOX15-dependent lipid mediators and exogenously applied LXA4 on AH development. A mouse model for alcoholic steatohepatitis (NIAAA model) was tested in Alox12/15+/+ and Alox12/15−/− mice, with or without supplementation of LXA4. Absence of Alox12/15 aggravated parameters of liver disease, increased hepatic immune cell infiltration in AH, and elevated systemic neutrophils as a marker for systemic inflammation. Interestingly, i.p. injections of LXA4 significantly lowered transaminase levels only in Alox12/15−/− mice and reduced hepatic immune cell infiltration as well as systemic inflammatory cytokine expression in both genotypes, even though steatosis progressed. Thus, while LXA4 injection attenuated selected parameters of disease progression in Alox12/15−/− mice, its beneficial impact on immunity was also apparent in Alox12/15+/+ mice. In conclusion, pro-resolving lipid mediators may be beneficial to reduce inflammation in alcoholic hepatitis.

Keywords: Alcoholic hepatitis, Arachidonate 12/15-lipoxygenase (Alox12/15), Lipoxin A4, Resolution of inflammation, Specialized pro-resolving lipid mediators (SPMs)


Madrid-Gambin, Francisco, Oller-Moreno, Sergio, Fernandez, Luis, Bartova, Simona, Giner, Maria Pilar, Joyce, Christopher, Ferraro, Francesco, Montoliu, Ivan, Moco, Sofia, Marco, Santiago, (2020). AlpsNMR: an R package for signal processing of fully untargeted NMR-based metabolomics Bioinformatics 36, (9), 2943–2945

NMR-based metabolomics is widely used to obtain metabolic fingerprints of biological systems. While targeted workflows require previous knowledge of metabolites, prior to statistical analysis, untargeted approaches remain a challenge. Computational tools dealing with fully untargeted NMR-based metabolomics are still scarce or not user-friendly. Therefore, we developed AlpsNMR (Automated spectraL Processing System for NMR), an R package that provides automated and efficient signal processing for untargeted NMR metabolomics. AlpsNMR includes spectra loading, metadata handling, automated outlier detection, spectra alignment and peak-picking, integration, and normalization. The resulting output can be used for further statistical analysis. AlpsNMR proved effective in detecting metabolite changes in a test case. The tool allows less experienced users to easily implement this workflow from spectra to a ready-to-use dataset in their routines.The AlpsNMR R package and tutorial is freely available to download from http://github.com/sipss/AlpsNMR under the MIT license.


Revilla-López, G., Sans, J., Casanovas, J., Bertran, O., Puiggalí, J., Turon, P., Alemán, C., (2020). Analysis of nitrogen fixation by a catalyst capable of transforming N2, CO2 and CH4 into amino acids under mild reactions conditions Applied Catalysis A: General 596, 117526

The processes related to the fixation of nitrogen in a catalyst able to produce glycine and alanine from a N2, CO2 and CH4 gas mixture at mild reaction conditions have been studied by combining experimental and theoretical investigations. Results have allowed to understand the role of different elements of the catalyst, which is constituted by permanently polarized hydroxyapatite (p-HAp), zirconia, and aminotris(methylenephosphonic acid) (ATMP). ATMP attracts N2 molecules towards the surface, maintaining them close to the zirconia and p-HAp components that are the most active from a catalytic point of view. On the other hand, the associative mechanism is thermodynamically favoured under mild reaction conditions with respect to the dissociative one, which is limited by the barrier associated to the Nsingle bondN bond cleavage. Because this reaction mechanism is similar to that employed in the nitrogen fixation by nitrogenase enzymes, these findings provide an opportunity to design new bioinspired catalysts.

Keywords: Artificial photosynthesis, Carbon fixation, Hydroxyapatite, N[sbnd]N bond cleavage


Ferrer-Lluís, I., Castillo-Escario, Y., Montserrat, J. M., Jané, R., (2020). Analysis of smartphone triaxial accelerometry for monitoring sleep disordered breathing and sleep position at home IEEE Access 8, 71231 - 71244

Obstructive sleep apnea (OSA) is a sleep disorder in which repetitive upper airway obstructive events occur during sleep. These events can induce hypoxia, which is a risk factor for multiple cardiovascular and cerebrovascular diseases. OSA is also known to be position-dependent in some patients, which is referred to as positional OSA (pOSA). Screening for pOSA is necessary in order to design more personalized and effective treatment strategies. In this article, we propose analyzing accelerometry signals, recorded with a smartphone, to detect and monitor OSA at home. Our objectives were to: (1) develop an algorithm for detecting thoracic movement associated with disordered breathing events; (2) compare the performance of smartphones as OSA monitoring tools with a type 3 portable sleep monitor; and (3) explore the feasibility of using smartphone accelerometry to retrieve reliable patient sleep position data and assess pOSA. Accelerometry signals were collected through simultaneous overnight acquisition using both devices with 13 subjects. The smartphone tool showed a high degree of concordance compared to the portable device and succeeded in estimating the apnea-hypopnea index (AHI) and classifying the severity level in most subjects. To assess the agreement between the two systems, an event-by-event comparison was performed, which found a sensitivity of 90% and a positive predictive value of 80%. It was also possible to identify pOSA by determining the ratio of events occurring in a specific position versus the time spent in that position during the night. These novel results suggest that smartphones are promising mHealth tools for OSA and pOSA monitoring at home.

Keywords: Accelerometry, Biomedical signal processing, mHealth, Monitoring, Sleep apnea, Sleep position, Smartphone


Morgese, G., de Waal, B. F. M., Varela-Aramburu, S., Palmans, A. R. A., Albertazzi, L., Meijer, E. W., (2020). Anchoring supramolecular polymers to human red blood cells by combining dynamic covalent and non-covalent chemistries Angewandte Chemie - International Edition 59, (39), 17229-17233

Understanding cell/material interactions is essential to design functional cell-responsive materials. While the scientific literature abounds with formulations of biomimetic materials, only a fraction of them focused on mechanisms of the molecular interactions between cells and material. To provide new knowledge on the strategies for materials/cell recognition and binding, supramolecular benzene-1,3,5-tricarboxamide copolymers bearing benzoxaborole moieties are anchored on the surface of human erythrocytes via benzoxaborole/sialic-acid binding. This interaction based on both dynamic covalent and non-covalent chemistries is visualized in real time by means of total internal reflection fluorescence microscopy. Exploiting this imaging method, we observe that the functional copolymers specifically interact with the cell surface. An optimal fiber affinity towards the cells as a function of benzoxaborole concentration demonstrates the crucial role of multivalency in these cell/material interactions.

Keywords: Boronic acid, Cell/material interactions, Multivalency, Red blood cells, Supramolecular polymers


Torres-Sánchez, A., Santos-Oliván, D., Arroyo, M., (2020). Approximation of tensor fields on surfaces of arbitrary topology based on local Monge parametrizations Journal of Computational Physics 405, 109168

We introduce a new method, the Local Monge Parametrizations (LMP) method, to approximate tensor fields on general surfaces given by a collection of local parametrizations, e.g. as in finite element or NURBS surface representations. Our goal is to use this method to solve numerically tensor-valued partial differential equations (PDEs) on surfaces. Previous methods use scalar potentials to numerically describe vector fields on surfaces, at the expense of requiring higher-order derivatives of the approximated fields and limited to simply connected surfaces, or represent tangential tensor fields as tensor fields in 3D subjected to constraints, thus increasing the essential number of degrees of freedom. In contrast, the LMP method uses an optimal number of degrees of freedom to represent a tensor, is general with regards to the topology of the surface, and does not increase the order of the PDEs governing the tensor fields. The main idea is to construct maps between the element parametrizations and a local Monge parametrization around each node. We test the LMP method by approximating in a least-squares sense different vector and tensor fields on simply connected and genus-1 surfaces. Furthermore, we apply the LMP method to two physical models on surfaces, involving a tension-driven flow (vector-valued PDE) and nematic ordering (tensor-valued PDE), on different topologies. The LMP method thus solves the long-standing problem of the interpolation of tensors on general surfaces with an optimal number of degrees of freedom.

Keywords: Approximation, Finite elements, Surface PDE, Tensor-valued PDE, Vector-valued PDE


Delcanale, P., Porciani, D., Pujals, S., Jurkevich, A., Chetrusca, A., Tawiah, K. D., Burke, D. H., Albertazzi, L., (2020). Aptamers with tunable affinity enable single-molecule tracking and localization of membrane receptors on living cancer cells Angewandte Chemie - International Edition 59, (42), 18546-18555

Tumor cell-surface markers are usually overexpressed or mutated protein receptors for which spatiotemporal regulation differs between and within cancers. Single-molecule fluorescence imaging can profile individual markers in different cellular contexts with molecular precision. However, standard single-molecule imaging methods based on overexpressed genetically encoded tags or cumbersome probes can significantly alter the native state of receptors. We introduce a live-cell points accumulation for imaging in nanoscale topography (PAINT) method that exploits aptamers as minimally invasive affinity probes. Localization and tracking of individual receptors are based on stochastic and transient binding between aptamers and their targets. We demonstrated single-molecule imaging of a model tumor marker (EGFR) on a panel of living cancer cells. Affinity to EGFR was finely tuned by rational engineering of aptamer sequences to define receptor motion and/or native receptor density.

Keywords: Aptamers, Cell-surface receptors, Live-cell imaging, PAINT, Single-molecule tracking


Fuentes, E., Gerth, M., Berrocal, J. A., Matera, C., Gorostiza, P., Voets, I. K., Pujals, S., Albertazzi, L., (2020). An azobenzene-based single-component supramolecular polymer responsive to multiple stimuli in water Journal of the American Chemical Society 142, (22), 10069-10078

One of the most appealing features of supramolecular assemblies is their ability to respond to external stimuli due to their noncovalent nature. This provides the opportunity to gain control over their size, morphology, and chemical properties and is key toward some of their applications. However, the design of supramolecular systems able to respond to multiple stimuli in a controlled fashion is still challenging. Here we report the synthesis and characterization of a novel discotic molecule, which self-assembles in water into a single-component supramolecular polymer that responds to multiple independent stimuli. The building block of such an assembly is a C3-symmetric monomer, consisting of a benzene-1,3,5-tricarboxamide core conjugated to a series of natural and non-natural functional amino acids. This design allows the use of rapid and efficient solid-phase synthesis methods and the modular implementation of different functionalities. The discotic monomer incorporates a hydrophobic azobenzene moiety, an octaethylene glycol chain, and a C-terminal lysine. Each of these blocks was chosen for two reasons: to drive the self-assembly in water by a combination of H-bonding and hydrophobicity and to impart specific responsiveness. With a combination of microscopy and spectroscopy techniques, we demonstrate self-assembly in water and responsiveness to temperature, light, pH, and ionic strength. This work shows the potential to integrate independent mechanisms for controlling self-assembly in a single-component supramolecular polymer by the rational monomer design and paves the way toward the use of multiresponsive systems in water.


Ruano, G., Díaz, A., Tononi, J., Torras, J., Puiggalí, J., Alemán, C., (2020). Biohydrogel from unsaturated polyesteramide: Synthesis, properties and utilization as electrolytic medium for electrochemical supercapacitors Polymer Testing 82, 106300

The utilization of hydrogels derived from biopolymers as solid electrolyte (SE) of electrochemical supercapacitors (ESCs) is a topic of increasing interest because of their promising applications in biomedicine (e.g. for energy storage in autonomous implantable devices). In this work an unsaturated polyesteramide that contains phenylalanine, butenediol and fumarate as building blocks has been photo-crosslinked to obtain a hydrogel (UPEA-h). The structure of UPEA-h, which is characterized by a network of open interconnected pores surrounded by regions with compact morphology, favors ion transport, while the biodegradability and biocompatibility conferred by the α-amino acid unit and the ester group are appropriated for its usage in the biomedical field. Voltammetric and galvanostatic assays have been conducted to evaluate the behavior of UPEA-h when used as SE in ESCs with poly(3,4-ethylenedioxythiophene) (PEDOT) electrodes. Hence, PEDOT/UPEA-h devices displayed supercapacitor response of up 179 F/g and capacitance retention higher than 90%. Moreover, the long-term stability, leakage-current, and self-discharging response of PEDOT/UPEA-h ESCs reflect the great potential of UPEA-h as ion-conductive electrolyte. Indeed, the performance of PEDOT/UPEA-h is higher than found in analogous devices constructed using other biohydrogels as SE (e.g. κ-carrageenan, poly-γ-glutamic acid and cellulose hydrogels).

Keywords: Energy storage, Hydrogel electronics, Ion conductivity, Photo-crosslinking, Wearable electronics


Wang, Lei, Song, Shidong, van Hest, Jan, Abdelmohsen, Loai K. E. A., Huang, Xin, Sánchez, Samuel, (2020). Biomimicry of cellular motility and communication based on synthetic soft-architectures Small 16, (27), 1907680

Cells, sophisticated membrane‐bound units that contain the fundamental molecules of life, provide a precious library for inspiration and motivation for both society and academia. Scientists from various disciplines have made great endeavors toward the understanding of the cellular evolution by engineering artificial counterparts (protocells) that mimic or initiate structural or functional cellular aspects. In this regard, several works have discussed possible building blocks, designs, functions, or dynamics that can be applied to achieve this goal. Although great progress has been made, fundamental—yet complex—behaviors such as cellular communication, responsiveness to environmental cues, and motility remain a challenge, yet to be resolved. Herein, recent efforts toward utilizing soft systems for cellular mimicry are summarized—following the main outline of cellular evolution, from basic compartmentalization, and biological reactions for energy production, to motility and communicative behaviors between artificial cell communities or between artificial and natural cell communities. Finally, the current challenges and future perspectives in the field are discussed, hoping to inspire more future research and to help the further advancement of this field.


Nonaka, P. N., Falcones, B., Farre, R., Artigas, A., Almendros, I., Navajas, D., (2020). Biophysically preconditioning mesenchymal stem cells improves treatment of ventilator-induced lung injury Archivos de Bronconeumología Archivos de Bronconeumologia , In press

Nonaka, P. N., Falcones, B., Farre, R., Artigas, A., Almendros, I., Navajas, D., (2020). Biophysically preconditioning mesenchymal stem cells improves treatment of ventilator-induced lung injury Archivos de Bronconeumología Archivos de Bronconeumologia , 56, (3), 179-181

Keridou, I., Cailloux, J., Martínez, J. C., Santana, O., Maspoch, M. L., Puiggalí, J., Franco, L., (2020). Biphasic polylactide/polyamide 6,10 blends: Influence of composition on polyamide structure and polyester crystallization Polymer 202, 122676

Blends with different ratios of polylactide and polyamide 6,10 (PA610) have been prepared by melt-mixing using a Brabender mixer equipment. Previously, a rheologically modified polylactide (PLAREx) was obtained through reactive extrusion using a multifunctional epoxide agent. It was expected that unreacted epoxy groups of PLAREx were able to improve the compatibility between the two polymers. SEM observations revealed a logical dependence of the morphology of immiscible phases with composition, and more interestingly a co-continuity at relatively low PA content (around 50%) was detected. This result contrasts with previous observations performed with non-modified PLA. Confined PA domains increased with the PA content and hardly crystallized at the typical crystallization temperature of the pure PA (195 °C). Synchrotron X-ray diffraction studies indicated that a PA crystallization at a lower temperature close to 120 °C was enhanced and led to a pseudohexagonal γ phase that differs from the characteristic layered structure of PA610. SAXS data revealed also that well differentiated lamellar entities could be assigned at both immiscible polymer phases. Clear differences were observed in the spherulitic morphologies attained under isothermal melt crystallization experiments. Results indicated that the texture of PLAREx spherulites was modified by the presence of PA. Compatibilization of PA molecules on the crystal lamellar boundaries of PLAREx led to an enhancement of the lamellar twisting frequency. Optical microscopy results also indicated that the crystal growth rate of PLAREx increased by the incorporation of PA, but in contrast this had an adverse effect on the nucleation process.

Keywords: Crystal growth rate, Epoxy modified polylactide, Nucleation, Polyamide 6,10, Polyamide crystalline structure, Polyamide/polylactide blend morphology, Thermal properties


Sans, J., Armelin, E., Sanz, V., Puiggalí, J., Turon, P., Alemán, C., (2020). Breaking-down the catalyst used for the electrophotosynthesis of amino acids by nitrogen and carbon fixation Journal of Catalysis 389, 646-656

The electrophotocatalytic synthesis of Glycine and Alanine from a simple gas mixture containing N2, CO2, CH4 and H2O under mild reaction conditions (95 °C and 6 bar) was recently developed using a catalyst formed by permanently polarized hydroxyapatite, which is achieved using a thermally stimulated polarization process, coated with two layers of aminotris(methylenephosphonic acid) (ATMP) separated by an intermediate layer of zirconyl chloride (ZC). This work reports the optimization of the ATMP- and ZC-coating content by examining the influence of their concentration of each component in each layer on the structural and electrochemical properties of the catalyst. After exhaustive analyses, such properties have been related with the efficiency of the catalysts prepared using different ATMP- and ZC-concentrations to yield Gly and Ala amino acids by fixing nitrogen from N2 and carbon from CO2 and CH4. Results show that, although the concentrations of ATMP and ZC in the first and the intermediate layers are important, the third layer plays a predominant role as is responsible of the apparition of supramolecular structures on the surface and the capacitive behavior of the coating

Keywords: Carbon dioxide fixation, Electrocatalyst, Heterogeneous catalysis, Phosphonic acid, Photocatalyst, Polarized hydroxyapatite, Surface chemistry, Zirconyl chloride


Matej, Trepat, X., (2020). Buckling up from the bottom Developmental Cell 54, (5), 569-571

In this issue of Developmental Cell, Trushko et al. (2020) develop a bottom-up approach to understand the physics underlying confined epithelial monolayer folding. Investigating this process is currently unattainable in vivo but is essential to our understanding of tissue formation from the gastrulating blastula to the developing nervous system.


Ferrer, Isidro, Andrés-Benito, Pol, Sala-Jarque, Julia, Gil, Vanessa, del Rio, José Antonio, (2020). Capacity for seeding and spreading of argyrophilic grain disease in a wild-type murine model; Comparisons with primary age-related tauopathy Frontiers in Molecular Neuroscience 13, 101

Argyrophilic grain disease (AGD) is a common 4R-tauopathy, causing or contributing to cognitive impairment in the elderly. AGD is characterized neuropathologically by pre-tangles in neurons, dendritic swellings called grains, threads, thorn-shaped astrocytes, and coiled bodies in oligodendrocytes in the limbic system. AGD has a characteristic pattern progressively involving the entorhinal cortex, amygdala, hippocampus, dentate gyrus, presubiculum, subiculum, hypothalamic nuclei, temporal cortex, and neocortex and brainstem, thus suggesting that argyrophilic grain pathology is a natural model of tau propagation. One series of WT mice was unilaterally inoculated in the hippocampus with sarkosyl-insoluble and sarkosyl-soluble fractions from “pure” AGD at the age of 3 or 7/12 months and killed 3 or 7 months later. Abnormal hyper-phosphorylated tau deposits were found in ipsilateral hippocampal neurons, grains (dots) in the hippocampus, and threads, dots and coiled bodies in the fimbria, as well as the ipsilateral and contralateral corpus callosum. The extension of lesions was wider in animals surviving 7 months compared with those surviving 3 months. Astrocytic inclusions were not observed at any time. Tau deposits were mainly composed of 4Rtau, but also 3Rtau. For comparative purposes, another series of WT mice was inoculated with sarkosyl-insoluble fractions from primary age-related tauopathy (PART), a pure neuronal neurofibrillary tangle 3Rtau + 4Rtau tauopathy involving the deep temporal cortex and limbic system. Abnormal hyper-phosphorylated tau deposits were found in neurons in the ipsilateral hippocampus, coiled bodies and threads in the fimbria, and the ipsilateral and contralateral corpus callosum, which extended with time along the anterior-posterior axis and distant regions such as hypothalamic nuclei and nuclei of the septum when comparing mice surviving 7 months with mice surviving 3 months. Astrocytic inclusions were not observed. Tau deposits were mainly composed of 4Rtau and 3Rtau. These results show the capacity for seeding and spreading of AGD tau and PART tau in the brain of WT mouse, and suggest that characteristics of host tau, in addition to those of inoculated tau, are key to identifying commonalities and differences between human tauopathies and corresponding murine models.

Keywords: Argyrophilic grain disease, Tauopathies, Tau, Seeding, Progression, Coiled Bodies, Primary age-related tauopathy


Praktiknjo, M., Monteiro, S., Grandt, J., Kimer, N., Madsen, J. L., Werge, M. P., William, P., Brol, M. J., Turco, L., Schierwagen, R., Chang, J., Klein, S., Uschner, F. E., Welsch, C., Moreau, R., Schepis, F., Bendtsen, F., Gluud, L. L., Møller, S., Trebicka, J., (2020). Cardiodynamic state is associated with systemic inflammation and fatal acute-on-chronic liver failure Liver International 40, (6), 1457-1466

Background & Aims: Acute-on-chronic liver failure (ACLF) is characterized by high short-term mortality and systemic inflammation (SI). Recently, different cardiodynamic states were shown to independently predict outcomes in cirrhosis. The relationship between cardiodynamic states, SI, and portal hypertension and their impact on ACLF development remains unclear. The aim of this study was therefore to evaluate the interplay of cardiodynamic state and SI on fatal ACLF development in cirrhosis. Results: At inclusion, hemodynamic measures including cardiac index (CI) and hepatic venous pressure gradient of 208 patients were measured. Patients were followed prospectively for fatal ACLF development (primary endpoint). SI was assessed by proinflammatory markers such as interleukins (ILs) 6 and 8 and soluble IL-33 receptor (sIL-33R). Patients were divided according to CI (<3.2; 3.2-4.2; >4.2 L/min/m2) in hypo- (n = 84), normo- (n = 69) and hyperdynamic group (n = 55). After a median follow-up of 3 years, the highest risk of fatal ACLF was seen in hyperdynamic (35%) and hypodynamic patients (25%) compared with normodynamic (14%) (P = .011). Hyperdynamic patients showed the highest rate of SI. The detectable level of IL-6 was an independent predictor of fatal ACLF development. Conclusions: Cirrhotic patients with hyperdynamic and hypodynamic circulation have a higher risk of fatal ACLF. Therefore, the cardiodynamic state is strongly associated with SI, which is an independent predictor of development of fatal ACLF.

Keywords: Acute-on-chronic liver failure, Circulation, Cirrhosis, Hemodynamic, Inflammation


Blanco-Cabra, Núria, Paetzold, Bernhard, Ferrar, Tony, Mazzolini, Rocco, Torrents, Eduard, Serrano, Luis, Lluch-Senar, Maria, (2020). Characterization of different alginate lyases for dissolving Pseudomonas aeruginosa biofilms Scientific Reports 10, (1), 9390

Aggregates of Pseudomonas aeruginosa form a protective barrier against antibiotics and the immune system. These barriers, known as biofilms, are associated with several infectious diseases. One of the main components of these biofilms is alginate, a homo- and hetero-polysaccharide that consists of β-D-mannuronate (M) and α-L-guluronate (G) units. Alginate lyases degrade this sugar and have been proposed as biotherapeutic agents to dissolve P. aeruginosa biofilms. However, there are contradictory reports in the literature regarding the efficacy of alginate lyases against biofilms and their synergistic effect with antibiotics. We found that most positive reports used a commercial crude extract from Flavobacterium multivorum as the alginate lyase source. By using anion exchange chromatography coupled to nano LC MS/MS, we identified two distinct enzymes in this extract, one has both polyM and polyG (polyM/G) degradation activities and it is similar in sequence to a broad-spectrum alginate lyase from Flavobacterium sp. S20 (Alg2A). The other enzyme has only polyG activity and it is similar in sequence to AlyA1 from Zobellia galactanivorans. By characterizing both of these enzymes together with three recombinant alginate lyases (a polyM, a polyG and a polyM/G), we showed that only enzymes with polyM/G activity such as Alg2A and A1-II’ (alginate lyase from Sphingomonas sp.) are effective in dissolving biofilms. Furthermore, both activities are required to have a synergistic effect with antibiotics.


Muzio, Martina Di, Millan-Solsona, Ruben, Borrell, Jordi H., Fumagalli, Laura, Gomila, Gabriel, (2020). Cholesterol effect on the specific capacitance of submicrometric DOPC bilayer patches measured by in-liquid scanning dielectric microscopy Langmuir 36, (43), 12963–12972

The specific capacitance of biological membranes is a key physical parameter in bioelectricity that also provides valuable physicochemical information on composition, phase, or hydration properties. Cholesterol is known to modulate the physicochemical properties of biomembranes, but its effect on the specific capacitance has not been fully established yet. Here we use the high spatial resolution capabilities of in-liquid scanning dielectric microscopy in force detection mode to directly demonstrate that DOPC bilayer patches at 50% cholesterol concentration show a strong reduction of their specific capacitance with respect to pure DOPC bilayer patches. The reduction observed (around 35%) cannot be explained by the small increase in bilayer thickness (around 16%). We suggest that the reduction of the specific capacitance might be due to the dehydration of the polar head groups caused by the insertion of cholesterol molecules in the bilayer. The results reported confirm the potential of in-liquid SDM to study the electrical and physicochemical properties of lipid bilayers at very small scales (down to around 200 nm here), with implications in fields such as biophysics, bioelectricity, biochemistry, and biosensing.


Olate-Moya, F., Arens, L., Wilhelm, M., Mateos-Timoneda, M. A., Engel, E., Palza, H., (2020). Chondroinductive alginate-based hydrogels having graphene oxide for 3D printed scaffold fabrication ACS Applied Materials and Interfaces 12, (4), 4343-4357

Scaffolds based on bioconjugated hydrogels are attractive for tissue engineering because they can partly mimic human tissue characteristics. For example, they can further increase their bioactivity with cells. However, most of the hydrogels present problems related to their processability, consequently limiting their use in 3D printing to produce tailor-made scaffolds. The goal of this work is to develop bioconjugated hydrogel nanocomposite inks for 3D printed scaffold fabrication through a micro-extrusion process having improved both biocompatibility and processability. The hydrogel is based on a photocrosslinkable alginate bioconjugated with both gelatin and chondroitin sulfate in order to mimic the cartilage extracellular matrix, while the nanofiller is based on graphene oxide to enhance the printability and cell proliferation. Our results show that the incorporation of graphene oxide into the hydrogel inks considerably improved the shape fidelity and resolution of 3D printed scaffolds because of a faster viscosity recovery post extrusion of the ink. Moreover, the nanocomposite inks produce anisotropic threads after the 3D printing process because of the templating of the graphene oxide liquid crystal. The in vitro proliferation assay of human adipose tissue-derived mesenchymal stem cells (hADMSCs) shows that bioconjugated scaffolds present higher cell proliferation than pure alginate, with the nanocomposites presenting the highest values at long times. Live/Dead assay otherwise displays full viability of hADMSCs adhered on the different scaffolds at day 7. Notably, the scaffolds produced with nanocomposite hydrogel inks were able to guide the cell proliferation following the direction of the 3D printed threads. In addition, the bioconjugated alginate hydrogel matrix induced chondrogenic differentiation without exogenous pro-chondrogenesis factors as concluded from immunostaining after 28 days of culture. This high cytocompatibility and chondroinductive effect toward hADMSCs, together with the improved printability and anisotropic structures, makes these nanocomposite hydrogel inks a promising candidate for cartilage tissue engineering based on 3D printing.

Keywords: 3D printing, Chondrogenesis, Graphene oxide, Hydrogels, Liquid crystals


Mateu-Sanz, M., Tornín, J., Brulin, B., Khlyustova, A., Ginebra, M. P., Layrolle, P., Canal, C., (2020). Cold plasma-treated ringer's saline: A weapon to target osteosarcoma Cancers 12, (1), 227

Osteosarcoma (OS) is the main primary bone cancer, presenting poor prognosis and difficult treatment. An innovative therapy may be found in cold plasmas, which show anti-cancer effects related to the generation of reactive oxygen and nitrogen species in liquids. In vitro models are based on the effects of plasma-treated culture media on cell cultures. However, effects of plasma-activated saline solutions with clinical application have not yet been explored in OS. The aim of this study is to obtain mechanistic insights on the action of plasma-activated Ringer’s saline (PAR) for OS therapy in cell and organotypic cultures. To that aim, cold atmospheric plasma jets were used to obtain PAR, which produced cytotoxic effects in human OS cells (SaOS-2, MG-63, and U2-OS), related to the increasing concentration of reactive oxygen and nitrogen species generated. Proof of selectivity was found in the sustained viability of hBM-MSCs with the same treatments. Organotypic cultures of murine OS confirmed the time-dependent cytotoxicity observed in 2D. Histological analysis showed a decrease in proliferating cells (lower Ki-67 expression). It is shown that the selectivity of PAR is highly dependent on the concentrations of reactive species, being the differential intracellular reactive oxygen species increase and DNA damage between OS cells and hBM-MSCs key mediators for cell apoptosis.

Keywords: Bone cancer, Cold atmospheric plasma, Organotypic model, Osteosarcoma, Plasma-activated liquid, Reactive species, Ringer's saline


Blancas, Maria, Maffei, Giovanni, Sánchez-Fibla, Martí, Vouloutsi, Vasiliki, Verschure, P., (2020). Collaboration variability in autism spectrum disorder Frontiers in Human Neuroscience 14, (412), 559793

This paper addresses how impairments in prediction in young adults with autism spectrum disorder (ASD) relate to their behavior during collaboration. To assess it, we developed a task where participants play in collaboration with a synthetic agent to maximize their score. The agent’s behavior changes during the different phases of the game, requiring participants to model the agent’s sensorimotor contingencies to play collaboratively. Our results (n = 30, 15 per group) show differences between autistic and neurotypical individuals in their behavioral adaptation to the other partner. Contrarily, there are no differences in the self-reports of that collaboration.

Keywords: Autism, Prediction, Collaboration, Sensorimotor contingencies, Neurodiversity


Liu, M., Apriceno, A., Sipin, M., Scarpa, E., Rodriguez-Arco, L., Poma, A., Marchello, G., Battaglia, G., Angioletti-Uberti, S., (2020). Combinatorial entropy behaviour leads to range selective binding in ligand-receptor interactions Nature Communications 11, (1), 4836

From viruses to nanoparticles, constructs functionalized with multiple ligands display peculiar binding properties that only arise from multivalent effects. Using statistical mechanical modelling, we describe here how multivalency can be exploited to achieve what we dub range selectivity, that is, binding only to targets bearing a number of receptors within a specified range. We use our model to characterise the region in parameter space where one can expect range selective targeting to occur, and provide experimental support for this phenomenon. Overall, range selectivity represents a potential path to increase the targeting selectivity of multivalent constructs.


Sola-Barrado, B., M. Leite, D., Scarpa, E., Duro-Castano, A., Battaglia, G., (2020). Combinatorial intracellular delivery screening of anticancer drugs Molecular Pharmaceutics 17, (12), 4709-4714

Conventional drug solubilization strategies limit the understanding of the full potential of poorly water-soluble drugs during drug screening. Here, we propose a screening approach in which poorly water-soluble drugs are entrapped in poly(2-(methacryloyloxyethyl phosphorylcholine)-poly(2-(diisopropylaminoethyl methacryate) (PMPC-PDPA) polymersomes (POs) to enhance drug solubility and facilitate intracellular delivery. By using a human pediatric glioma cell model, we demonstrated that PMPC-PDPA POs mediated intracellular delivery of cytotoxic and epigenetic drugs by receptor-mediated endocytosis. Additionally, when delivered in combination, drug-loaded PMPC-PDPA POs triggered both an enhanced drug efficacy and synergy compared to that of a conventional combinatorial screening. Hence, our comprehensive synergy analysis illustrates that our screening methodology, in which PMPC-PDPA POs are used for intracellular codelivery of drugs, allows us to identify potent synergistic profiles of anticancer drugs.

Keywords: Combination therapy, Drug screening, Drug solubilization, Intracellular drug delivery, Polymeric nanoparticles, Synergy analysis


Babeli, I., Ruano, G., Casanovas, J., Ginebra, M. P., García-Torres, J., Alemán, C., (2020). Conductive, self-healable and reusable poly(3,4-ethylenedioxythiophene)-based hydrogels for highly sensitive pressure arrays Journal of Materials Chemistry C 8, (25), 8654-8667

Although challenging, the preparation of pure conducting polymer (CP) hydrogels as conductive flexible networks for developing high-performance functional platforms is an outstanding alternative to conventional approaches, as for example those based on the cross-linking of insulating polymers with CP segments and the simple utilization of CPs as fillers of insulating hydrogel networks. In this work, we propose the employment of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) to prepare conductive hydrogels by partially replacing the PSS dopant by alginate (Alg) chains, which is energetically favoured. The capacity of Alg chains to be electrostatically cross-linked by Ca2+ ions has allowed us to obtain hydrogels with good electrical percolation response and mechanical properties. Hydrogels were prepared in a very simple one-step process by adding CaCl2 to different mixtures of PEDOT PSS and alginic acid (13, 11 and 31). After structural, chemical and physical characterization, the 13 PEDOT/Alg hydrogel was moulded to fabricate stretchable touch-pressure sensor arrays, which exhibited fast response and good spatial resolution of the pressure distribution. In addition, the PEDOT/Alg hydrogel is self-healable which allowed us to prepare reusable pressure sensors (i.e. devices that can be reprocessed to be used in their original application) thanks to the reversibility of the noncovalent Ca2+ crosslinks. Reusable devices are different to reclaimed and recycled devices as these are no longer used for the same application because the materials lose their properties. With our hydrogels we are a step closer to a circular economy by allowing the reuse of electronic devices and reducing electronic waste worldwide. Moreover, the superior performance of the PEDOT/Alg hydrogel opens up its utilization as an efficient and flexible pressure sensor for wearable human-electronic interfaces, in which reusability would be an added value.


Gómez-Domínguez, D., Epifano, C., Miguel, F., Castaño, A. G., Vilaplana-Martí, B., Martín, A., Amarilla-Quintana, S., Bertrand, A. T., Bonne, G., Ramón-Azcón, J., Rodríguez-Milla, M. A., Pérez de Castro, I., (2020). Consequences of Lmna exon 4 mutations in myoblast function Cells 9, (5), 1286

Laminopathies are causally associated with mutations on the Lamin A/C gene (LMNA). To date, more than 400 mutations in LMNA have been reported in patients. These mutations are widely distributed throughout the entire gene and are associated with a wide range of phenotypes. Unfortunately, little is known about the mechanisms underlying the effect of the majority of these mutations. This is the case of more than 40 mutations that are located at exon 4. Using CRISPR/Cas9 technology, we generated a collection of Lmna exon 4 mutants in mouse C2C12 myoblasts. These cell models included different types of exon 4 deletions and the presence of R249W mutation, one of the human variants associated with a severe type of laminopathy, LMNA-associated congenital muscular dystrophy (L-CMD). We characterized these clones by measuring their nuclear circularity, myogenic differentiation capacity in 2D and 3D conditions, DNA damage, and levels of p-ERK and p-AKT (phosphorylated Mitogen-Activated Protein Kinase 1/3 and AKT serine/threonine kinase 1). Our results indicated that Lmna exon 4 mutants showed abnormal nuclear morphology. In addition, levels and/or subcellular localization of different members of the lamin and LINC (LInker of Nucleoskeleton and Cytoskeleton) complex were altered in all these mutants. Whereas no significant differences were observed for ERK and AKT activities, the accumulation of DNA damage was associated to the Lmna p.R249W mutant myoblasts. Finally, significant myogenic differentiation defects were detected in the Lmna exon 4 mutants. These results have key implications in the development of future therapeutic strategies for the treatment of laminopathies.

Keywords: CRISPR, Laminopathy, LMNA, Nuclear envelope


La Montanara, Paolo, Hervera, Arnau, Baltussen, Lucas L., Hutson, Thomas H., Palmisano, Ilaria, De Virgiliis, Francesco, Kong, Guiping, Chadwick, Jessica, Gao, Yunan, Bartus, Katalin, Majid, Qasim A., Gorgoraptis, Nikos, Wong, Kingsley, Downs, Jenny, Pizzorusso, Tommaso, Ultanir, Sila K., Leonard, Helen, Yu, Hongwei, Millar, David S., Istvan, Nagy, Mazarakis, Nicholas D., Di Giovanni, Simone, (2020). Cyclin-dependent–like kinase 5 is required for pain signaling in human sensory neurons and mouse models Science Translational Medicine 12, (551), eaax4846

CDKL5 deficiency disorder (CDD) is a developmental encephalopathy caused by mutations in the cyclin-dependent–like kinase 5 (CDKL5) gene. Now, La Montanara et al. found that patients with CDD, in addition to the known symptoms, had altered pain sensitivity. Mechanistically, the authors found that CDKL5 is expressed in sensory neurons and regulates CaMKII-dependent TRPV1 signaling, thus affecting pain perception. In rodents, Cdkl5 deletion in sensory neurons resulted in reduced pain sensitivity. The results suggest that restoration of pain perception should be considered when developing therapies for treating CDD. Cyclin-dependent–like kinase 5 (CDKL5) gene mutations lead to an X-linked disorder that is characterized by infantile epileptic encephalopathy, developmental delay, and hypotonia. However, we found that a substantial percentage of these patients also report a previously unrecognized anamnestic deficiency in pain perception. Consistent with a role in nociception, we found that CDKL5 is expressed selectively in nociceptive dorsal root ganglia (DRG) neurons in mice and in induced pluripotent stem cell (iPS)–derived human nociceptors. CDKL5-deficient mice display defective epidermal innervation, and conditional deletion of CDKL5 in DRG sensory neurons impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, CDKL5 interacts with calcium/calmodulin-dependent protein kinase II α (CaMKIIα) to control outgrowth and transient receptor potential cation channel subfamily V member 1 (TRPV1)–dependent signaling, which are disrupted in both CDKL5 mutant murine DRG and human iPS–derived nociceptors. Together, these findings unveil a previously unrecognized role for CDKL5 in nociception, proposing an original regulatory mechanism for pain perception with implications for future therapeutics in CDKL5 deficiency disorder.


Tian, X., De Pace, C., Ruiz-Perez, L., Chen, B., Su, R., Zhang, M., Zhang, R., Zhang, Q., Wang, Q., Zhou, H., Wu, J., Zhang, Z., Tian, Y., Battaglia, G., (2020). A Cyclometalated iridium (III) complex as a microtubule probe for correlative super-resolution fluorescence and electron microscopy Advanced Materials 32, (39), 2003901

The visualization of microtubules by combining optical and electron microscopy techniques provides valuable information to understand correlated intracellular activities. However, the lack of appropriate probes to bridge both microscopic resolutions restricts the areas and structures that can be comprehended within such highly assembled structures. Here, a versatile cyclometalated iridium (III) complex is designed that achieves synchronous fluorescence–electron microscopy correlation. The selective insertion of the probe into a microtubule triggers remarkable fluorescence enhancement and promising electron contrast. The long-life, highly photostable probe allows live-cell super-resolution imaging of tubulin localization and motion with a resolution of ≈30 nm. Furthermore, correlative light–electron microscopy and energy-filtered transmission electron microscopy reveal the well-associated optical and electron signal at a high specificity, with an interspace of ≈41 Å of microtubule monomer in cells.

Keywords: Correlation light–electron microscopy, Microtubules, Organometallic probes, Super-resolution microscopy


Duro-Castano, A., Moreira Leite, D., Forth, J., Deng, Y., Matias, D., Noble Jesus, C., Battaglia, G., (2020). Designing peptide nanoparticles for efficient brain delivery Advanced Drug Delivery Reviews 160, 52-77

The targeted delivery of therapeutic compounds to the brain is arguably the most significant open problem in drug delivery today. Nanoparticles (NPs) based on peptides and designed using the emerging principles of molecular engineering show enormous promise in overcoming many of the barriers to brain delivery faced by NPs made of more traditional materials. However, shortcomings in our understanding of peptide self-assembly and blood–brain barrier (BBB) transport mechanisms pose significant obstacles to progress in this area. In this review, we discuss recent work in engineering peptide nanocarriers for the delivery of therapeutic compounds to the brain: from synthesis, to self-assembly, to in vivo studies, as well as discussing in detail the biological hurdles that a nanoparticle must overcome to reach the brain.

Keywords: Alzheimer's disease, Blood-brain barrier, Drug delivery, Glioma, Parkinson's disease, Peptides, Self-assembly, Transcytosis


Biosca, A., Bouzón-Arnáiz, I., Spanos, L., Siden-Kiamos, I., Iglesias, V., Ventura, S., Fernàndez-Busquets, X., (2020). Detection of protein aggregation in live Plasmodium parasites Antimicrobial Agents and Chemotherapy 64, (6), e02135-19

The rapid evolution of resistance in the malaria parasite to every single drug developed against it calls for the urgent identification of new molecular targets. Using a stain specific for the detection of intracellular amyloid deposits in live cells, we have detected the presence of abundant protein aggregates in Plasmodium falciparum blood stages and female gametes cultured in vitro, in the blood stages of mice infected by Plasmodium yoelii, and in the mosquito stages of the murine malaria species Plasmodium berghei. Aggregated proteins could not be detected in early rings, the parasite form that starts the intraerythrocytic cycle. A proteomics approach was used to pinpoint actual aggregating polypeptides in functional P. falciparum blood stages, which resulted in the identification of 369 proteins, with roles particularly enriched in nuclear import-related processes. Five aggregation-prone short peptides selected from this protein pool exhibited different aggregation propensity according to Thioflavin-T fluorescence measurements, and were observed to form amorphous aggregates and amyloid fibrils in transmission electron microscope images. The results presented suggest that generalized protein aggregation might have a functional role in malaria parasites. Future antimalarial strategies based on the upsetting of the pathogen’s proteostasis and therefore affecting multiple gene products could represent the entry to new therapeutic approaches

Keywords: Malaria, Protein aggregation


Klein, L. M., Chang, J., Gu, W., Manekeller, S., Jansen, C., Lingohr, P., Praktiknjo, M., Kalf, J. C., Schulz, M., Spengler, U., Strassburg, C., Cárdenas, A., Arroyo, V., Trebicka, J., (2020). The development and outcome of acute-on-chronic liver failure after surgical interventions Liver Transplantation 26, (2), 227-237

Acute-on-chronic liver failure (ACLF) is a syndrome with high short-term mortality. Precipitating events, including hemorrhage and infections, contribute to ACLF development, but the role of surgery remains unknown. We investigated the development of ACLF in patients with cirrhosis undergoing surgery. In total, 369 patients with cirrhosis were included in the study. The clinical and laboratory data were collected prior to and on days 1-2, 3-8, and 9-28, and at 3 and 12 months after surgery. Surgery type was classified as limited or extensive, as well as liver and nonliver surgery. A total of 39 patients had baseline ACLF. Surgery was performed during acute decompensation in 35% of the rest of the 330 patients, and 81 (24.5%) developed ACLF within 28 days after surgery. Surrogate markers of systemic inflammation were similar in patients who developed ACLF or not. Age, sex, serum sodium, baseline bacterial infection, and abdominal nonliver surgery were independent predictors for the development of ACLF after surgery. Patients who developed ACLF within 28 days after surgery had a higher mortality at 3, 6, and 12 months. Survival did not differ between patients with ACLF at surgery and those developing ACLF after surgery. Development of ACLF within 28 days after surgery and elevated alkaline phosphatase and international normalized ratio were independent predictors of 90-day mortality. Independent predictors of 1-year all-cause mortality were alkaline phosphatase, Model for End-Stage Liver Disease score, and preoperative hepatic encephalopathy, whereas nonliver surgery was associated with improved survival. ACLF frequently develops in patients with cirrhosis undergoing surgery, especially in those with active bacterial infection, lower serum sodium, and kidney or coagulation dysfunction. Prognoses of ACLF both at and after surgery are similarly poor. Patients with cirrhosis should be carefully managed perioperatively.


Rubí-Sans, G., Recha-Sancho, L., Pérez-Amodio, S., Mateos-Timoneda, M. Á., Semino, C. E., Engel, E., (2020). Development of a three-dimensional bioengineered platform for articular cartilage regeneration Biomolecules 10, (1), 52

Degenerative cartilage pathologies are nowadays a major problem for the world population. Factors such as age, genetics or obesity can predispose people to suffer from articular cartilage degeneration, which involves severe pain, loss of mobility and consequently, a loss of quality of life. Current strategies in medicine are focused on the partial or total replacement of affected joints, physiotherapy and analgesics that do not address the underlying pathology. In an attempt to find an alternative therapy to restore or repair articular cartilage functions, the use of bioengineered tissues is proposed. In this study we present a three-dimensional (3D) bioengineered platform combining a 3D printed polycaprolactone (PCL) macrostructure with RAD16-I, a soft nanofibrous self-assembling peptide, as a suitable microenvironment for human mesenchymal stem cells’ (hMSC) proliferation and differentiation into chondrocytes. This 3D bioengineered platform allows for long-term hMSC culture resulting in chondrogenic differentiation and has mechanical properties resembling native articular cartilage. These promising results suggest that this approach could be potentially used in articular cartilage repair and regeneration.

Keywords: 3D printing, Chondrogenic differentiation, Polycaprolactone, RAD16-I self-assembling peptide


Romero-Montero, A., Labra-Vázquez, P., Del Valle, L. J., Puiggalí, J., García-Arrazola, R., Montiel, C., Gimeno, M., (2020). Development of an antimicrobial and antioxidant hydrogel/nano-electrospun wound dressing RSC Advances 10, (51), 30508-30518

A nanocomposite based on an antibiotic-loaded hydrogel into a nano-electrospun fibre with antimicrobial and antioxidant capacities is investigated. The material is composed of nanofibres of enzymatic PCL grafted with poly(gallic acid) (PGAL), a recently developed enzyme-mediated hydrophilic polymer that features a multiradical and polyanionic nature in a helicoidal secondary structure. An extensive experimental–theoretical study on the molecular structure and morphological characterizations for this nanocomposite are discussed. The hydrogel network is formed by sodium carboxymethylcellulose (CMC) loaded with the broad-spectrum antibiotic clindamycin. This nano electrospun biomaterial inhibits a strain of Staphylococcus aureus, which is the main cause of nosocomial infections. The SPTT assay demonstrates that PGAL side chains also improve the release rates for this bactericide owing to the crosslinking to the CMC hydrogel matrix. The absence of hemolytic activity and the viability of epithelial cells demonstrates that this nanocomposite has no cytotoxicity.


Macedo, M.H., Martínez, Elena, Barrias, Cristina C., Sarmento, B., (2020). Development of an improved 3D in vitro intestinal model to perform permeability studies of paracellular compounds Frontiers in Bioengineering and Biotechnology 8, 524018

The small intestine is the primary site of drug absorption following oral administration, making paramount the proper monitoring of the absorption process. In vitro tools to predict intestinal absorption are particularly important in preclinical drug development since they are less laborious and cost-intensive and raise less ethical considerations compared to in vivo studies. The Caco-2 model is considered the gold standard of in vitro intestinal models regarding the prediction of absorption of orally delivered compounds. However, this model presents several drawbacks, such as the expression of tighter tight junctions, not being suitable to perform permeability of paracellular compounds. Besides, cells are representative of only one intestinal cell type, without considering the role of non-absorptive cells on the absorption pathway of drugs. In the present study, we developed a new three-dimensional (3D) intestinal model that aims to bridge the gap between in vitro tools and animal studies. Our 3D model comprises a collagen layer with human intestinal fibroblasts (HIFs) embedded, mimicking the intestinal lamina propria and providing 3D support for the epithelium, composed of Caco-2 cells and mucus-producing HT29-MTX cells, creating a model that can better resemble, both in terms of composition and regarding the outcomes of drug permeability when testing paracellular compounds, the human small intestine. The optimization of the collagen layer with HIFs was performed, testing different collagen concentrations and HIF seeding densities in order to avoid collagen contraction before day 14, maintaining HIF metabolically active inside the collagen disks during time in culture. HIF morphology and extracellular matrix (ECM) deposition were assessed, confirming that fibroblasts presented a normal and healthy elongated shape and secreted fibronectin and laminin, remodeling the collagen matrix. Regarding the epithelial layer, transepithelial electrical resistance (TEER) values decreased when cells were in the 3D configuration, comparing with the 2D analogs (Caco-2 and coculture of Caco-2+HT29-MTX models), becoming more similar with in vivo values. The permeability assay with fluorescein isothiocyanate (FITC)–Dextran 4 kDa showed that absorption in the 3D models is significantly higher than that in the 2D models, confirming the importance of using a more biorelevant model when testing the paracellular permeability of compounds.


Lantero, E., Belavilas-Trovas, A., Biosca, A., Recolons, P., Moles, E., Sulleiro, E., Zarzuela, F., Ávalos-Padilla, Y., Ramírez, M., Fernàndez-Busquets, X., (2020). Development of DNA aptamers against Plasmodium falciparum blood stages using cell-systematic evolution of ligands by exponential enrichment Journal of biomedical nanotechnology Journal of Biomedical Nanotechnology , 16, (3), 315-334

New biomarkers have to be developed in order to increase the performance of current antigen-based malaria rapid diagnosis. Antibody production often involves the use of laboratory animals and is time-consuming and costly, especially when the target is Plasmodium, whose variable antigen expression complicates the development of long-lived biomarkers. To circumvent these obstacles, we have applied the Systematic Evolution of Ligands by EXponential enrichment method to the rapid identification of DNA aptamers against Plasmodium falciparum-infected red blood cells (pRBCs). Five 70 b-long ssDNA sequences, and their shorter forms without the flanking PCR primer-binding regions, have been identified having a highly specific binding of pRBCs versus non-infected erythrocytes. Structural analysis revealed G-enriched sequences compatible with the formation of G-quadruplexes. The selected aptamers recognized intracellular epitopes with apparent Kds in the μM range in both fixed and non-fixed saponin-permeabilized pRBCs, improving >30-fold the pRBC detection in comparison with aptamers raised against Plasmodium lactate dehydrogenase, the gold standard antigen for current malaria diagnostic tests. In thin blood smears of clinical samples the aptamers reported in this work specifically bound all P. falciparum stages versus non-infected erythrocytes, and also detected early and late stages of the human malaria parasites Plasmodium vivax, Plasmodium ovale and Plasmodium malariae. The results are discussed in the context of their potential application in future malaria diagnostic devices.


Rodríguez-Contreras, A., Torres, D., Guillem-Marti, J., Sereno, P., Ginebra, M. P., Calero, J. A., Manero, J. M., Rupérez, E., (2020). Development of novel dual-action coatings with osteoinductive and antibacterial properties for 3D-printed titanium implants Surface and Coatings Technology 403, 126381

Gallium (Ga) has been recently proposed as a novel therapeutic agent, since it promotes bone formation and exhibits antibacterial properties. This work focuses on the optimization of a thermochemical treatment that incorporates Ga ions by the addition of the body-friendly Ga nitrate approved by the Food and Drug Administration. The objective was to simultaneously provide the inner and the outer surfaces of porous‑titanium surfaces obtained by 3D-printing with bioactivity and antibacterial properties. The apatite-forming ability of the coating, as well as the antibacterial activity and SaOS-2 cell adhesion, proliferation, differentiation and mineralization were evaluated and compared with untreated Ti surfaces. The characterization of the surfaces revealed the presence of a Ga-containing calcium titanate layer, which was non cytotoxic and in simulated body fluid produced a homogeneous apatite coating well adhered to the substrate. The formation of this apatite layer was accelerated with increasing Ga amounts present on the surface, resulting also in an increase in thickness. An initial quick release of Ga ion promoted the antibacterial effect against gram positive strains, especially for Pseudomonas aeruginosa, one of the most frequent resistant pathogens in nosocomial infections. SaOS-2 cells adhered and proliferated on the Ga-doped Ti surfaces, its presence contributed to cell differentiation and to considerably increase the mineralization levels. Thus, the developed multifunctional coatings could provide bioactivity to the porous Ti implants while protecting them from the most frequent gram-negative pathogens.

Keywords: 3D-printing, Antibacterial activity, Biomaterials, Gallium, Porous structures, Titanium implants


Hakimi, O., Gelpi, J. L., Krallinger, M., Curi, F., Repchevsky, D., Ginebra, M. P., (2020). The devices, experimental scaffolds, and biomaterials ontology (DEB): A tool for mapping, annotation, and analysis of biomaterials data Advanced Functional Materials 30, (16), 1909910

The size and complexity of the biomaterials literature makes systematic data analysis an excruciating manual task. A practical solution is creating databases and information resources. Implant design and biomaterials research can greatly benefit from an open database for systematic data retrieval. Ontologies are pivotal to knowledge base creation, serving to represent and organize domain knowledge. To name but two examples, GO, the gene ontology, and CheBI, Chemical Entities of Biological Interest ontology and their associated databases are central resources to their respective research communities. The creation of the devices, experimental scaffolds, and biomaterials ontology (DEB), an open resource for organizing information about biomaterials, their design, manufacture, and biological testing, is described. It is developed using text analysis for identifying ontology terms from a biomaterials gold standard corpus, systematically curated to represent the domain's lexicon. Topics covered are validated by members of the biomaterials research community. The ontology may be used for searching terms, performing annotations for machine learning applications, standardized meta-data indexing, and other cross-disciplinary data exploitation. The input of the biomaterials community to this effort to create data-driven open-access research tools is encouraged and welcomed.

Keywords: Biomaterials, Databases, Ontology


Fabregas, R., Gomila, G., (2020). Dielectric nanotomography based on electrostatic force microscopy: A numerical analysis Journal of Applied Physics 127, (2), 024301

Electrostatic force microscopy (EFM) can image nanoscale objects buried below the surface. Here, we theoretically show that this capability can be used to obtain nanotomographic information, i.e., the physical dimensions and dielectric properties, of buried nano-objects. These results constitute a first step toward implementing a nondestructive dielectric nanotomography technique based on EFM with applications in materials sciences and life sciences.


Del Mar Cendra, Maria, Torrents, Eduard, (2020). Differential adaptability between reference strains and clinical isolates of Pseudomonas aeruginosa into the lung epithelium intracellular lifestyle Virulence 11, (1), 862-876

Intracellular invasion is an advantageous mechanism used by pathogens to evade host defense and antimicrobial therapy. In patients, the intracellular microbial lifestyle can lead to infection persistence and recurrence, thus worsening outcomes. Lung infections caused by Pseudomonas aeruginosa, especially in cystic fibrosis (CF) patients, are often aggravated by intracellular invasion and persistence of the pathogen. Proliferation of the infectious species relies on a continuous deoxyribonucleotide (dNTP) supply, for which the ribonucleotide reductase enzyme (RNR) is the unique provider. The large genome plasticity of P. aeruginosa and its ability to rapidly adapt to different environments are challenges for studying the pathophysiology associated with this type of infection. Using different reference strains and clinical isolates of P. aeruginosa independently combined with alveolar (A549) and bronchial (16HBE14o- and CF-CFBE41o-) epithelial cells, we analyzed host–pathogen interactions and intracellular bacterial persistence with the aim of determining a cell type-directed infection promoted by the P. aeruginosa strains. The oscillations in cellular toxicity and oxygen consumption promoted by the intracellular persistence of the strains were also analyzed among the different infectious lung models. Significantly, we identified class II RNR as the enzyme that supplies dNTPs to intracellular P. aeruginosa. This discovery could contribute to the development of RNR-targeted strategies against the chronicity occurring in this type of lung infection. Overall our study demonstrates that the choice of bacterial strain is critical to properly study the type of infectious process with relevant translational outcomes.

Keywords: Pseudomonas aeruginosa, Intracellular persistence, Lung, Epithelial cells, Clinical isolates, Host-pathogen interactions, Intracellular lifestyle, Chronic infections, Cystic fibrosis, Ribonucleotide reductase


Williams, I., Lee, S., Apriceno, A., Sear, R. P., Battaglia, G., (2020). Diffusioosmotic and convective flows induced by a nonelectrolyte concentration gradient Proceedings of the National Academy of Sciences of the United States of America 117, (41), 25263-25271

Glucose is an important energy source in our bodies, and its consumption results in gradients over length scales ranging from the subcellular to entire organs. Concentration gradients can drive material transport through both diffusioosmosis and convection. Convection arises because concentration gradients are mass density gradients. Diffusioosmosis is fluid flow induced by the interaction between a solute and a solid surface. A concentration gradient parallel to a surface creates an osmotic pressure gradient near the surface, resulting in flow. Diffusioosmosis is well understood for electrolyte solutes, but is more poorly characterized for nonelectrolytes such as glucose. We measure fluid flow in glucose gradients formed in a millimeter-long thin channel and find that increasing the gradient causes a crossover from diffusioosmosis-dominated to convection-dominated flow. We cannot explain this with established theories of these phenomena which predict that both scale linearly. In our system, the convection speed is linear in the gradient, but the diffusioosmotic speed has a much weaker concentration dependence and is large even for dilute solutions. We develop existing models and show that a strong surface-solute interaction, a heterogeneous surface, and accounting for a concentration-dependent solution viscosity can explain our data. This demonstrates how sensitive nonelectrolyte diffusioosmosis is to surface and solution properties and to surface-solute interactions. A comprehensive understanding of this sensitivity is required to understand transport in biological systems on length scales from micrometers to millimeters where surfaces are invariably complex and heterogeneous.

Keywords: Convection, Diffusioosmosis, Microfluidics


Monferrer, E., Sanegre, S., Martínn-Vañó, S., GarcÃía-Lizarribar, A., Burgos-Panadero, R., López-Carrasco, A., Navarro, S., Samitier, J., Noguera, R., (2020). Digital image analysis applied to tumor cell proliferation, aggressiveness, and migration-related protein synthesis in neuroblastoma 3d models International Journal of Molecular Sciences 21, (22), 8676

Patient-derived cancer 3D models are a promising tool that will revolutionize personalized cancer therapy but that require previous knowledge of optimal cell growth conditions and the most advantageous parameters to evaluate biomimetic relevance and monitor therapy efficacy. This study aims to establish general guidelines on 3D model characterization phenomena, focusing on neuroblastoma. We generated gelatin-based scaffolds with different stiffness and performed SK-N-BE(2) and SH-SY5Y aggressive neuroblastoma cell cultures, also performing co-cultures with mouse stromal Schwann cell line (SW10). Model characterization by digital image analysis at different time points revealed that cell proliferation, vitronectin production, and migration-related gene expression depend on growing conditions and are specific to the tumor cell line. Morphometric data show that 3D in vitro models can help generate optimal patient-derived cancer models, by creating, identifying, and choosing patterns of clinically relevant artificial microenvironments to predict patient tumor cell behavior and therapeutic responses.

Keywords: 3D cancer modeling, DOCK8, KANK1, Ki67, Preclinical therapeutic studies, Vitronectin


Lopez-Muñoz, Gerardo A., Ortega, Maria Alejandra, Ferret-Miñana, Ainhoa, De Chiara, Francesco, Ramón-Azcón, Javier, (2020). Direct and label-free monitoring of albumin in 2D fatty liver disease model using plasmonic nanogratings Nanomaterials 10, (12), 2520

Non-alcoholic fatty liver (NAFLD) is a metabolic disorder related to a chronic lipid accumulation within the hepatocytes. This disease is the most common liver disorder worldwide, and it is estimated that it is present in up to 25% of the world’s population. However, the real prevalence of this disease and the associated disorders is unknown mainly because reliable and applicable diagnostic tools are lacking. It is known that the level of albumin, a pleiotropic protein synthesized by hepatocytes, is correlated with the correct function of the liver. The development of a complementary tool that allows direct, sensitive, and label-free monitoring of albumin secretion in hepatocyte cell culture can provide insight into NAFLD’s mechanism and drug action. With this aim, we have developed a simple integrated plasmonic biosensor based on gold nanogratings from periodic nanostructures present in commercial Blu-ray optical discs. This sensor allows the direct and label-free monitoring of albumin in a 2D fatty liver disease model under flow conditions using a highly-specific polyclonal antibody. This technology avoids both the amplification and blocking steps showing a limit of detection within pM range (≈0.26 ng/mL). Thanks to this technology, we identified the optimal fetal bovine serum (FBS) concentration to maximize the cells’ lipid accumulation. Moreover, we discovered that the hepatocytes increased the amount of albumin secreted on the third day from the lipids challenge. These data demonstrate the ability of hepatocytes to respond to the lipid stimulation releasing more albumin. Further investigation is needed to unveil the biological significance of that cell behavior.

Keywords: 2D fatty liver in vitro model, Blu-Ray disc, Plasmonic nanomaterials, Label-Free Biosensing


Lidón, Laia, Urrea, Laura, Llorens, Franc, Gil, Vanessa, Alvarez, Ignacio, Diez-Fairen, Monica, Aguilar, Miguel, Pastor, Pau, Zerr, Inga, Alcolea, Daniel, Lleó, Alberto, Vidal, Enric, Gavín, Rosalina, Ferrer, Isidre, Del Rio, Jose Antonio, (2020). Disease-specific changes in Reelin protein and mRNA in Nnurodegenerative diseases Cells 9, (5), 1252

Reelin is an extracellular glycoprotein that modulates neuronal function and synaptic plasticity in the adult brain. Decreased levels of Reelin activity have been postulated as a key factor during neurodegeneration in Alzheimer’s disease (AD) and in aging. Thus, changes in levels of full-length Reelin and Reelin fragments have been revealed in cerebrospinal fluid (CSF) and in post-mortem brains samples of AD patients with respect to non-AD patients. However, conflicting studies have reported decreased or unchanged levels of full-length Reelin in AD patients compared to control (nND) cases in post-mortem brains and CSF samples. In addition, a compelling analysis of Reelin levels in neurodegenerative diseases other than AD is missing. In this study, we analyzed brain levels of RELN mRNA and Reelin protein in post-mortem frontal cortex samples from different sporadic AD stages, Parkinson’s disease with dementia (PDD), and Creutzfeldt-Jakob disease (sCJD), obtained from five different Biobanks. In addition, we measured Reelin protein levels in CSF samples of patients with mild cognitive impairment (MCI), dementia, or sCJD diagnosis and a group of neurologically healthy cases. The results indicate an increase in RELN mRNA in the frontal cortex of advanced stages of AD and in sCJD(I) compared to controls. This was not observed in PDD and early AD stages. However, Reelin protein levels in frontal cortex samples were unchanged between nND and advanced AD stages and PDD. Nevertheless, they decreased in the CSF of patients with dementia in comparison to those not suffering with dementia and patients with MCI. With respect to sCJD, there was a tendency to increase in brain samples in comparison to nND and to decrease in the CSF with respect to nND. In conclusion, Reelin levels in CSF cannot be considered as a diagnostic biomarker for AD or PDD. However, we feel that the CSF Reelin changes observed between MCI, patients with dementia, and sCJD might be helpful in generating a biomarker signature in prodromal studies of unidentified dementia and sCJD.

Keywords: Reelin, Creutzfeldt-Jakob disease, Alzheimer’s disease, Parkinson’s disease dementia, a-synucleopathies, Cerebrospinal fluid


Verschure, P., (2020). The distributed adaptive control theory of the mind and brain as a candidate standard model of the human mind Common Model of Cognition Bulletin 1, (2 - A Standard Model of the Mind), 481-486

This article presents the Distributed Adaptive Control (DAC) theory of mind and brain as a candidate standard model of the human mind. DAC is defined against a reformulation of the criteria for unified theories of cognition advanced by Allen Newell, or the Unified Theories of Embodied Minds – Standard Model benchmark (UTEM-SM) that emphasizes real-world and real-time embodied action. DAC considers mind and brain as the function and implementation of a multi-layered control system and addresses the fundamental question of how the mind, as the product of embodied and situated brains, can obtain, retain and express valid knowledge of its world and transform this into policies for action. DAC provides an explanatory framework for biological minds and brains by satisfying well-defined constraints faced by theories of mind and brain and provides a route for the convergent validation of anatomy, physiology, and behavior in our explanation of biological minds. DAC is a well validated integration and synthesis framework for artificial minds and exemplifies the role of the synthetic method in understanding mind and brain. This article describes the core components of DAC, its performance on specific benchmarks derived from the engagement with the physical and the social world (or the H4W and the H5W problems) and lastly analyzes DAC’s performance on the UTEM-SM benchmark and its relationship with contemporary developments in AI.


Delcanale, P., Albertazzi, L., (2020). DNA-PAINT super-resolution imaging data of surface exposed active sites on particles Data in Brief 30, 105468

Surface functionalization with targeting ligands confers to nanomaterials the ability of selectively recognize a biological target. Therefore, a quantitative characterization of surface functional molecules is critical for the rational development of nanomaterials-based applications, especially in nanomedicine research. Single-molecule localization microscopy can provide visualization of surface molecules at the level of individual particles, preserving the integrity of the material and overcoming the limitations of analytical methods based on ensemble averaging. Here we provide single-molecule localization data obtained on streptavidin-coated polystyrene particles, which can be exploited as a model system for surface-functionalized materials. After loading of the active sites of streptavidin molecules with a biotin-conjugated probe, they were imaged with a DNA-PAINT imaging approach, which can provide single-molecule imaging at subdiffraction resolution and molecule counting. Both raw records and analysed data, consisting in a list of space-time single-molecule coordinates, are shared. Additionally, Matlab functions are provided that analyse the single-molecule coordinates in order to quantify features of individual particles. These data might constitute a valuable reference for applications of similar quantitative imaging methodologies to other types of functionalized nanomaterials.

Keywords: DNA-PAINT, Functional materials, Nanoparticles, Single-molecule localization microscopy, Super-resolution microscopy


Ruano, G., Tononi, J., Curcó, D., Puiggalí, J., Torras, J., Alemán, C., (2020). Doped photo-crosslinked polyesteramide hydrogels as solid electrolytes for supercapacitors Soft Matter 16, (34), 8033-8046

High-performance hydrogels play a crucial role as solid electrolytes for flexible electrochemical supercapacitors (ESCs). More specifically, all solid-state ESCs based on renewable, biodegradable and/or biocompatible hydrogels doped with inorganic salts as electrolytes are attractive not only because of their contribution to reducing resource consumption and/or the generation of electronic garbage, but also due to their potential applicability in the biomedical field. Here, computer simulations have been combined with experimental measurements to probe the outstanding capability as solid electrolytes of photo-crosslinked unsaturated polyesteramide hydrogels containing phenylalanine, butenediol and fumarate, and doped with NaCl (UPEA-Phe/NaCl). Atomistic molecular dynamics simulations have shown the influence of the hydrogel pore structure in the migration of Na+ and Cl− ions, suggesting that UPEA-Phe/NaCl hydrogels prepared without completing the photo-crosslinking reaction will exhibit better behavior as solid electrolytes. Theoretical predictions have been confirmed by potentiodynamic and galvanostatic studies on ESCs fabricated using poly(3,4-ethylenedioxythiophene) electrodes and UPEA-Phe/NaCl hydrogels, which were obtained using different times of exposure to UV radiation (i.e. 4 and 8 h for incomplete and complete photo-crosslinking reaction). Moreover, the behavior as a solid electrolyte of the UPEA-Phe/NaCl hydrogel prepared using a photo-polymerization time of 4 h has been found to be significantly superior to those exhibited by different polypeptide and polysaccharide hydrogels, which were analyzed using ESCs with identical electrodes and experimental conditions.


Sunyer, R., Trepat, X., (2020). Durotaxis Current Biology 30, (9), R383-R387

In this Primer, Sunyer and Trepat introduce durotaxis, the mode of migration by which cells follow gradients of extracellular matrix stiffness.


Barber, D. L., Trepat, X., (2020). Editorial overview: Cell dynamics: Integrating cell dynamics across scales Current Opinion in Cell Biology 66, 130-132

Dynamics has its origins in the Greek word dynamis, meaning force or power. Dynamics is used as a descriptor ranging from personality traits to physics for bodies in motion. In cell biology, dynamics generally indicates changing as opposed to static. To highlight the importance of dynamics in cell biology, COCB initiated in 2016 special interest issues devoted to Cell Dynamics. Past issues on this topic focused on cell division, integrating cell behaviors and tissue architecture, cell decision-making, and unifying concepts in development, tissue remodeling, and cancer. Our current issue integrates cell dynamics across scales, from subcellular to supracellular to multicellular. As with overlapping and intersecting processes and paradigms in cell biology, the articles in this issue defy a best-fit organization, and we grappled with organizing our overview by thematic topics or scales. We settled on the latter because integrating dynamic processes across scales is a challenge cell biologists are increasingly addressing. We start with fundamental principles and building blocks within subcellular scales, segue to how these affect tissue organization, and conclude with tools and imaging modalities for controlling and quantitatively capturing cell dynamics in motion. Regardless of the organization of our overview, each article stands alone for an outstanding discussion of current work, insightful integration of multiple points of view, and importantly what we hope for the reader, thought-provoking ideas on how to advance new discovery.


Fernánez-Majada, V., García-Díaz, María, Torras, N., Raghunath, M., Martínez, Elena, (2020). Editorial: When the shape does matter: Three-dimensional in vitro models of epithelial barriers Frontiers in Bioengineering and Biotechnology 8, 617361

Fletcher, H.V., Cho, P.S.P., Loong, S.L., Estrada-Petrocelli, L., Patel, A.S., Birring, S.S., Lee, K.K., (2020). Effect of continuous positive airway pressure on maximal exercise capacity in patients with obstructive sleep apnea: A systematic review and meta-analysis Journal of Clinical Sleep Medicine 16, (11), 1847-1855

STUDY OBJECTIVES:Exercise capacity is impaired in obstructive sleep apnea (OSA). There are conflicting reports on the effect of continuous positive airway pressure (CPAP) on maximal exercise capacity. The objective of this review was to determine if there is a change in exercise capacity and anaerobic threshold following CPAP treatment in OSA patients. METHODS:We conducted a systematic review and meta-analyses to summarize the changes in peak rate of oxygen uptake (V̇O2 peak) or maximum rate of oxygen uptake (V̇O2 max) and anaerobic threshold (AT) during cardiopulmonary exercise testing following CPAP intervention in patients with OSA. A systematic literature review was conducted to identify published literature on markers of V̇O2 peak, V̇O2 max, and AT pre- vs post-CPAP using a web-based literature search of PubMed/MEDLINE, Embase, CINAHL, and Cochrane review (CENTRAL) databases. Two independent reviewers screened the articles for data extraction and analysis. RESULTS:The total search of all the databases returned 470 relevant citations. Following application of eligibility criteria, 6 studies were included in the final meta-analysis for V̇O2 peak, 2 studies for V̇O2 max, and five studies for AT. The meta-analysis showed a mean net difference in V̇O2 peak between pre- and post-CPAP of 2.69 mL·kg–1·min–1, P = .02, favoring treatment with CPAP. There was no difference in V̇O2 max or AT with CPAP treatment (mean net difference 0.66 mL·kg–1·min–1 [P = .78] and –144.98 mL·min–1 [P = .20] respectively). CONCLUSIONS:There is a paucity of high-quality studies investigating the effect of CPAP on exercise capacity. Our meta-analysis shows that V̇O2 peak increases following CPAP treatment in patients with OSA, but we did not observe any change in V̇O2 max or AT. Our findings should be considered preliminary and we recommend further randomized controlled trials to confirm our findings and to clarify the peak and maximum rates of oxygen uptake adaptations with CPAP therapy.


Marafon, G., Moretto, A., Zanuy, D., Alemán, C., Crisma, M., Toniolo, C., (2020). Effect on the conformation of a terminally blocked, (E) β,γ-unsaturated δ-amino acid residue induced by carbon methylation Journal of Organic Chemistry 85, (3), 1513-1524

Peptides are well-known to play a fundamental therapeutic role and to represent building blocks for numerous useful biomaterials. Stabilizing their active 3D-structure by appropriate modifications remains, however, a challenge. In this study, we have expanded the available literature information on the conformational propensities of a promising backbone change of a terminally blocked δ-amino acid residue, a dipeptide mimic, by replacing its central amide moiety with an (E) Cβ═Cγ alkene unit. Specifically, we have examined by DFT calculations, X-ray diffraction in the crystalline state, and FT-IR absorption/NMR spectroscopies in solution the extended vs folded preferences of analogues of this prototype system either unmodified or possessing single or multiple methyl group substituents on each of its four −CH2-CH═CH-CH2– main-chain carbon atoms. The theoretical and experimental results obtained clearly point to the conclusion that increasing the number of adequately positioned methylations will enhance the preference of the original sequence to fold, thus opening interesting perspectives in the design of conformationally constrained peptidomimetics.


Ruiz-Vega, G., Arias-Alpízar, K., de la Serna, E., Borgheti-Cardoso, L. N., Sulleiro, E., Molina, I., Fernàndez-Busquets, X., Sánchez-Montalvá, A., del Campo, F. J., Baldrich, E., (2020). Electrochemical POC device for fast malaria quantitative diagnosis in whole blood by using magnetic beads, Poly-HRP and microfluidic paper electrodes Biosensors and Bioelectronics 150, 111925

Malaria, a parasitic infection caused by Plasmodium parasites and transmitted through the bite of infected female Anopheles mosquitos, is one of the main causes of mortality in many developing countries. Over 200 million new infections and nearly half a million deaths are reported each year, and more than three billion people are at risk of acquiring malaria worldwide. Nevertheless, most malaria cases could be cured if detected early. Malaria eradication is a top priority of the World Health Organisation. However, achieving this goal will require mass population screening and treatment, which will be hard to accomplish with current diagnostic tools. We report an electrochemical point-of-care device for the fast, simple and quantitative detection of Plasmodium falciparum lactate dehydrogenase (PfLDH) in whole blood samples. Sample analysis includes 5-min lysis to release intracellular parasites, and stirring for 5 more min with immuno-modified magnetic beads (MB) along with an immuno-modified signal amplifier. The rest of the magneto-immunoassay, including sample filtration, MB washing and electrochemical detection, is performed at a disposable paper electrode microfluidic device. The sensor provides PfLDH quantitation down to 2.47 ng mL−1 in spiked samples and for 0.006–1.5% parasitemias in Plasmodium-infected cultured red blood cells, and discrimination between healthy individuals and malaria patients presenting parasitemias >0.3%. Quantitative malaria diagnosis is attained with little user intervention, which is not achieved by other diagnostic methods.

Keywords: Electrochemical magneto-immunosensor, Malaria quantitative diagnosis, Paper microfluidic electrode, Plasmodium LDH, Point-of-care (POC) testing


Landa-Castro, Midori, Sebastián, Paula, Giannotti, Marina I., Serrà, Albert, Gómez, Elvira, (2020). Electrodeposition of nanostructured cobalt films from a deep eutectic solvent: Influence of the substrate and deposition potential range Electrochimica Acta 359, 136928

The purpose of this systematic study was to investigate the effects of specific substrates and potential conditions applied while tailoring the morphology and chemical composition of nanostructured Co films. In particular, Co electrodeposition in sustainable choline chloride-urea deep eutectic solvent was assessed, using glassy carbon and two metals widely employed in electrocatalysis and biocompatible purposes, Pt and Au, as substrates for modification with Co. Various in situ electrochemical techniques were combined with a broad range of ex-situ characterization and chemical-composition techniques for a detailed analysis of the prepared Co films. Among the results, nanostructured Co films with high extended active surface areas and variable composition of oxo and hydroxyl species could be tuned by simply modulating the applied potential limits, and without using additives or surfactant agents. The study highlights the effectiveness of using deep eutectic solvent as suitable electrolyte for surface modification by controlled deposition of nanostructured Co films with further application in electrocatalysis.

Keywords: Cobalt electrodeposition, Deep eutectic solvent, First growth stages, Substrate influence


Hoogduijn, M.J., Montserrat, N., van der Laan, L.J.W., Dazzi, F., Perico, N., Kastrup, J., Gilbo, N., Ploeg, R.J., Roobrouck, V., Casiraghi, F., Johnson, C.L., Franquesa, M., Dahlke, M.H., Massey, E., Hosgood, S., Reinders, M.E.J., (2020). The emergence of regenerative medicine in organ transplantation: 1st European Cell Therapy and Organ Regeneration Section meeting Transplant International 33, (8), 833-840

Regenerative medicine is emerging as a novel field in organ transplantation. In September 2019, the European Cell Therapy and Organ Regeneration Section (ECTORS) of the European Society for Organ Transplantation (ESOT) held its first meeting to discuss the state-of-the-art of regenerative medicine in organ transplantation. The present article highlights the key areas of interest and major advances in this multidisciplinary field in organ regeneration and discusses its implications for the future of organ transplantation.

Keywords: Cell therapy, Machine perfusion, Mesenchymal stromal cell, Organoid, Regeneration, Transplantation


Rubi-Sans, G., Castaño, O., Cano, I., Mateos-Timoneda, M. A., Perez-Amodio, S., Engel, E., (2020). Engineering cell-derived matrices: From 3D models to advanced personalized therapies Advanced Functional Materials 30, (44), e2000496

Regenerative medicine and disease models have evolved in recent years from two to three dimensions, providing in vitro constructs that are more similar to in vivo tissues. By mimicking native tissues, cell-derived matrices (CDMs) have emerged as new modifiable extracellular matrices for a variety of tissues, allowing researchers to study basic cellular processes in tissue-like structures, test tissue regeneration approaches, and model disease development. In this review, different fabrication techniques and characterization methods of CDMs are presented and examples of their application in cell behavior studies, tissue regeneration, and disease models are provided. In addition, future guidelines and perspectives in the field of CDMs are discussed.

Keywords: 3D models, Biomaterials, Cell-derived matrices, Extracellular matrix, Personalized therapies


van Moolenbroek, Guido T., Patiño, Tania, Llop, Jordi, Sánchez, Samuel, (2020). Engineering intelligent nanosystems for enhanced medical imaging Advanced Intelligent Systems 2, (10), 2000087

Medical imaging serves to obtain anatomical and physiological data, supporting medical diagnostics as well as providing therapeutic evaluation and guidance. A variety of contrast agents have been developed to enhance the recorded signals and to provide molecular imaging. However, fast clearance from the body or nonspecific biodistribution often limit their efficiency, constituting challenges that need to be overcome. Nanoparticle-based systems are currently emerging as versatile and highly integrated platforms providing improved circulating times, tissue specificity, high loading capacity for signaling moieties, and multimodal imaging features. Furthermore, nanoengineered devices can be tuned for specific applications and the development of responsive behaviors. Responses include in situ modulation of nanoparticle size, increased intratissue mobility through active propulsion of motorized particles, and active modulation of the particle surroundings such as the extracellular matrix for an improved penetration and retention at the desired locations. Once accumulated in the targeted tissue, smart nanoparticle-based contrast agents can provide molecular sensing of biomarkers or characteristics of the tissue microenvironment. In this case, the signal or contrast provided by the nanosystem is responsive to the presence or concentration of an analyte. Herein, recent developments of intelligent nanosystems to improve medical imaging are presented.


Labay, C., Roldán, M., Tampieri, F., Stancampiano, A., Bocanegra, P. E., Ginebra, M. P., Canal, C., (2020). Enhanced generation of reactive species by cold plasma in gelatin solutions for selective cancer cell death ACS Applied Materials and Interfaces 12, (42), 47256-47269

Atmospheric pressure plasma jets generate reactive oxygen and nitrogen species (RONS) in liquids and biological media, which find application in the new area of plasma medicine. These plasma-treated liquids were demonstrated recently to possess selective properties on killing cancer cells and attracted attention toward new plasma-based cancer therapies. These allow for local delivery by injection in the tumor but can be quickly washed away by body fluids. By confining these RONS in a suitable biocompatible delivery system, great perspectives can be opened in the design of novel biomaterials aimed for cancer therapies. Gelatin solutions are evaluated here to store RONS generated by atmospheric pressure plasma jets, and their release properties are evaluated. The concentration of RONS was studied in 2% gelatin as a function of different plasma parameters (treatment time, nozzle distance, and gas flow) with two different plasma jets. Much higher production of reactive species (H2O2 and NO2-) was revealed in the polymer solution than in water after plasma treatment. The amount of RONS generated in gelatin is greatly improved with respect to water, with concentrations of H2O2 and NO2- between 2 and 12 times higher for the longest plasma treatments. Plasma-treated gelatin exhibited the release of these RONS to a liquid media, which induced an effective killing of bone cancer cells. Indeed, in vitro studies on the sarcoma osteogenic (SaOS-2) cell line exposed to plasma-treated gelatin led to time-dependent increasing cytotoxicity with the longer plasma treatment time of gelatin. While the SaOS-2 cell viability decreased to 12%-23% after 72 h for cells exposed to 3 min of treated gelatin, the viability of healthy cells (hMSC) was preserved (?90%), establishing the selectivity of the plasma-treated gelatin on cancer cells. This sets the basis for designing improved hydrogels with high capacity to deliver RONS locally to tumors.

Keywords: Cold atmospheric plasma, Hydrogel, Osteosarcoma, Reactive oxygen and nitrogen species


Burgués, Javier, Marco, Santiago, (2020). Environmental chemical sensing using small drones: A review Science of The Total Environment 748, 141172

Recent advances in miniaturization of chemical instrumentation and in low-cost small drones are catalyzing exponential growth in the use of such platforms for environmental chemical sensing applications. The versatility of chemically sensitive drones is reflected by their rapid adoption in scientific, industrial, and regulatory domains, such as in atmospheric research studies, industrial emission monitoring, and in enforcement of environmental regulations. As a result of this interdisciplinarity, progress to date has been reported across a broad spread of scientific and non-scientific databases, including scientific journals, press releases, company websites, and field reports. The aim of this paper is to assemble all of these pieces of information into a comprehensive, structured and updated review of the field of chemical sensing using small drones. We exhaustively review current and emerging applications of this technology, as well as sensing platforms and algorithms developed by research groups and companies for tasks such as gas concentration mapping, source localization, and flux estimation. We conclude with a discussion of the most pressing technological and regulatory limitations in current practice, and how these could be addressed by future research.

Keywords: Unmanned aircraft systems, Remotely piloted aircraft systems, Chemical sensors, Gas sensors, Environmental monitoring, Industrial emission monitoring


Wang, Lei, Marciello, Marzia, Estévez-Gay, Miquel, Soto Rodriguez, Paul E. D., Luengo Morato, Yurena, Iglesias-Fernández, Javier, Huang, Xin, Osuna, Sílvia, Filice, Marco, Sánchez, Samuel, (2020). Enzyme conformation influences the performance of lipase-powered nanomotors Angewandte Chemie - International Edition 59, (47), 21080-21087

Enzyme‐powered micro/nanomotors have myriads of potential applications in various areas. To efficiently reach those applications, it is necessary and critical to understand the fundamental aspects affecting the motion dynamics. Herein, we explored the impact of enzyme orientation on the performance of lipase-powered nanomotors by tuning the lipase immobilization strategies. The influence of the lipase orientation and lid conformation on substrate binding and catalysis was analyzed using molecular dynamics simulations. Besides, the motion performance indicates that the hydrophobic binding (via OTES) represents the best orienting strategy, providing 48.4 % and 95.4 % increase in diffusion coefficient compared to hydrophilic binding (via APTES) and Brownian motion (no fuel), respectively (with C[triacetin] of 100 mm). This work provides vital evidence for the importance of immobilization strategy and corresponding enzyme orientation for the catalytic activity and in turn, the motion performance of nanomotors, and is thus helpful to future applications.


Yang, Y., Arqué, X., Patiño, T., Guillerm, V., Blersch, P. R., Pérez-Carvajal, J., Imaz, I., Maspoch, D., Sánchez, S., (2020). Enzyme-powered porous micromotors built from a hierarchical micro- and mesoporous UiO-type metal-organic framework Journal of the American Chemical Society 142, (50), 20962–20967

Here, we report the design, synthesis, and functional testing of enzyme-powered porous micromotors built from a metal–organic framework (MOF). We began by subjecting a presynthesized microporous UiO-type MOF to ozonolysis, to confer it with mesopores sufficiently large to adsorb and host the enzyme catalase (size: 6–10 nm). We then encapsulated catalase inside the mesopores, observing that they are hosted in those mesopores located at the subsurface of the MOF crystals. In the presence of H2O2 fuel, MOF motors (or MOFtors) exhibit jet-like propulsion enabled by enzymatic generation of oxygen bubbles. Moreover, thanks to their hierarchical pore system, the MOFtors retain sufficient free space for adsorption of additional targeted species, which we validated by testing a MOFtor for removal of rhodamine B during self-propulsion.


Ikemori, R., Gabasa, M., Duch, P., Vizoso, M., Bragado, P., Arshakyan, M., Luis, I. C., Marín, A., Moran, S., Castro, M., Fuster, G., Gea-Sorli, S., Jauset, T., Soucek, L., Montuenga, L. M., Esteller, M., Monso, E., Peinado, V. I., Gascon, P., Fillat, C., Hilberg, F., Reguart, N., Alcaraz, J., (2020). Epigenetic SMAD3 repression in tumor-associated fibroblasts impairs fibrosis and response to the antifibrotic drug nintedanib in lung squamous cell carcinoma Cancer Research 80, (2), 276-290

The tumor-promoting fibrotic stroma rich in tumor-associated fibroblasts (TAF) is drawing increased therapeutic attention. Intriguingly, a trial with the antifibrotic drug nintedanib in non–small cell lung cancer reported clinical benefits in adenocarcinoma (ADC) but not squamous cell carcinoma (SCC), even though the stroma is fibrotic in both histotypes. Likewise, we reported that nintedanib inhibited the tumor-promoting fibrotic phenotype of TAFs selectively in ADC. Here we show that tumor fibrosis is actually higher in ADC-TAFs than SCC-TAFs in vitro and patient samples. Mechanistically, the reduced fibrosis and nintedanib response of SCC-TAFs was associated with increased promoter methylation of the profibrotic TGFβ transcription factor SMAD3 compared with ADC-TAFs, which elicited a compensatory increase in TGFβ1/SMAD2 activation. Consistently, forcing global DNA demethylation of SCC-TAFs with 5-AZA rescued TGFβ1/SMAD3 activation, whereas genetic downregulation of SMAD3 in ADC-TAFs and control fibroblasts increased TGFβ1/SMAD2 activation, and reduced their fibrotic phenotype and antitumor responses to nintedanib in vitro and in vivo. Our results also support that smoking and/or the anatomic location of SCC in the proximal airways, which are more exposed to cigarette smoke particles, may prime SCC-TAFs to stronger SMAD3 epigenetic repression, because cigarette smoke condensate selectively increased SMAD3 promoter methylation. Our results unveil that the histotype-specific regulation of tumor fibrosis in lung cancer is mediated through differential SMAD3 promoter methylation in TAFs and provide new mechanistic insights on the selective poor response of SCC-TAFs to nintedanib. Moreover, our findings support that patients with ADC may be more responsive to antifibrotic drugs targeting their stromal TGFβ1/SMAD3 activation. Significance: This study implicates the selective epigenetic repression of SMAD3 in SCC-TAFs in the clinical failure of nintedanib in SCC and supports that patients with ADC may benefit from antifibrotic drugs targeting stromal TGFβ1/SMAD3.


Hino, N., Rossetti, L., Marín-Llauradó, A., Aoki, K., Trepat, X., Matsuda, M., Hirashima, T., (2020). ERK-mediated mechanochemical waves direct collective cell polarization Developmental Cell 53, (6), 646-660.e8

During collective migration of epithelial cells, the migration direction is aligned over a tissue-scale expanse. Although the collective cell migration is known to be directed by mechanical forces transmitted via cell-cell junctions, it remains elusive how the intercellular force transmission is coordinated with intracellular biochemical signaling to achieve collective movements. Here, we show that intercellular coupling of extracellular signal-regulated kinase (ERK)-mediated mechanochemical feedback yields long-distance transmission of guidance cues. Mechanical stretch activates ERK through epidermal growth factor receptor (EGFR) activation, and ERK activation triggers cell contraction. The contraction of the activated cell pulls neighboring cells, evoking another round of ERK activation and contraction in the neighbors. Furthermore, anisotropic contraction based on front-rear polarization guarantees unidirectional propagation of ERK activation, and in turn, the ERK activation waves direct multicellular alignment of the polarity, leading to long-range ordered migration. Our findings reveal that mechanical forces mediate intercellular signaling underlying sustained transmission of guidance cues for collective cell migration.

Keywords: Collective cell migration, EGFR, ERK/MAPK, FRET, Front-rear polarity, Intercellular signal transfer, Mathematical model, Mechanochemical feedback, Mechanotransduction, wave propagation


Minguela, J., Slawik, S., Mücklich, F., Ginebra, M. P., Llanes, L., Mas-Moruno, C., Roa, J. J., (2020). Evolution of microstructure and residual stresses in gradually ground/polished 3Y-TZP Journal of the European Ceramic Society 40, (4), 1582-1591

A comprehensive study of progressively ground/polished 3Y-TZP was performed with the aim of better understanding the mechanisms driving the microstructural modifications observed after such procedures, and identifying the processing parameters leading to optimal microstructures (i.e. ageing-protective and damage-free). Gradually ground/polished surfaces were produced, yielding four different topographies of increasing roughness (grades 1–4) and two different textures (unidirectionally, U, and multidirectionally, M). Phase transformation, microstructure and residual stresses were investigated by means of advanced characterization techniques. It was found that low-roughness mildly ground/polished specimens (i.e. 2-M/U) presented a nanometric layer with the ageing-related protective features generally associated with coarsely ground specimens. A lower limit for grain refinement in terms of surface abrasion was also found, in which partial recrystallization took place (i.e. 1-M/U). A mathematical relation was established between average surface roughness (Sa), monoclinic volume fraction (Vm) and surface compressive residual stresses, demonstrating that if the processing parameters are controlled, both Vm and residual stresses can be predicted by the measurement of Sa.

Keywords: Grinding, Microstructure, Phase transformation, Residual stresses, Zirconia


Donnelly, Joanna L., Offenbartl-Stiegert, Daniel, Marín-Beloqui, José M., Rizzello, Loris, Battaglia, Guiseppe, Clarke, Tracey M., Howorka, Stefan, Wilden, Jonathan D., (2020). Exploring the relationship between BODIPY structure and spectroscopic properties to design fluorophores for bioimaging Chemistry - A European Journal 26, (4), 863-872

Designing chromophores for biological applications requires a fundamental understanding of how the chemical structure of a chromophore influences its photophysical properties. We here describe the synthesis of a library of BODIPY dyes, exploring diversity at various positions around the BODIPY core. The results show that the nature and position of substituents have a dramatic effect on the spectroscopic properties. Substituting in a heavy atom or adjusting the size and orientation of a conjugated system provides a means of altering the spectroscopic profiles with high precision. The insight from the structure–activity relationship was applied to devise a new BODIPY dye with rationally designed photochemical properties including absorption towards the near-infrared region. The dye also exhibited switch-on fluorescence to enable visualisation of cells with high signal-to-noise ratio without washing-out of unbound dye. The BODIPY-based probe is non-cytotoxic and compatible with staining procedures including cell fixation and immunofluorescence microscopy.


Park, D., Wershof, E., Boeing, S., Labernadie, A., Jenkins, R. P., George, S., Trepat, X., Bates, P. A., Sahai, E., (2020). Extracellular matrix anisotropy is determined by TFAP2C-dependent regulation of cell collisions Nature Materials 19, 227-238

The isotropic or anisotropic organization of biological extracellular matrices has important consequences for tissue function. We study emergent anisotropy using fibroblasts that generate varying degrees of matrix alignment from uniform starting conditions. This reveals that the early migratory paths of fibroblasts are correlated with subsequent matrix organization. Combined experimentation and adaptation of Vicsek modelling demonstrates that the reorientation of cells relative to each other following collision plays a role in generating matrix anisotropy. We term this behaviour ‘cell collision guidance’. The transcription factor TFAP2C regulates cell collision guidance in part by controlling the expression of RND3. RND3 localizes to cell–cell collision zones where it downregulates actomyosin activity. Cell collision guidance fails without this mechanism in place, leading to isotropic matrix generation. The cross-referencing of alignment and TFAP2C gene expression signatures against existing datasets enables the identification and validation of several classes of pharmacological agents that disrupt matrix anisotropy.

Keywords: Biomaterials – cells, Cell migration, Self-assembly, Tissues


Borgheti-Cardoso, L. N., Kooijmans, S. A. A., Gutiérrez Chamorro, L., Biosca, A., Lantero, E., Ramírez, M., Avalos-Padilla, Y., Crespo, I., Fernández, I., Fernandez-Becerra, C., del Portillo, H. A., Fernàndez-Busquets, X., (2020). Extracellular vesicles derived from Plasmodium-infected and non-infected red blood cells as targeted drug delivery vehicles International Journal of Pharmaceutics 587, 119627

Among several factors behind drug resistance evolution in malaria is the challenge of administering overall doses that are not toxic for the patient but that, locally, are sufficiently high to rapidly kill the parasites. Thus, a crucial antimalarial strategy is the development of drug delivery systems capable of targeting antimalarial compounds to Plasmodium with high specificity. In the present study, extracellular vesicles (EVs) have been evaluated as a drug delivery system for the treatment of malaria. EVs derived from naive red blood cells (RBCs) and from Plasmodium falciparum-infected RBCs (pRBCs) were isolated by ultrafiltration followed by size exclusion chromatography. Lipidomic characterization showed that there were no significant qualitative differences between the lipidomic profiles of pRBC-derived EVs (pRBC-EVs) and RBC-derived EVs (RBC-EVs). Both EVs were taken up by RBCs and pRBCs, although pRBC-EVs were more efficiently internalized than RBC-EVs, which suggested their potential use as drug delivery vehicles for these cells. When loaded into pRBC-EVs, the antimalarial drugs atovaquone and tafenoquine inhibited in vitro P. falciparum growth more efficiently than their free drug counterparts, indicating that pRBC-EVs can potentially increase the efficacy of several small hydrophobic drugs used for the treatment of malaria.

Keywords: Antimalarial drugs, Drug delivery, Extracellular vesicles, Malaria, Plasmodium falciparum


Ferrer, Isidro, Andrés-Benito, Pol, Zelaya, Maria Victoria, Aguirre, Maria Elena Erro, Carmona, Margarita, Ausín, Karina, Lachén-Montes, Mercedes, Fernández-Irigoyen, Joaquín, Santamaría, Enrique, del Río, José Antonio, (2020). Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy Acta Neuropathologica 139, (4), 735-771

Globular glial tauopathy (GGT) is a progressive neurodegenerative disease involving the grey matter and white matter (WM) and characterized by neuronal deposition of hyper-phosphorylated, abnormally conformed, truncated, oligomeric 4Rtau in neurons and in glial cells forming typical globular astrocyte and oligodendrocyte inclusions (GAIs and GOIs, respectively) and coiled bodies. Present studies centre on four genetic GGT cases from two unrelated families bearing the P301T mutation in MAPT and one case of sporadic GGT (sGGT) and one case of GGT linked to MAPT K317M mutation, for comparative purposes. Clinical and neuropathological manifestations and biochemical profiles of phospho-tau are subjected to individual variations in patients carrying the same mutation, even in carriers of the same family, independently of the age of onset, gender, and duration of the disease. Immunohistochemistry, western blotting, transcriptomic, proteomics and phosphoproteomics, and intra-cerebral inoculation of brain homogenates to wild-type (WT) mice were the methods employed. In GGT cases linked to MAPT P301T mutation, astrocyte markers GFAP, ALDH1L1, YKL40 mRNA and protein, GJA1 mRNA, and AQ4 protein are significantly increased; glutamate transporter GLT1 (EAAT2) and glucose transporter (SLC2A1) decreased; mitochondrial pyruvate carrier 1 (MPC1) increased, and mitochondrial uncoupling protein 5 (UCP5) almost absent in GAIs in frontal cortex (FC). Expression of oligodendrocyte markers OLIG1 and OLIG2mRNA, and myelin-related genes MBP, PLP1, CNP, MAG, MAL, MOG, and MOBP are significantly decreased in WM; CNPase, PLP1, and MBP antibodies reveal reduction and disruption of myelinated fibres; and SMI31 antibodies mark axonal damage in the WM. Altered expression of AQ4, GLUC-t, and GLT-1 is also observed in sGGT and in GGT linked to MAPT K317M mutation. These alterations point to primary astrogliopathy and oligodendrogliopathy in GGT. In addition, GGT linked to MAPT P301T mutation proteotypes unveil a proteostatic imbalance due to widespread (phospho)proteomic dearrangement in the FC and WM, triggering a disruption of neuron projection morphogenesis and synaptic transmission. Identification of hyper-phosphorylation of variegated proteins calls into question the concept of phospho-tau-only alteration in the pathogenesis of GGT. Finally, unilateral inoculation of sarkosyl-insoluble fractions of GGT homogenates from GGT linked to MAPT P301T, sGGT, and GGT linked to MAPT K317M mutation in the hippocampus, corpus callosum, or caudate/putamen in wild-type mice produces seeding, and time- and region-dependent spreading of phosphorylated, non-oligomeric, and non-truncated 4Rtau and 3Rtau, without GAIs and GOIs but only of coiled bodies. These experiments prove that host tau strains are important in the modulation of cellular vulnerability and phenotypes of phospho-tau aggregates.

Keywords: Globular glial tauopathy, Tau, Astrogliopathy, Oligodendrogliopathy, Phosphoproteome, Seeding and spreading


Burgués, Javier, Marco, Santiago, (2020). Feature extraction for transient chemical sensor signals in response to turbulent plumes: Application to chemical source distance prediction Sensors and Actuators B: Chemical 320, 128235

This paper describes the design of a linear phase low-pass differentiator filter with a finite impulse response (FIR) for extracting transient features of gas sensor signals (the so-called “bouts”). The detection of these bouts is relevant for estimating the distance of a gas source in a turbulent plume. Our current proposal addresses the shortcomings of previous ‘bout’ estimation methods, namely: (i) they were based in non-causal digital filters precluding real time operation, (ii) they used non-linear phase filters leading to waveform distortions and (iii) the smoothing action was achieved by two filters in cascade, precluding an easy tuning of filter performance. The presented method is based on a low-pass FIR differentiator, plus proper post-processing, allowing easy algorithmic implementation for real-time robotic exploration. Linear phase filters preserve signal waveform in the bandpass region for maximum reliability concerning both ‘bout’ detection and amplitude estimation. As a case study, we apply the proposed filter to predict the source distance from recordings obtained with metal oxide (MOX) gas sensors in a wind tunnel. We first perform a joint optimization of the cut-off frequency of the filter and the bout amplitude threshold, for different wind speeds, uncovering interesting relationships between these two parameters. We demonstrate that certain combinations of parameters can reduce the prediction error to 8 cm (in a distance range of 1.45 m) improving previously reported performances in the same dataset by a factor of 2.5. These results are benchmarked against traditional source distance estimators such as the mean, variance and maximum of the response. We also study how the length of the measurement window affects the performance of different signal features, and how to select the filter parameters to make the predictive models more robust to changes in wind speed. Finally, we provide a MATLAB implementation of the bout detection algorithm and all analysis code used in this study.

Keywords: Gas sensors, Differentiator, Low pass filter, Metal oxide semiconductor, MOX sensors, Signal processing, Feature extraction, Gas source localization, Robotics


Prat-Vidal, C., Rodríguez-Gómez, L., Aylagas, M., Nieto-Nicolau, N., Gastelurrutia, P., Agustí, E., Gálvez-Montón, C., Jorba, I., Teis, A., Monguió-Tortajada, M., Roura, S., Vives, J., Torrents-Zapata, S., Coca, M. I., Reales, L., Cámara-Rosell, M. L., Cediel, G., Coll, R., Farré, R., Navajas, D., Vilarrodona, A., García-López, J., Muñoz-Guijosa, C., Querol, S., Bayes-Genis, A., (2020). First-in-human PeriCord cardiac bioimplant: Scalability and GMP manufacturing of an allogeneic engineered tissue graft EBioMedicine 54, 102729

Background Small cardiac tissue engineering constructs show promise for limiting post-infarct sequelae in animal models. This study sought to scale-up a 2-cm2 preclinical construct into a human-size advanced therapy medicinal product (ATMP; PeriCord), and to test it in a first-in-human implantation. Methods The PeriCord is a clinical-size (12–16 cm2) decellularised pericardial matrix colonised with human viable Wharton's jelly-derived mesenchymal stromal cells (WJ-MSCs). WJ-MSCs expanded following good manufacturing practices (GMP) met safety and quality standards regarding the number of cumulative population doublings, genomic stability, and sterility. Human decellularised pericardial scaffolds were tested for DNA content, matrix stiffness, pore size, and absence of microbiological growth. Findings PeriCord implantation was surgically performed on a large non-revascularisable scar in the inferior wall of a 63-year-old male patient. Coronary artery bypass grafting was concomitantly performed in the non-infarcted area. At implantation, the 16-cm2 pericardial scaffold contained 12·5 × 106 viable WJ-MSCs (85·4% cell viability; <0·51 endotoxin units (EU)/mL). Intraoperative PeriCord delivery was expeditious, and secured with surgical glue. The post-operative course showed non-adverse reaction to the PeriCord, without requiring host immunosuppression. The three-month clinical follow-up was uneventful, and three-month cardiac magnetic resonance imaging showed ~9% reduction in scar mass in the treated area. Interpretation This preliminary report describes the development of a scalable clinical-size allogeneic PeriCord cardiac bioimplant, and its first-in-human implantation. Funding La Marató de TV3 Foundation, Government of Catalonia, Catalan Society of Cardiology, “La Caixa” Banking Foundation, Spanish Ministry of Science, Innovation and Universities, Institute of Health Carlos III, and the European Regional Development Fund.

Keywords: Advanced therapy medicinal product (ATMP), Biofabrication, Cardiac tissue engineering, Myocardial infarction, Scaffold, Wharton's jelly-derived mesenchymal stromal cells (WJ-MSCs)


Molina, B. G., Lopes-Rodrigues, M., Estrany, F., Michaux, C., Perpète, E. A., Armelin, E., Alemán, C., (2020). Free-standing flexible and biomimetic hybrid membranes for ions and ATP transport Journal of Membrane Science 601, 117931

The transport of metabolites across robust, flexible and free-standing biomimetic membranes made of three perforated poly (lactic acid) (pPLA) layers, separated by two anodically polymerized conducting layers of poly (3,4-ethylenedioxythiophene-co-3-dodecylthiophene), and functionalized on the external pPLA layers with a voltage dependent anion channel (VDAC) protein, has been demonstrated. The three pPLA layers offer robustness and flexibility to the bioactive platform and the possibility of obtaining conducing polymer layers by in situ anodic polymerization. The incorporation of dodecylthiophene units, which bear a 12 carbon atoms long linear alkyl chain, to the conducting layers allows mimicking the amphiphilic environment offered by lipids in cells, increasing 32% the efficiency of the functionalization. Electrochemical impedance measurements in NaCl and adenosine triphosphate (ATP) solutions prove that the integration of the VDAC porin inside the PLA perforations considerably increases the membrane conductivity and is crucial for the electrolyte diffusion. Such results open the door for the development of advanced sensing devices for a broad panel of biomedical applications.

Keywords: Conducting polymers, Membrane proteins, Membranes, Polylactic acid, Self-supported films


Sánchez-Fibla, M., Forestier, S., Moulin-Frier, C., Puigbò, J. Y., Verschure, P., (2020). From motor to visually guided bimanual affordance learning Adaptive Behavior 28, (2), 63-78

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


Burgués, Javier, Hernández, Victor, Lilienthal, Achim J., Marco, Santiago, (2020). Gas distribution mapping and source localization using a 3D grid of metal oxide semiconductor sensors Sensors and Actuators B: Chemical 304, 127309

The difficulty to obtain ground truth (i.e. empirical evidence) about how a gas disperses in an environment is one of the major hurdles in the field of mobile robotic olfaction (MRO), impairing our ability to develop efficient gas source localization strategies and to validate gas distribution maps produced by autonomous mobile robots. Previous ground truth measurements of gas dispersion have been mostly based on expensive tracer optical methods or 2D chemical sensor grids deployed only at ground level. With the ever-increasing trend towards gas-sensitive aerial robots, 3D measurements of gas dispersion become necessary to characterize the environment these platforms can explore. This paper presents ten different experiments performed with a 3D grid of 27 metal oxide semiconductor (MOX) sensors to visualize the temporal evolution of gas distribution produced by an evaporating ethanol source placed at different locations in an office room, including variations in height, release rate and air flow. We also studied which features of the MOX sensor signals are optimal for predicting the source location, considering different lengths of the measurement window. We found strongly time-varying and counter-intuitive gas distribution patterns that disprove some assumptions commonly held in the MRO field, such as that heavy gases disperse along ground level. Correspondingly, ground-level gas distributions were rarely useful for localizing the gas source and elevated measurements were much more informative. We make the dataset and the code publicly available to enable the community to develop, validate, and compare new approaches related to gas sensing in complex environments.

Keywords: Mobile robotic olfaction, Metal oxide gas sensors, Signal processing, Sensor networks, Gas source localization, Gas distribution mapping


Sanchez-Herrero, J. F., Bernabeu, M., Prieto, A., Hüttener, M., Juárez, A., (2020). Gene duplications in the genomes of staphylococci and enterococci Frontiers in Molecular Biosciences 7, 160

Gene duplications are a feature of bacterial genomes. In the present work we analyze the extent of gene duplications in the genomes of three microorganisms that belong to the Firmicutes phylum and that are etiologic agents of several nosocomial infections: Staphylococcus aureus, Enterococcus faecium, and Enterococcus faecalis. In all three groups, there is an irregular distribution of duplications in the genomes of the strains analyzed. Whereas in some of the strains duplications are scarce, hundreds of duplications are present in others. In all three species, mobile DNA accounts for a large percentage of the duplicated genes: phage DNA in S. aureus, and plasmid DNA in the enterococci. Duplicates also include core genes. In all three species, a reduced group of genes is duplicated in all strains analyzed. Duplication of the deoC and rpmG genes is a hallmark of S. aureus genomes. Duplication of the gene encoding the PTS IIB subunit is detected in all enterococci genomes. In E. faecalis it is remarkable that the genomes of some strains encode duplicates of the prgB and prgU genes. They belong to the prgABCU cluster, which responds to the presence of the peptide pheromone cCF10 by expressing the surface adhesins PrgA, PrgB, and PrgC.

Keywords: Bacterial genomics, Enterococcus faecalis, Enterococcus faecium, Gene duplication, Staphylococcus aureus


Lynch, Cian J., Bernad, Raquel, Martínez-Val, Ana, Shahbazi, Marta N., Nóbrega-Pereira, Sandrina, Calvo, Isabel, Blanco-Aparicio, Carmen, Tarantino, Carolina, Garreta, Elena, Richart-Ginés, Laia, Alcazar, Noelia, Graña-Castro, Osvaldo, Gómez-Lopez, Gonzalo, Aksoy, Irene, Muñoz-Martín, Maribel, Martinez, Sonia, Ortega, Sagrario, Prieto, Susana, Simboeck, Elisabeth, Camasses, Alain, Stephan-Otto Attolini, Camille, Fernandez, Agustin F., Sierra, Marta I., Fraga, Mario F., Pastor, Joaquin, Fisher, Daniel, Montserrat, Nuria, Savatier, Pierre, Muñoz, Javier, Zernicka-Goetz, Magdalena, Serrano, Manuel, (2020). Global hyperactivation of enhancers stabilizes human and mouse naive pluripotency through inhibition of CDK8/19 Mediator kinases Nature Cell Biology 22, (10), 1223-1238

Pluripotent stem cells (PSCs) transition between cell states in vitro, reflecting developmental changes in the early embryo. PSCs can be stabilized in the naive state by blocking extracellular differentiation stimuli, particularly FGF–MEK signalling. Here, we report that multiple features of the naive state in human and mouse PSCs can be recapitulated without affecting FGF–MEK signalling or global DNA methylation. Mechanistically, chemical inhibition of CDK8 and CDK19 (hereafter CDK8/19) kinases removes their ability to repress the Mediator complex at enhancers. CDK8/19 inhibition therefore increases Mediator-driven recruitment of RNA polymerase II (RNA Pol II) to promoters and enhancers. This efficiently stabilizes the naive transcriptional program and confers resistance to enhancer perturbation by BRD4 inhibition. Moreover, naive pluripotency during embryonic development coincides with a reduction in CDK8/19. We conclude that global hyperactivation of enhancers drives naive pluripotency, and this can be achieved in vitro by inhibiting CDK8/19 kinase activity. These principles may apply to other contexts of cellular plasticity.


Pedraz, Lucas, Blanco-Cabra, Núria, Torrents, Eduard, (2020). Gradual adaptation of facultative anaerobic pathogens to microaerobic and anaerobic conditions The FASEB Journal 34, (2), 2912-2928

Many notable human pathogens are facultative anaerobes. These pathogens exhibit redundant metabolic pathways and a whole array of regulatory systems to adapt to changing oxygen levels. However, our knowledge of facultative anaerobic pathogens is mostly based on fully aerobic or anaerobic cultures, which does not reflect real infection conditions, while the microaerobic range remains understudied. Here, we examine the behavior of pathogenic and nonpathogenic strains of two facultative anaerobes, Escherichia coli and Pseudomonas aeruginosa, during the aerobic-anaerobic transition. To do so, we introduce a new technique named AnaeroTrans, in which we allow self-consumption of oxygen by steady-state cultures and monitor the system by measuring the gas-phase oxygen concentration. We explore the different behavior of the studied species toward oxygen and examine how this behavior is associated with the targeted infection sites. As a model, we characterize the adaptation profile of the ribonucleotide reductase network, a complex oxygen-dependent enzymatic system responsible for the generation of the deoxyribonucleotides. We also explore the actions of the most important anaerobic regulators and how these regulators influence bacterial fitness. Our results allow us to classify the different elements that compose the aerobic-anaerobic transition into reproducible stages, thus showing the different adaptation mechanisms of the studied species.


Convertino, D., Fabbri, F., Mishra, N., Mainardi, M., Cappello, V., Testa, G., Capsoni, S., Albertazzi, L., Luin, S., Marchetti, L., Coletti, C., (2020). Graphene promotes axon elongation through local stall of nerve growth factor signaling endosomes Nano Letters 20, (5), 3633-3641

Several works reported increased differentiation of neuronal cells grown on graphene; however, the molecular mechanism driving axon elongation on this material has remained elusive. Here, we study the axonal transport of nerve growth factor (NGF), the neurotrophin supporting development of peripheral neurons, as a key player in the time course of axonal elongation of dorsal root ganglion neurons on graphene. We find that graphene drastically reduces the number of retrogradely transported NGF vesicles in favor of a stalled population in the first 2 days of culture, in which the boost of axon elongation is observed. This correlates with a mutual charge redistribution, observed via Raman spectroscopy and electrophysiological recordings. Furthermore, ultrastructural analysis indicates a reduced microtubule distance and an elongated axonal topology. Thus, both electrophysiological and structural effects can account for graphene action on neuron development. Unraveling the molecular players underneath this interplay may open new avenues for axon regeneration applications.

Keywords: Axon elongation, Graphene, Material-neuron interface, Membrane-associated periodic skeleton, Nerve growth factor retrograde transport, Peripheral dorsal root ganglion neuron


Calvo, Mireia, González, Rubèn, Seijas, Núria, Vela, Emili, Hernández, Carme, Batiste, Guillem, Miralles, Felip, Roca, Josep, Cano, Isaac, Jané, Raimon, (2020). Health outcomes from home hospitalization: Multisource predictive modeling Journal of Medical Internet Research 22, (10), e21367

Background: Home hospitalization is widely accepted as a cost-effective alternative to conventional hospitalization for selected patients. A recent analysis of the home hospitalization and early discharge (HH/ED) program at Hospital Clínic de Barcelona over a 10-year period demonstrated high levels of acceptance by patients and professionals, as well as health value-based generation at the provider and health-system levels. However, health risk assessment was identified as an unmet need with the potential to enhance clinical decision making. Objective: The objective of this study is to generate and assess predictive models of mortality and in-hospital admission at entry and at HH/ED discharge. Methods: Predictive modeling of mortality and in-hospital admission was done in 2 different scenarios: at entry into the HH/ED program and at discharge, from January 2009 to December 2015. Multisource predictive variables, including standard clinical data, patients’ functional features, and population health risk assessment, were considered. Results: We studied 1925 HH/ED patients by applying a random forest classifier, as it showed the best performance. Average results of the area under the receiver operating characteristic curve (AUROC; sensitivity/specificity) for the prediction of mortality were 0.88 (0.81/0.76) and 0.89 (0.81/0.81) at entry and at home hospitalization discharge, respectively; the AUROC (sensitivity/specificity) values for in-hospital admission were 0.71 (0.67/0.64) and 0.70 (0.71/0.61) at entry and at home hospitalization discharge, respectively. Conclusions: The results showed potential for feeding clinical decision support systems aimed at supporting health professionals for inclusion of candidates into the HH/ED program, and have the capacity to guide transitions toward community-based care at HH discharge.

Keywords: Home hospitalization, Health risk assessment, Predictive modeling, Chronic care, Integrated care, Modeling, Hospitalization, Health risk, Prediction, Mortality, Clinical decision support


Lantero, E., Fernandes, J., Aláez-Versón, C. R., Gomes, J., Silveira, H., Nogueira, F., Fernàndez-Busquets, X., (2020). Heparin administered to anopheles in membrane feeding assays blocks plasmodium development in the mosquito Biomolecules 10, (8), 1136

Innovative antimalarial strategies are urgently needed given the alarming evolution of resistance to every single drug developed against Plasmodium parasites. The sulfated glycosaminoglycan heparin has been delivered in membrane feeding assays together with Plasmodium berghei-infected blood to Anopheles stephensi mosquitoes. The transition between ookinete and oocyst pathogen stages in the mosquito has been studied in vivo through oocyst counting in dissected insect midguts, whereas ookinete interactions with heparin have been followed ex vivo by flow cytometry. Heparin interferes with the parasite’s ookinete–oocyst transition by binding ookinetes, but it does not affect fertilization. Hypersulfated heparin is a more efficient blocker of ookinete development than native heparin, significantly reducing the number of oocysts per midgut when offered to mosquitoes at 5 µg/mL in membrane feeding assays. Direct delivery of heparin to mosquitoes might represent a new antimalarial strategy of rapid implementation, since it would not require clinical trials for its immediate deployment.

Keywords: Anopheles, Antimalarial drugs, Heparin, Malaria, Mosquito, Ookinete, Plasmodium, Transmission blocking


Sohn, Lydia L., Schwille, Petra, Hierlemann, Andreas, Tay, Savas, Samitier, Josep, Fu, Jianping, Loskill, Peter, (2020). How can microfluidic and microfabrication approaches make experiments more physiologically relevant? Cell Systems 11, (3), 209-211

Microfabricated and microfluidic devices enable standardized handling, precise spatiotemporal manipulation of cells and liquids, and recapitulation of cellular environments, tissues, and organ-level biology. We asked researchers how these devices can make in vitro experiments more physiologically relevant.


Zoufaly, Alexander, Poglitsch, Marko, Aberle, Judith H., Hoepler, Wolfgang, Seitz, Tamara, Traugott, Marianna, Grieb, Alexander, Pawelka, Erich, Laferl, Hermann, Wenisch, Christoph, Neuhold, Stephanie, Haider, Doris, Stiasny, Karin, Bergthaler, Andreas, Puchhammer-Stoeckl, Elisabeth, Mirazimi, Ali, Montserrat, Nuria, Zhang, Haibo, Slutsky, Arthur S., Penninger, Josef M., (2020). Human recombinant soluble ACE2 in severe COVID-19 The Lancet Respiratory Medicine 8, (11), 1154-1158

Angiotensin converting enzyme 2 (ACE2) is the crucial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor and protects multiple tissues, including the lung, from injury as a regulator of the renin–angiotensin system.1 Therefore, ACE2 has become the focus of COVID-19 research and a plethora of drug development efforts. Among the novel compounds under development is human recombinant soluble ACE2 (hrsACE2 [APN01; Apeiron Biologics, Vienna, Austria]), which has two mechanisms of action that theoretically should be of benefit in COVID-19.2 The first involves binding the viral spike protein and thereby neutralising SARS-CoV-2,3 and the second is minimising injury to multiple organs, including the lungs, kidneys, and heart, because of unabated renin–angiotensin system hyperactivation and increased angiotensin II concentrations.4, 5, 6 hrsACE2 has been tested in 89 patients, namely in healthy volunteers in phase 1 studies and in patients with acute respiratory distress syndrome (ARDS) in phase 2 clinical studies, with a good safety profile.7, 8 Moreover, hrsACE2 can reduce SARS-CoV-2 load by a factor of 1000–5000 in in-vitro cell-culture experiments and engineered organoids, directly demonstrating that ACE2 can effectively neutralise SARS-CoV-2.3 We describe in this Case Report the first course of treatment with hrsACE2 of a patient with severe COVID-19.


Monteil, Vanessa, Dyczynski, Matheus, Lauschke, Volker M., Kwon, Hyesoo, Wirnsberger, Gerald, Youhanna, Sonia, Zhang, Haibo, Slutsky, Arthur S., Hurtado del Pozo, Carmen, Horn, Moritz, Montserrat, Nuria, Penninger, Josef M., Mirazimi, Ali, (2020). Human soluble ACE2 improves the effect of remdesivir in SARS-CoV-2 infection EMBO Molecular Medicine , e13426

There is a critical need for safe and effective drugs for COVID-19. Only remdesivir has received authorization for COVID-19 and has been shown to improve outcomes but not decrease mortality. However, the dose of remdesivir is limited by hepatic and kidney toxicity. ACE2 is the critical cell surface receptor for SARS-CoV-2. Here, we investigated additive effect of combination therapy using remdesivir with recombinant soluble ACE2 (high/low dose) on Vero E6 and kidney organoids, targeting two different modalities of SARS-CoV-2 life cycle: cell entry via its receptor ACE2 and intracellular viral RNA replication. This combination treatment markedly improved their therapeutic windows against SARS-CoV-2 in both models. By using single amino-acid resolution screening in haploid ES cells, we report a singular critical pathway required for remdesivir toxicity, namely, Adenylate Kinase 2. The data provided here demonstrate that combining two therapeutic modalities with different targets, common strategy in HIV treatment, exhibit strong additive effects at sub-toxic concentrations. Our data lay the groundwork for the study of combinatorial regimens in future COVID-19 clinical trials.


Pijpers, Imke A. B., Cao, Shoupeng, Llopis-Lorente, Antoni, Zhu, Jianzhi, Song, Shidong, Joosten, Rick R. M., Meng, Fenghua, Friedrich, Heiner, Williams, David S., Sánchez, Samuel, van Hest, Jan C. M., Abdelmohsen, Loai K. E. A., (2020). Hybrid biodegradable nanomotors through compartmentalized synthesis Nano Letters 20, (6), 4472-4480

Designer particles that are embued with nanomachinery for autonomous motion have great potential for biomedical applications; however, their development is highly demanding with respect to biodegradability/compatibility. Previously, biodegradable propulsive machinery based on enzymes has been presented. However, enzymes are highly susceptible to proteolysis and deactivation in biological milieu. Biodegradable hybrid nanomotors powered by catalytic inorganic nanoparticles provide a proteolytically stable alternative to those based upon enzymes. Herein we describe the assembly of hybrid biodegradable nanomotors capable of transducing chemical energy into motion. Such nanomotors are constructed through a process of compartmentalized synthesis of inorganic MnO2 nanoparticles (MnPs) within the cavity of organic stomatocytes. We show that the nanomotors remain active in cellular environments and do not compromise cell viability. Effective tumor penetration of hybrid nanomotors is also demonstrated in proof-of-principle experiments. Overall, this work represents a new prospect for engineering of nanomotors that can retain their functionality within biological contexts.


Vila, A., Torras, N., Castaño, Albert G., García-Díaz, María, Comelles, Jordi, Pérez-Berezo, T., Corregidor, C., Castaño, O., Engel, E., Fernández-Majada, Vanesa, Martínez, Elena, (2020). Hydrogel co-networks of gelatine methacrylate and poly(ethylene glycol) diacrylate sustain 3D functional in vitro models of intestinal mucosa Biofabrication 12, 025008

Mounting evidence supports the importance of the intestinal epithelial barrier and its permeability both in physiological and pathological conditions. Conventional in vitro models to evaluate intestinal permeability rely on the formation of tightly packed epithelial monolayers grown on hard substrates. These two-dimensional (2D) models lack the cellular and mechanical components of the non-epithelial compartment of the intestinal barrier, the stroma, which are key contributors to the barrier permeability in vivo. Thus, advanced in vitro models approaching the in vivo tissue composition are fundamental to improve precision in drug absorption predictions, to provide a better understanding of the intestinal biology, and to faithfully represent related diseases. Here, we generate photo-crosslinked gelatine methacrylate (GelMA) - poly(ethylene glycol) diacrylate (PEGDA) hydrogel co-networks that provide the required mechanical and biochemical features to mimic both the epithelial and stromal compartments of the intestinal mucosa, i.e., they are soft, cell adhesive and cell-loading friendly, and suitable for long-term culturing. We show that fibroblasts can be embedded in the GelMA-PEGDA hydrogels while epithelial cells can grow on top to form a mature epithelial monolayer that exhibits barrier properties which closely mimic those of the intestinal barrier in vivo, as shown by the physiologically relevant transepithelial electrical resistance (TEER) and permeability values. The presence of fibroblasts in the artificial stroma compartment accelerates the formation of the epithelial monolayer and boosts the recovery of the epithelial integrity upon temporary barrier disruption, demonstrating that our system is capable of successfully reproducing the interaction between different cellular compartments. As such, our hydrogel co-networks offer a technologically simple yet sophisticated approach to produce functional three-dimensional (3D) in vitro models of epithelial barriers with epithelial and stromal cells arranged in a spatially relevant manner and near-physiological functionality.


Bortolla, R., Cavicchioli, M., Soler Rivaldi, J., Pascual Mateos, J.C., Verschure, P., Maffei, C., (2020). Hypersensitivity or hyperreactivity? An experimental investigation in Borderline Personality Disorder Mediterranean Journal of Clinical Psychology 8, (1), 1-17

Objective: Starting from the controversial results showed by empirical research on Linehan’s Biosocial model of Borderline Personality Disorder (BPD), this study aims to empirically evaluate Linehan’s conceptualization of emotional hypersensitivity and hyperreactivity, as well as to investigate the role of pre-existing emotional states in BPD altered physiological responsivity. Methods: We asked 24 participants (BPD = 12; Healthy Controls = 12) to complete a self-reported questionnaire (Positive and Negative Affect Schedule) in order to assess their pre-task affective state. Subsequently, 36 emotional pictures from four valence categories (i.e. erotic, negative, positive, neutral) were administered while assessing participants self-reported and electrodermal responses. Results: BPD patients showed higher levels of pre-task negative affectivity as well as an enhanced physiological response to neutral stimuli. No main BPD group effect was found for the physiological data. Moreover, pre-task negative affectivity levels were exclusively related to physiological responses among BPD subjects. Discussion: Our findings supported the hypersensitivity hypothesis operationalized as an enhanced responsiveness to non-emotional cues. Hyperreactivity assumption was not supported. Conversely, our study revealed heightened physiological responses in relation to pre-existent negative emotional states in BPD. We discussed our results in the context of the putative pathological processes underlying BPD.

Keywords: Borderline Personality Disorder, Biosocial model, Hyperreactivity, Hypersensitivity, Negative affectivity, Physiology.


Castillo-Escario, Y., Rodríguez-Cañón, M., García-Alías, G., Jané, R., (2020). Identifying muscle synergies from reaching and grasping movements in rats IEEE Access 8, 62517-62530

Reaching and grasping (R&G) is a skilled voluntary movement which is critical for animals. In this work, we aim to identify muscle synergy patterns from R&G movements in rats and show how these patterns can be used to characterize such movements and investigate their consistency and repeatability. For that purpose, we analyzed the electromyographic (EMG) activity of five forelimb muscles recorded while the animals were engaged in R&G tasks. Our dataset included 200 R&G attempts from three different rats. Non-negative matrix factorization was used to decompose EMG signals and extract muscle synergies. We compared all pairs of attempts and created cross-validated models to study intra- and inter-subject variability. We found that three synergies were enough to accurately reconstruct the EMG envelopes. These muscle synergies and their corresponding activation coefficients were very similar for all the attempts in the database, providing a general pattern to describe the movement. Results suggested that the movement strategy adopted by an individual in its different attempts was highly repetitive, but also resembled the strategies adopted by the other animals. Inter-subject variability was not much higher than intra-subject variability. This study is a proof-of-concept, but the proposed approaches can help to establish whether there is a stereotyped pattern of neuromuscular activity in R&G movement in healthy rats, and the changes that occur in animal models of acute neurological injuries. Research on muscle synergies could elucidate motor control mechanisms, and lead to quantitative tools for evaluating upper limb motor impairment after an injury.

Keywords: Electromyography, Motor control, Muscle synergies, Reaching and grasping, Upper limb


Altay, Gizem, Tosi, Sébastien, García-Díaz, María, Martínez, Elena, (2020). Imaging the cell morphological response to 3D topography and curvature in engineered intestinal tissues Frontiers in Bioengineering and Biotechnology 8, 294

While conventional cell culture methodologies have relied on flat, two-dimensional cell monolayers, three-dimensional engineered tissues are becoming increasingly popular. Often, engineered tissues can mimic the complex architecture of native tissues, leading to advancements in reproducing physiological functional properties. In particular, engineered intestinal tissues often use hydrogels to mimic villi structures. These finger-like protrusions of a few hundred microns in height have a well-defined topography and curvature. Here, we examined the cell morphological response to these villus-like microstructures at single-cell resolution using a novel embedding method that allows for the histological processing of these delicate hydrogel structures. We demonstrated that by using photopolymerisable poly(ethylene) glycol as an embedding medium, the villus-like microstructures were successfully preserved after sectioning with vibratome or cryotome. Moreover, high-resolution imaging of these sections revealed that cell morphology, nuclei orientation, and the expression of epithelial polarization markers were spatially encoded along the vertical axis of the villus-like microstructures and that this cell morphological response was dramatically affected by the substrate curvature. These findings, which are in good agreement with the data reported for in vivo experiments on the native tissue, are likely to be the origin of more physiologically relevant barrier properties of engineered intestinal tissues when compared with standard monolayer cultures. By showcasing this example, we anticipate that the novel histological embedding procedure will have a positive impact on the study of epithelial cell behavior on three-dimensional substrates in both physiological and pathological situations.

Keywords: Hydrogel scaffold, Confocal microscopy, Substrate curvature, Cell morphology, Cell orientation, Histological section, Small intestine, Villus


Steeves, A.J., Ho, W., Munisso, M.C., Lomboni, D.J., Larrañaga, E., Omelon, S., Martínez, Elena, Spinello, D., Variola, F., (2020). The implication of spatial statistics in human mesenchymal stem cell response to nanotubular architectures International Journal of Nanomedicine 15, 2151-2169

Introduction: In recent years there has been ample interest in nanoscale modifications of synthetic biomaterials to understand fundamental aspects of cell-surface interactions towards improved biological outcomes. In this study, we aimed at closing in on the effects of nanotubular TiO2 surfaces with variable nanotopography on the response on human mesenchymal stem cells (hMSCs). Although the influence of TiO2 nanotubes on the cellular response, and in particular on hMSC activity, has already been addressed in the past, previous studies overlooked critical morphological, structural and physical aspects that go beyond the simple nanotube diameter, such as spatial statistics. Methods: To bridge this gap, we implemented an extensive characterization of nanotubular surfaces generated by anodization of titanium with a focus on spatial structural variables including eccentricity, nearest neighbour distance (NND) and Voronoi entropy, and associated them to the hMSC response. In addition, we assessed the biological potential of a two-tiered honeycomb nanoarchitecture, which allowed the detection of combinatory effects that this hierarchical structure has on stem cells with respect to conventional nanotubular designs. We have combined experimental techniques, ranging from Scanning Electron (SEM) and Atomic Force (AFM) microscopy to Raman spectroscopy, with computational simulations to characterize and model nanotubular surfaces. We evaluated the cell response at 6 hrs, 1 and 2 days by fluorescence microscopy, as well as bone mineral deposition by Raman spectroscopy, demonstrating substrate-induced differential biological cueing at both the short- and long-term. Results: Our work demonstrates that the nanotube diameter is not sufficient to comprehensively characterize nanotubular surfaces and equally important parameters, such as eccentricity and wall thickness, ought to be included since they all contribute to the overall spatial disorder which, in turn, dictates the overall bioactive potential. We have also demonstrated that nanotubular surfaces affect the quality of bone mineral deposited by differentiated stem cells. Lastly, we closed in on the integrated effects exerted by the superimposition of two dissimilar nanotubular arrays in the honeycomb architecture. Discussion: This work delineates a novel approach for the characterization of TiO2 nanotubes which supports the incorporation of critical spatial structural aspects that have been overlooked in previous research. This is a crucial aspect to interpret cellular behaviour on nanotubular substrates. Consequently, we anticipate that this strategy will contribute to the unification of studies focused on the use of such powerful nanostructured surfaces not only for biomedical applications but also in other technology fields, such as catalysis.

Keywords: Nanotubes, Nanotopography, Spatial statistics, Stem cells, Bone quality


Majchrowicz, A., Roguska, A., Krawczy, Lewandowska, M., Martí-Muñoz, J., Engel, E., Castano, O., (2020). In vitro evaluation of degradable electrospun polylactic acid/bioactive calcium phosphate ormoglass scaffolds Archives of Civil and Mechanical Engineering 20, (2), 50

Nowadays, the main limitation for clinical application of scaffolds is considered to be an insufficient vascularization of the implanted platforms and healing tissues. In our studies, we proposed a novel PLA-based hybrid platform with aligned and random fibrous internal structure and incorporated calcium phosphate (CaP) ormoglass nanoparticles (0, 10, 20 and 30 wt%) as an off-the-shelf method for obtaining scaffolds with pro-angiogenic properties. Complex morphological and physicochemical evaluation of PLA–CaP ormoglass composites was performed before and after in vitro degradation test in SBF solution to assess their biological potential. The degradation process of PLA–CaP ormoglass composites was accompanied by numerous CaP-based precipitations with extended topography and cauliflower-like shape which may enhance bonding of the material with the bone tissue and accelerate the regenerative process. Random fiber orientation was preferable for CaP compounds deposition upon in vitro degradation. CaP compounds precipitated firstly for randomly oriented composite nonwovens with 20 and 30 wt% addition of ormoglass. Moreover, the preliminary bioactivity test has shown that BSA adsorbed to PLA–CaP ormoglass composites (both aligned and randomly oriented) with 20 and 30 wt% of ormoglass nanoparticles which was not observed for pure PLA scaffolds.

Keywords: Calcium phosphate ormoglass, Composites, Degradation, Electrospinning, PLA


Altay, Gizem, Batlle, Eduard, Fernández-Majada, Vanesa, Martínez, Elena, (2020). In vitro self-organized mouse small intestinal epithelial monolayer protocol Bio-protocol 10, (3), e3514

Developing protocols to obtain intestinal epithelial monolayers that recapitulate in vivo physiology to overcome the limitations of the organoids’ closed geometry has become of great interest during the last few years. Most of the developed culture models showed physiological-relevant cell composition but did not prove self-renewing capacities. Here, we show a simple method to obtain mouse small intestine-derived epithelial monolayers organized into proliferative crypt-like domains, containing stem cells, and differentiated villus-like regions, closely resembling the in vivo cell composition and distribution. In addition, we adapted our model to a tissue culture format compatible with functional studies and prove close to physiological barrier properties of our in vitro epithelial monolayers. Thus, we have set-up a protocol to generate physiologically relevant intestinal epithelial monolayers to be employed in assays where independent access to both luminal and basolateral compartments is needed, such as drug absorption, intracellular trafficking and microbiome-epithelium interaction assays.

Keywords: Mouse intestinal organoids, Adult intestinal stem cells, Matrigel, Intestinal epithelial monolayer, In vitro intestinal epithelial model, Tissue-like functionality, TEER


Sadowska, J. M., Ginebra, M. P., (2020). Inflammation and biomaterials: Role of the immune response in bone regeneration by inorganic scaffolds Journal of Materials Chemistry B 8, (41), 9404-9427

The regulatory role of the immune system in maintaining bone homeostasis and restoring its functionality, when disturbed due to trauma or injury, has become evident in recent years. The polarization of macrophages, one of the main constituents of the immune system, into the pro-inflammatory or anti-inflammatory phenotype has great repercussions for cellular crosstalk and the subsequent processes needed for proper bone regeneration such as angiogenesis and osteogenesis. In certain scenarios, the damaged osseous tissue requires the placement of synthetic bone grafts to facilitate the healing process. Inorganic biomaterials such as bioceramics or bioactive glasses are the most widely used due to their resemblance to the mineral phase of bone and superior osteogenic properties. The immune response of the host to the inorganic biomaterial, which is of an exogenous nature, might determine its fate, leading either to active bone regeneration or its failure. Therefore, various strategies have been employed, like the modification of structural/chemical features or the incorporation of bioactive molecules, to tune the interplay with the immune cells. Understanding how these particular modifications impact the polarization of macrophages and further osteogenic and osteoclastogenic events is of great interest in view of designing a new generation of osteoimmunomodulatory materials that support the regeneration of osseous tissue during all stages of bone healing.


Minguela, J., Ginebra, M. P., Llanes, L., Mas-Moruno, C., Roa, J. J., (2020). Influence of grinding/polishing on the mechanical, phase stability and cell adhesion properties of yttria-stabilized zirconia Journal of the European Ceramic Society 40, (12), 4304-4314

The changes in mechanical properties, hydrothermal degradation and cell adhesion were studied in 3Y-TZP under two different superficial modification patterns (uni- and multidirectional) with a surface roughness ranging from 16 to 603 nm. In this sense, mechanical properties (i.e. hardness, indentation fracture toughness and scratch) and accelerated tests in water steam were measured to evaluate the influence of the surface treatments on the superficially modified layer. Moreover, a detailed characterization through micro-Raman spectroscopy and X-Ray diffraction was performed. Finally, SaOS-2 osteoblasts were used for the evaluation of the cell adhesion behaviour on the surfaces. Overall, ground/polished specimens increased the mechanical properties and ageing resistance of mirror-like polished specimens, although resistance to degradation was maximum at intermediate conditions (Sa ≈ 40−180 nm). The studied surfaces allowed cell attachment, but promoted contact guidance (i.e. cell alignment) only on unidirectionally ground surfaces above Sa = 150 nm.

Keywords: Cell adhesion, Grinding, Hydrothermal degradation, Mechanical properties, Zirconia


Monteil, Vanessa, Kwon, Hyesoo, Prado, Patricia, Hagelkrüys, Astrid, Wimmer, Reiner A., Stahl, Martin, Leopoldi, Alexandra, Garreta, Elena, Hurtado Del Pozo, Carmen, Prosper, Felipe, Romero, Juan Pablo, Wirnsberger, Gerald, Zhang, Haibo, Slutsky, Arthur S., Conder, Ryan, Montserrat, Nuria, Mirazimi, Ali, Penninger, Josef M., (2020). Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2 Cell 181, (4), 905-913.e7

We have previously provided the first genetic evidence that angiotensin converting enzyme 2 (ACE2) is the critical receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), and ACE2 protects the lung from injury, providing a molecular explanation for the severe lung failure and death due to SARS-CoV infections. ACE2 has now also been identified as a key receptor for SARS-CoV-2 infections, and it has been proposed that inhibiting this interaction might be used in treating patients with COVID-19. However, it is not known whether human recombinant soluble ACE2 (hrsACE2) blocks growth of SARS-CoV-2. Here, we show that clinical grade hrsACE2 reduced SARS-CoV-2 recovery from Vero cells by a factor of 1,000-5,000. An equivalent mouse rsACE2 had no effect. We also show that SARS-CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2. These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections.

Keywords: COVID-19, Angiotensin converting enzyme 2, Blood vessels, Human organoids, Kidney, Severe acute respiratory syndrome coronavirus, Spike glycoproteins, Treatment


Eixarch, Herena, Calvo-Barreiro, Laura, Costa, Carme, Reverter-Vives, Gemma, Castillo, Mireia, Gil, Vanessa, Del Río, José Antonio, Montalban, Xavier, Espejo, Carmen, (2020). Inhibition of the BMP signaling pathway ameliorated established clinical symptoms of experimental autoimmune encephalomyelitis Neurotherapeutics 17, 1988–2003

Bone morphogenetic proteins (BMPs) are secreted growth factors that belong to the transforming growth factor beta superfamily. BMPs have been implicated in physiological processes, but they are also involved in many pathological conditions. Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS); however, its etiology remains elusive. Some evidence points to BMPs as important players in the pathogenesis of inflammatory and autoimmune disorders. In the present work, we studied the expression of BMP2, BMP4, BMP5, BMP6, BMP7, BMP type II receptor, and noggin in the immune system during different phases of experimental autoimmune encephalomyelitis (EAE). Major changes in the expression of BMPs took place in the initial phases of EAE. Indeed, those changes mainly affected BMP6 (whose expression was abrogated), BMP2, and BMP7 (whose expression was increased). In addition, we showed that in vivo inhibition of the BMP signaling pathway with small molecules ameliorated the already established clinical symptoms of EAE, as well as the CNS histopathological features. At the immune level, we observed an expansion of plasmacytoid dendritic cells (pDCs) in mice treated with small molecules that inhibit the BMP signaling pathway. pDCs could play an important role in promoting the expansion of antigen-specific regulatory T cells. Altogether, our data suggest a role for BMPs in early immune events that take place in myelin oligodendrocyte glycoprotein (MOG)-induced EAE. In addition, the clinical outcome of the disease was improved when the BMP signaling pathway was inhibited in mice that presented established EAE symptoms.

Keywords: Bone morphogenetic protein, DMH1, Dorsomorphin, Experimental autoimmune encephalomyelitis, Immune response, Multiple sclerosis.


Khurana, K., Guillem-Marti, J., Soldera, F., Mücklich, F., Canal, C., Ginebra, M. P., (2020). Injectable calcium phosphate foams for the delivery of Pitavastatin as osteogenic and angiogenic agent Journal of Biomedical Materials Research - Part B Applied Biomaterials 108, (3), 760-770

Apatitic bone cements have been used as a clinical bone substitutes and drug delivery vehicles for therapeutic agents in orthopedic applications. This has led to their combination with different drugs with known ability to foster bone formation. Recent studies have evaluated Simvastatin for its role in enhanced bone regeneration, but its lipophilicity hampers incorporation and release to and from the bone graft. In this study, injectable calcium phosphate foams (i-CPF) based on α-tricalcium phosphate were loaded for the first time with Pitavastatin. The stability of the drug in different conditions relevant to this study, the effect of the drug on the i-CPFs properties, the release profile, and the in vitro biological performance with regard to mineralization and vascularization were investigated. Pitavastatin did not cause any changes in neither the micro nor the macro structure of the i-CPFs, which retained their biomimetic features. PITA-loaded i-CPFs showed a dose-dependent drug release, with early stage release kinetics clearly affected by the evolving microstructure due to the setting of cement. in vitro studies showed dose-dependent enhancement of mineralization and vascularization. Our findings contribute towards the design of controlled release with low drug dosing bone grafts: i-CPFs loaded with PITA as osteogenic and angiogenic agent.

Keywords: Controlled drug release, Endothelial progenitor cells, Mineralization, Rat mesenchymal stem cells, Vascularization


Lerche, Martina, Elosegui-Artola, Alberto, Kechagia, Jenny Z., Guzmán, Camilo, Georgiadou, Maria, Andreu, Ion, Gullberg, Donald, Roca-Cusachs, Pere, Peuhu, Emilia, Ivaska, Johanna, (2020). Integrin binding dynamics modulate ligand-specific mechanosensing in mammary gland fibroblasts iScience 23, (3), 100907

The link between integrin activity regulation and cellular mechanosensing of tissue rigidity, especially on different extracellular matrix ligands, remains poorly understood. Here, we find that primary mouse mammary gland stromal fibroblasts (MSFs) are able to spread efficiently, generate high forces, and display nuclear YAP on soft collagen-coated substrates, resembling the soft mammary gland tissue. We describe that loss of the integrin inhibitor, SHARPIN, impedes MSF spreading specifically on soft type I collagen but not on fibronectin. Through quantitative experiments and computational modeling, we find that SHARPIN-deficient MSFs display faster force-induced unbinding of adhesions from collagen-coated beads. Faster unbinding, in turn, impairs force transmission in these cells, particularly, at the stiffness optimum observed for wild-type cells. Mechanistically, we link the impaired mechanotransduction of SHARPIN-deficient cells on collagen to reduced levels of collagen-binding integrin α11β1. Thus integrin activity regulation and α11β1 play a role in collagen-specific mechanosensing in MSFs.

Keywords: Biological Sciences, Cell Biology, Functional Aspects of Cell Biology


Gabasa, M., Arshakyan, M., Llorente, A., Chuliá-Peris, L., Pavelescu, I., Xaubet, A., Pereda, J., Alcaraz, J., (2020). Interleukin-1β modulation of the mechanobiology of primary human pulmonary fibroblasts: Potential implications in lung repair International Journal of Molecular Sciences 21, (22), 8417

Pro-inflammatory cytokines like interleukin-1β (IL-1β) are upregulated during early responses to tissue damage and are expected to transiently compromise the mechanical microenvironment. Fibroblasts are key regulators of tissue mechanics in the lungs and other organs. However, the effects of IL-1β on fibroblast mechanics and functions remain unclear. Here we treated human pulmonary fibroblasts from control donors with IL-1β and used Atomic Force Microscopy to unveil that IL-1β significantly reduces the stiffness of fibroblasts concomitantly with a downregulation of filamentous actin (F-actin) and alpha-smooth muscle (α-SMA). Likewise, COL1A1 mRNA was reduced, whereas that of collagenases MMP1 and MMP2 were upregulated, favoring a reduction of type-I collagen. These mechanobiology changes were functionally associated with reduced proliferation and enhanced migration upon IL-1β stimulation, which could facilitate lung repair by drawing fibroblasts to sites of tissue damage. Our observations reveal that IL-1β may reduce local tissue rigidity by acting both intracellularly and extracellularly through the downregulation of fibroblast contractility and type I collagen deposition, respectively. These IL-1β-dependent mechanical effects may enhance lung repair further by locally increasing pulmonary tissue compliance to preserve normal lung distension and function. Moreover, our results support that IL-1β provides innate anti-fibrotic protection that may be relevant during the early stages of lung repair.

Keywords: Cell mechanics, Collagen, IL-1β, MMPs, Pulmonary fibroblasts, Repair


Trueba-Santiso, A., Fernández-Verdejo, D., Marco Rius, I., Soder-Walz, J. M., Casabella, O., Vicent, T., Marco-Urrea, E., (2020). Interspecies interaction and effect of co-contaminants in an anaerobic dichloromethane-degrading culture Chemosphere 240, 124877

An anaerobic stable mixed culture dominated by bacteria belonging to the genera Dehalobacterium, Acetobacterium, Desulfovibrio, and Wolinella was used as a model to study the microbial interactions during DCM degradation. Physiological studies indicated that DCM was degraded in this mixed culture at least in a three-step process: i) fermentation of DCM to acetate and formate, ii) formate oxidation to CO2 and H2, and iii) H2/CO2 reductive acetogenesis. The 16S rRNA gene sequencing of cultures enriched with formate or H2 showed that Desulfovibrio was the dominant population followed by Acetobacterium, but sequences representing Dehalobacterium were only present in cultures amended with DCM. Nuclear magnetic resonance analyses confirmed that acetate produced from 13C-labelled DCM was marked at the methyl ([2–13C]acetate), carboxyl ([1–13C]acetate), and both ([1,2–13C]acetate) positions, which is in accordance to acetate formed by both direct DCM fermentation and H2/CO2 acetogenesis. The inhibitory effect of ten different co-contaminants frequently detected in groundwaters on DCM degradation was also investigated. Complete inhibition of DCM degradation was observed when chloroform, perfluorooctanesulfonic acid, and diuron were added at 838, 400, and 107 μM, respectively. However, the inhibited cultures recovered the DCM degradation capability when transferred to fresh medium without co-contaminants. Findings derived from this work are of significant relevance to provide a better understanding of the synergistic interactions among bacteria to accomplish DCM degradation as well as to predict the effect of co-contaminants during anaerobic DCM bioremediation in groundwater. © 2019 Elsevier Ltd

Keywords: Bioremediation, Co-contaminants, Dehalobacterium, Dichloromethane, Inhibition


Manthe, Rachel L., Loeck, Maximilian, Bhowmick, Tridib, Solomon, Melani, Muro, Silvia, (2020). Intertwined mechanisms define transport of anti-ICAM nanocarriers across the endothelium and brain delivery of a therapeutic enzyme Journal of Controlled Release 324, 181-193

The interaction of drug delivery systems with tissues is key for their application. An example is drug carriers targeted to endothelial barriers, which can be transported to intra-endothelial compartments (lysosomes) or transcellularly released at the tissue side (transcytosis). Although carrier targeting valency influences this process, the mechanism is unknown. We studied this using polymer nanocarriers (NCs) targeted to intercellular adhesion molecule-1 (ICAM-1), an endothelial-surface glycoprotein whose expression is increased in pathologies characterized by inflammation. A bell-shaped relationship was found between NC targeting valency and the rate of transcytosis, where high and low NC valencies rendered less efficient transcytosis rates than an intermediate valency formulation. In contrast, an inverted bell-shape relationship was found for NC valency and lysosomal trafficking rates. Data suggested a model where NC valency plays an opposing role in the two sub-processes involved in transcytosis: NC binding-uptake depended directly on valency and exocytosis-detachment was inversely related to this parameter. This is because the greater the avidity of the NC-receptor interaction the more efficient uptake becomes, but NC-receptor detachment post-transport is more compromised. Cleavage of the receptor at the basolateral side of endothelial cells facilitated NC transcytosis, likely by helping NC detachment post-transport. Since transcytosis encompasses both sets of events, the full process finds an optimum at the intersection of these inverted relationships, explaining the bell-shaped behavior. NCs also trafficked to lysosomes from the apical side and, additionally, from the basolateral side in the case of high valency NCs which are slower at detaching from the receptor. This explains the opposite behavior of NC valency for transcytosis vs. lysosomal transport. Anti-ICAM NCs were verified to traffic into the brain after intravenous injection in mice, and both cellular and in vivo data showed that intermediate valency NCs resulted in higher delivery of a therapeutic enzyme, acid sphingomyelinase, required for types A and B Niemann-Pick disease.

Keywords: Blood-brain barrier, ICAM-1-targeted nanocarriers, Targeting valency, Receptor-mediated transport, Lysosomal transcytosis destinations


Hamouda, I., Labay, C., Ginebra, M. P., Nicol, E., Canal, C., (2020). Investigating the atmospheric pressure plasma jet modification of a photo-crosslinkable hydrogel Polymer 192, 122308

Atmospheric pressure plasma jets (APPJ) have great potential in wound healing, bacterial disinfection and in cancer therapy. Recent studies pointed out that hydrogels can be used as screens during APPJ treatment, or even be used as reservoirs for reactive oxygen and nitrogen species generated by APPJ in liquids. Thus, novel applications are emerging for hydrogels which deserve fundamental exploration of the possible modifications undergone by the polymers in solution due to the reactivity with plasmas. Here we investigate the possible modifications occurred by APPJ treatment of an amphiphilic poly(ethylene oxide)-based triblock copolymer (tPEO) photo-crosslinkable hydrogel. While APPJ treatments lead to a certain degradation of the self-assembly of the polymeric chains at low concentrations (<2 g/L), at the higher concentrations required to form a hydrogel (>2 g/L), the polymeric chains are unaffected by APPJ and the hydrogel forming ability is kept. APPJ treatments induced a pre-crosslinking of the network with an increase of the mechanical properties of the hydrogel. Overall, the small modifications induced allow thinking of polymer solutions with hydrogel forming ability a new platform for several applications related to plasma medicine, and thus, with potential in different therapies.

Keywords: Atmospheric pressure plasma jet, Hydrogel, Photo-crosslinking, Polymer solution, Self-assembly


Arqué, Xavier, Andrés, Xavier, Mestre, Rafael, Ciraulo, Bernard, Ortega Arroyo, Jaime, Quidant, Romain, Patiño, Tania, Sánchez, Samuel, (2020). Ionic species affect the self-propulsion of urease-powered micromotors Research 2020, 2424972

Enzyme-powered motors self-propel through the catalysis of in situ bioavailable fuels, which makes them excellent candidates for biomedical applications. However, fundamental issues like their motion in biological fluids and the understanding of the propulsion mechanism are critical aspects to be tackled before a future application in biomedicine. Herein, we investigated the physicochemical effects of ionic species on the self-propulsion of urease-powered micromotors. Results showed that the presence of PBS, NaOH, NaCl, and HEPES reduced self-propulsion of urease-powered micromotors pointing towards ion-dependent mechanisms of motion. We studied the 3D motion of urease micromotors using digital holographic microscopy to rule out any motor-surface interaction as the cause of motion decay when salts are present in the media. In order to protect and minimize the negative effect of ionic species on micromotors’ performance, we coated the motors with methoxypolyethylene glycol amine (mPEG) showing higher speed compared to noncoated motors at intermediate ionic concentrations. These results provide new insights into the mechanism of urease-powered micromotors, study the effect of ionic media, and contribute with potential solutions to mitigate the reduction of mobility of enzyme-powered micromotors.


Casanellas, Ignasi, Lagunas, Anna, Vida, Yolanda, Pérez-Inestrosa, Ezequiel, Andrades, J. A., Becerra, J., Samitier, Josep, (2020). The Janus role of adhesion in chondrogenesis International Journal of Molecular Sciences 21, (15), 5269

Tackling the first stages of the chondrogenic commitment is essential to drive chondrogenic differentiation to healthy hyaline cartilage and minimize hypertrophy. During chondrogenesis, the extracellular matrix continuously evolves, adapting to the tissue adhesive requirements at each stage. Here, we take advantage of previously developed nanopatterns, in which local surface adhesiveness can be precisely tuned, to investigate its effects on prechondrogenic condensation. Fluorescence live cell imaging, immunostaining, confocal microscopy and PCR analysis are used to follow the condensation process on the nanopatterns. Cell tracking parameters, condensate morphology, cell–cell interactions, mechanotransduction and chondrogenic commitment are evaluated in response to local surface adhesiveness. Results show that only condensates on the nanopatterns of high local surface adhesiveness are stable in culture and able to enter the chondrogenic pathway, thus highlighting the importance of controlling cell–substrate adhesion in the tissue engineering strategies for cartilage repair.

Keywords: Dendrimer, Nanopatterning, RGD, Mesenchymal cell condensation, Cell–cell interactions, YAP, Chondrogenesis


Polenghi, Alice, Nieus, Thierry, Guazzi, Stefania, Gorostiza, Pau, Petrini, Enrica Maria, Barberis, Andrea, (2020). Kainate receptor activation shapes short-term synaptic plasticity by controlling receptor lateral mobility at glutamatergic synapses Cell Reports 31, (10), 107735

Kainate receptors (KARs) mediate postsynaptic currents with a key impact on neuronal excitability. However, the molecular determinants controlling KAR postsynaptic localization and stabilization are poorly understood. Here, we exploit optogenetic and single-particle tracking approaches to study the role of KAR conformational states induced by glutamate binding on KAR lateral mobility at synapses. We report that following glutamate binding, KARs are readily and reversibly trapped at glutamatergic synapses through increased interaction with the β-catenin/N-cadherin complex. We demonstrate that such activation-dependent synaptic immobilization of KARs is crucial for the modulation of short-term plasticity of glutamatergic synapses. Thus, the present study unveils the crosstalk between conformational states and lateral mobility of KARs, a mechanism regulating glutamatergic signaling, particularly in conditions of sustained synaptic activity.


Duran, Jordi, Brewer, M. Kathryn, Hervera, Arnau, Gruart, Agnès, del Rio, Jose Antonio, Delgado-García, José M., Guinovart, Joan J., (2020). Lack of astrocytic glycogen alters synaptic plasticity but not seizure susceptibility Molecular Neurobiology 57, 4657–4666

Brain glycogen is mainly stored in astrocytes. However, recent studies both in vitro and in vivo indicate that glycogen also plays important roles in neurons. By conditional deletion of glycogen synthase (GYS1), we previously developed a mouse model entirely devoid of glycogen in the central nervous system (GYS1Nestin-KO). These mice displayed altered electrophysiological properties in the hippocampus and increased susceptibility to kainate-induced seizures. To understand which of these functions are related to astrocytic glycogen, in the present study, we generated a mouse model in which glycogen synthesis is eliminated specifically in astrocytes (GYS1Gfap-KO). Electrophysiological recordings of awake behaving mice revealed alterations in input/output curves and impaired long-term potentiation, similar, but to a lesser extent, to those obtained with GYS1Nestin-KO mice. Surprisingly, GYS1Gfap-KO mice displayed no change in susceptibility to kainate-induced seizures as determined by fEPSP recordings and video monitoring. These results confirm the importance of astrocytic glycogen in synaptic plasticity.

Keywords: Astrocyte, Epilepsy, Glycogen, Long-term potentiation, Metabolism, Plasticity.


Bueno, C. Z., Apolinário, A. C., Duro-Castano, A., Poma, A., Pessoa, A., Jr., Rangel-Yagui, C. O., Battaglia, G., (2020). L-Asparaginase encapsulation into asymmetric permeable polymersomes ACS Macro Letters 9, (10), 1471-1477

This work reports, for the encapsulation of l-asparaginase, an anticancer enzyme into hybrid PMPC25-PDPA70/PEO16-PBO22 asymmetric polymersomes previously developed by our group, with loading capacities with over 800 molecules per vesicle. Enzyme-loaded polymersomes show permeability and capacity to hydrolyze l-asparagine, which is essential to cancer cells. The nanoreactors proposed in this work can be potentially used in further studies to develop novel therapeutic alternatives based on l-asparaginase.


Paoli, R., Bulwan, M., Castaño, O., Engel, E., Rodriguez-Cabello, J. C., Homs-Corbera, A., Samitier, J., (2020). Layer-by-layer modification effects on a nanopore's inner surface of polycarbonate track-etched membranes RSC Advances 10, (59), 35930-35940

The control of the morphology, as well as the physical and chemical properties, of nanopores is a key issue for many applications. Reducing pore size is important in nanopore-based sensing applications as it helps to increase sensitivity. Changes of other physical properties such as surface net charge can also modify transport selectivity of the pores. We have studied how polyelectrolyte layer-by-layer (LBL) surface modification can be used to change the characteristics of nanoporous membranes. Studies were performed with a custom made three-dimensional multilayer microfluidic device able to fit membrane samples. The device allowed us to efficiently control LBL film deposition over blank low-cost commercially available polycarbonate track-etched (PCTE) membranes. We have demonstrated pore diameter reduction and deposition of the layers inside the pores through confocal and SEM images. Posterior impedance measurement studies served to evaluate experimentally the effect of the LBL deposition on the net inner nanopore surface charge and diameter. Measurements using direct current (DC) and alternative current (AC) voltages have demonstrated contrasted behaviors depending on the number and parity of deposited opposite charge layers. PCTE membranes are originally negatively charged and results evidenced higher impedance increases for paired charge LBL depositions. Impedance decreased when an unpaired positive layer was added. These results showed a different influence on the overall ion motility due to the effect of different surface charges. Results have been fit into a model that suggested a strong dependence of nanopores' impedance module to surface charge on conductive buffers, such as Phosphate Buffer Saline (PBS), even on relatively large nanopores. In AC significant differences between paired and unpaired charged LBL depositions tended to disappear as the total number of layers increased.


Hortelão , Ana C., García-Jimeno, Sonia, Cano-Sarabia, Mary, Patiño, Tania, Maspoch, Daniel, Sánchez, Samuel, (2020). LipoBots: Using liposomal vesicles as protective shell of urease-based nanomotors Advanced Functional Materials 30, (42), 2002767

Developing self-powered nanomotors made of biocompatible and functional components is of paramount importance in future biomedical applications. Herein, the functional features of LipoBots (LBs) composed of a liposomal carrier containing urease enzymes for propulsion, including their protective properties against acidic conditions and their on-demand triggered activation, are reported. Given the functional nature of liposomes, enzymes can be either encapsulated or coated on the surface of the vesicles. The influence of the location of urease on motion dynamics is first studied, finding that the surface-urease LBs undergo self-propulsion whereas the encapsulated-urease LBs do not. However, adding a percolating agent present in the bile salts to the encapsulated-urease LBs triggers active motion. Moreover, it is found that when both types of nanomotors are exposed to a medium of similar pH found in the stomach, the surface-urease LBs lose activity and motion capabilities, while the encapsulated-urease LBs retain activity and mobility. The results for the protection enzyme activity through encapsulation within liposomes and in situ triggering of the motion of LBs upon exposure to bile salts may open new avenues for the use of liposome-based nanomotors in drug delivery, for example, in the gastrointestinal tract, where bile salts are naturally present in the intestine.


Trebicka, J., Sundaram, V., Moreau, R., Jalan, R., Arroyo, V., (2020). Liver transplantation for acute-on-chronic liver failure: Science or fiction? Liver Transplantation 26, (7), 906-915

Acute clinical deterioration of a patient with chronic liver disease remains a decisive time point both in terms of medical management and prognosis. This condition, also known as acute decompensation (AD), is an important event determining a crossroad in the trajectory of patients. A significant number of patients with AD may develop hepatic or extrahepatic organ failure, or both, which defines the syndrome acute-on-chronic liver failure (ACLF), and ACLF is associated with a high morbidity and short-term mortality. ACLF may occur at any phase during chronic liver disease and is pathogenetically defined by systemic inflammation and immune metabolic dysfunction. When organ failures develop in the presence of cirrhosis, especially extrahepatic organ failures, liver transplantation (LT) may be the only curative treatment. This review outlines the evidence supporting LT in ACLF patients, highlighting the role of timing, bridging to LT, and possible indicators of futility. Importantly, prospective studies on ACLF and transplantation are urgently needed.


Garmendia, O., Rodríguez-Lazaro, M. A., Otero, J., Phan, P., Stoyanova, A., Dinh-Xuan, A. T., Gozal, D., Navajas, D., Montserrat, J. M., Farré, R., (2020). Low-cost, easy-to-build noninvasive pressure support ventilator for under-resourced regions: Open source hardware description, performance and feasibility testing European Respiratory Journal 55, (6), 2000846

Aim Current pricing of commercial mechanical ventilators in low-/middle-income countries (LMICs) markedly restricts their availability, and consequently a considerable number of patients with acute/chronic respiratory failure cannot be adequately treated. Our aim was to design and test an affordable and easy-to-build noninvasive bilevel pressure ventilator to allow a reduction in the serious shortage of ventilators in LMICs. Methods The ventilator was built using off-the-shelf materials available via e-commerce and was based on a high-pressure blower, two pressure transducers and an Arduino Nano controller with a digital display (total retail cost <75 USD), with construction details provided open source for free replication. The ventilator was evaluated, and compared with a commercially available device (Lumis 150 ventilator; Resmed, San Diego, CA, USA): 1) in the bench setting using an actively breathing patient simulator mimicking a range of obstructive/restrictive diseases; and b) in 12 healthy volunteers wearing high airway resistance and thoracic/abdominal bands to mimic obstructive/restrictive patients. Results The designed ventilator provided inspiratory/expiratory pressures up to 20/10 cmH2O, respectively, with no faulty triggering or cycling; both in the bench test and in volunteers. The breathing difficulty score rated (1–10 scale) by the loaded breathing subjects was significantly (p<0.005) decreased from 5.45±1.68 without support to 2.83±1.66 when using the prototype ventilator, which showed no difference with the commercial device (2.80±1.48; p=1.000). Conclusion The low-cost, easy-to-build noninvasive ventilator performs similarly to a high-quality commercial device, with its open-source hardware description, which will allow for free replication and use in LMICs, facilitating application of this life-saving therapy to patients who otherwise could not be treated.


Torres, M., Martinez-Garcia, M. A., Campos-Rodriguez, F., Gozal, D., Montserrat, J. M., Navajas, D., Farré, R., Almendros, I., (2020). Lung cancer aggressiveness in an intermittent hypoxia murine model of postmenopausal sleep apnea Menopause 27, (6), 706-713

Objective: Intermittent hypoxia (IH)—a hallmark of obstructive sleep apnea (OSA)—enhances lung cancer progression in mice via altered host immune responses that are also age and sex-dependent. However, the interactions of menopause with IH on tumor malignant properties remain unexplored. Here, we aimed to investigate lung cancer outcomes in the context of ovariectomy (OVX)-induced menopause in a murine model of OSA. Methods: Thirty-four female mice (C57BL/6, 12-week-old) were subjected to bilateral OVX or to Sham intervention. Six months after surgery, mice were pre-exposed to either IH or room air (RA) for 2 weeks. Then, 105 lung carcinoma (LLC1) cells were injected subcutaneously in the left flank, with IH or RA exposures continued for 4 weeks. Tumor weight, tumor invasion, and spontaneous lung metastases were assessed. Tumor-associated macrophages (TAMs) were isolated and subjected to flow cytometry polarity evaluation along with assessment of TAMs modulation of LLC1 proliferation in vitro. To determine the effect of IH and OVX on each experimental variable, a two-way analysis of variance was performed. Results: IH and OVX promoted a similar increase in tumor growth (2-fold; P = 0.05 and 1.74-fold; P < 0.05, respectively), and OVX-IH further increased it. Regarding lung metastasis, the concurrence of OVX in mice exposed to IH enhanced the number of metastases (23.7 ± 8.0) in comparison to those without OVX (7.9 ± 2.8; P < 0.05). The pro-tumoral phenotype of TAMS, assessed as M2/M1 ratio, was increased in OVX (0.06 ± 0.01; P < 0.01) and IH (0.06 ± 0.01; P < 0.01) compared with sham/RA conditions (0.14 ± 0.03). The co-culture of TAMS with naive LLC1 cells enhanced their proliferation only under IH. Conclusion: In female mice, both the IH that is characteristically present in OSA and OVX as a menopause model emerge as independent contributors that promote lung cancer aggressiveness and seemingly operate through alterations in the host immune response.

Keywords: Animal models, Cancer progression, Intermittent hypoxia, Menopause, Obstructive sleep apnea, Ovariectomy


Mas, S., Torro, A., Fernández, L., Bec, N., Gongora, C., Larroque, C., Martineau, P., de Juan, A., Marco, S., (2020). MALDI imaging mass spectrometry and chemometric tools to discriminate highly similar colorectal cancer tissues Talanta 208, 120455

Intratumour heterogeneity due to cancer cell clonal evolution and microenvironment composition and tumor differences due to genetic variations between patients suffering of the same cancer pathology play a crucial role in patient response to therapies. This study is oriented to show that matrix-assisted laser-desorption ionization-Mass spectrometry imaging (MALDI-MSI), combined with an advanced multivariate data processing pipeline can be used to discriminate subtle variations between highly similar colorectal tumors. To this aim, experimental tumors reproducing the emergence of drug-resistant clones were generated in athymic mice using subcutaneous injection of different mixes of two isogenic cell lines, the irinotecan-resistant HCT116-SN50 (R) and its sibling human colon adenocarcinoma sensitive cell line HCT116 (S). Because irinotecan-resistant and irinotecan-sensitive are derived from the same original parental HCT116 cell line, their genetic characteristics and molecular compositions are closely related. The multivariate data processing pipeline proposed relies on three steps: (a) multiset multivariate curve resolution (MCR) to separate biological contributions from background; (b) multiset K-means segmentation using MCR scores of the biological contributions to separate between tumor and necrotic parts of the tissues; and (c) partial-least squares discriminant analysis (PLS-DA) applied to tumor pixel spectra to discriminate between R and S tumor populations. High levels of correct classification rates (0.85), sensitivity (0.92) and specificity (0.77) for the PLS-DA classification model were obtained. If previously labelled tissue is available, the multistep modeling strategy proposed constitutes a good approach for the identification and characterization of highly similar phenotypic tumor subpopulations that could be potentially applicable to any kind of cancer tissue that exhibits substantial heterogeneity. © 2019 Elsevier B.V.

Keywords: Chemometrics, Colorectal cancer, MALDI imaging, Multivariate analysis, Tumor heterogeneity


Millán, Rubén, Checa, Marti, Fumagalli, Laura, Gomila, Gabriel, (2020). Mapping the capacitance of self-assembled monolayers at metal/electrolyte interfaces at the nanoscale by In-liquid scanning dielectric microscopy Nanoscale 12, (40), 20658-20668

Organic self-assembled monolayers (SAMs) at metal/electrolyte interfaces have been thoroughly investigated both from fundamental and applied points of views. A relevant figure of merit of metal/SAM/electrolyte interfaces is the specific capacitance, which determines the charge that can be accumulated at the metal electrode. Here, we show that the specific capacitance of non-uniform alkanethiol SAMs at gold/electrolyte interfaces can be quantitatively measured and mapped at the nanoscale with in-liquid Scanning Dielectric Microscopy in force detection mode. We show that sub-100 nm spatial resolution in ultrathin (< 1 nm) SAMs can be achieved, largely improving the performance of current sensing characterization techniques. Present results open the access to study the dielectric properties of metal/SAM/electrolyte interfaces at scales that have remained unexplored until now.


Gómez-González, M., Latorre, E., Arroyo, M., Trepat, X., (2020). Measuring mechanical stress in living tissues Nature Reviews Physics 2, (6), 300-317

Living tissues are active, multifunctional materials capable of generating, sensing, withstanding and responding to mechanical stress. These capabilities enable tissues to adopt complex shapes during development, to sustain those shapes during homeostasis and to restore them during healing and regeneration. Abnormal stress is associated with a broad range of pathological conditions, including developmental defects, inflammatory diseases, tumour growth and metastasis. A number of techniques are available to measure mechanical stress in living tissues at cellular and subcellular resolution. 2D techniques that map stress in cultured cell monolayers provide the highest resolution and accessibility, and include 2D traction force microscopy, micropillar arrays, monolayer stress microscopy and monolayer stretching between flexible cantilevers. Mapping stresses in tissues cultured in 3D can be achieved using 3D traction force microscopy and the microbulge test. Techniques for measuring stress in vivo include servo-null methods for measuring luminal pressure, deformable inclusions, Förster resonance energy transfer tension sensors, laser ablation and computational methods for force inference. Although these techniques are far from becoming everyday tools in biomedical laboratories, their rapid development is fostering key advances in our understanding of the role of mechanics in morphogenesis, homeostasis and disease.


Riccobelli, D., Noselli, G., Arroyo, M., DeSimone, A., (2020). Mechanics of axisymmetric sheets of interlocking and slidable rods Journal of the Mechanics and Physics of Solids 141, 103969

In this work, we study the mechanics of metamaterial sheets inspired by the pellicle of Euglenids. They are composed of interlocking elastic rods which can freely slide along their edges. We characterize the kinematics and the mechanics of these structures using the special Cosserat theory of rods and by assuming axisymmetric deformations of the tubular assembly. Through an asymptotic expansion, we investigate both structures that comprise a discrete number of rods and the limit case of a sheet composed by infinitely many rods. We apply our theoretical framework to investigate the stability of these structures in the presence of an axial load. Through a linear analysis, we compute the critical buckling force for both the discrete and the continuous case. For the latter, we also perform a numerical post-buckling analysis, studying the non-linear evolution of the bifurcation through finite elements simulations.

Keywords: Biomimetic structures, Elastic structures, Helical rods, Mechanical instabilities, Metamaterials, Post-buckling analysis


Comelles, Jordi, Fernández-Majada, Vanesa, Berlanga-Navarro, Nuria, Acevedo, Verónica, Paszkowska, Karolina, Martínez, Elena, (2020). Microfabrication of poly(acrylamide) hydrogels with independently controlled topography and stiffness Biofabrication 12, (2), 025023

The stiffness and topography of a cell's extracellular matrix are physical cues that play a key role in regulating processes that determine cellular fate and function. While substrate stiffness can dictate cell differentiation lineage, migration, and self-organization, topographical features can change the cell's differentiation profile or migration ability. Although both physical cues are present and intrinsic to the native tissues in vivo, in vitro studies have been hampered by the lack of technological set-ups that would be compatible with cell culture and characterization. In vitro studies therefore either focused on screening stiffness effects in cells cultured on flat substrates or on determining topography effects in cells cultured onto hard materials. Here, we present a reliable, microfabrication method to obtain well defined topographical structures of micrometer size (5-10 µm) on soft polyacrylamide hydrogels with tunable mechanical stiffness (3-145 kPa) that closely mimic the in vivo situation. Topographically microstructured polyacrylamide hydrogels are polymerized by capillary force lithography using flexible materials as molds. The topographical microstructures are resistant to swelling, can be conformally functionalized by extracellular matrix proteins and sustain the growth of cell lines (fibroblasts and myoblasts) and primary cells (mouse intestinal epithelial cells). Our method can independently control stiffness and topography, which allows to individually assess the contribution of each physical cue to cell response or to explore potential synergistic effects. We anticipate that our fabrication method will be of great utility in tissue engineering and biophysics, especially for applications where the use of complex in vivo-like environments is of paramount importance.


Rivas, L., Dulay, S., Miserere, S., Pla, L., Marin, S. B., Parra, J., Eixarch, E., Gratacós, E., Illa, M., Mir, M., Samitier, J., (2020). Micro-needle implantable electrochemical oxygen sensor: ex-vivo and in-vivo studies Biosensors and Bioelectronics 153, 112028

Oxygen is vital for energy metabolism in mammals and the variability of the concentration is considered a clinical alert for a wide range of metabolic malfunctions in medicine. In this article, we describe the development and application of a micro-needle implantable platinum-based electrochemical sensor for measuring partial pressure of oxygen in intramuscular tissue (in-vivo) and vascular blood (ex-vivo). The Pt-Nafion® sensor was characterized morphological and electrochemically showing a higher sensitivity of −2.496 nA/mmHg (−1.495 nA/μM) when comparing with its bare counterpart. Our sensor was able to discriminate states with different oxygen partial pressures (pO2) for ex-vivo (blood) following the same trend of the commercial gas analyzer used as standard. For in-vivo (intramuscular) experiments, since there is not a gold standard for measuring pO2 in tissue, it was not possible to correlate the obtained currents with the pO2 in tissue. However, our sensor was able to detect clear statistical differences of O2 between hyperoxia and hypoxia states in tissue.

Keywords: Hypoxia, Implantable sensor, In-vivo test, Ischemia, Nafion, Oxygen sensor


Freire, Ismael T., Moulin-Frier, Clement, Sanchez-Fibla, Marti, Arsiwalla, Xerxes D., Verschure, P., (2020). Modeling the formation of social conventions from embodied real-time interactions PLoS ONE PLOS ONE , 15, (6), e0234434

What is the role of real-time control and learning in the formation of social conventions? To answer this question, we propose a computational model that matches human behavioral data in a social decision-making game that was analyzed both in discrete-time and continuous-time setups. Furthermore, unlike previous approaches, our model takes into account the role of sensorimotor control loops in embodied decision-making scenarios. For this purpose, we introduce the Control-based Reinforcement Learning (CRL) model. CRL is grounded in the Distributed Adaptive Control (DAC) theory of mind and brain, where low-level sensorimotor control is modulated through perceptual and behavioral learning in a layered structure. CRL follows these principles by implementing a feedback control loop handling the agent’s reactive behaviors (pre-wired reflexes), along with an Adaptive Layer that uses reinforcement learning to maximize long-term reward. We test our model in a multi-agent game-theoretic task in which coordination must be achieved to find an optimal solution. We show that CRL is able to reach human-level performance on standard game-theoretic metrics such as efficiency in acquiring rewards and fairness in reward distribution.


Bertran, O., Saldías, C., Díaz, D. D., Alemán, C., (2020). Molecular dynamics simulations on self-healing behavior of ionene polymer-based nanostructured hydrogels Polymer 211, 123072

The microscopic mechanism accounting for the self-healing attribute of aromatic ionene-forming hydrogels derived from 1,4-diazabicyclo [2.2.2]octane (DABCO) and N,N’-(x-phenylene)dibenzamide (x = ortho-/meta-/para-) is unknown. Interestingly, the self-healing property of such DABCO-containing hydrogels is largely dependent on the polymer topology, the ortho ionene being the only self-healable without adding oppositely charged species. In this work, Molecular Dynamics (MD) simulations have been conducted to evaluate the influence of the topology on ionene···ionene and ionene··water interactions, as well as their effect on the self-healing behavior. For this purpose, destabilized and structurally damaged models were produced for ionene hydrogels with ortho, meta and para topologies and used as starting geometries for simulations. These models were allowed to evolve without any restriction during MD production runs and, subsequently, the temporal evolution of ionene···ionene and water···ionene interactions was examined. Analysis of the results indicated that the ortho-isomer rapidly forms unique interactions that are not detected for other two isomers. Thus, in addition to the interactions also identified for the meta-and para-ionenes, the ortho-isomer exhibits the formation of strong intermolecular three-centered (N–)H⋯O (=C)⋯H (–N) hydrogen bonds, intramolecular planar sandwich π-π stacking interactions and Cl−···N+ electrostatic interactions. Furthermore, the amount of intermolecular π-π stacking interactions and the strength of water···polymer interaction are also influenced by the topology, favoring the stabilization of the ortho-ionene reconstituted hydrogels. Overall, the arrangement of the functional groups in the ortho topology favors the formation of more types of ionene···ionene interactions, as well as stronger interactions, than in the meta and para topologies.

Keywords: DABCO, Econstituted hydrogels, Molecular dynamics, Polyelectrolyte hydrogels, Self-healing mechanism


Moya-Andérico, Laura, Admella, Joana, Fernandes, Rodrigo, Torrents, Eduard, (2020). Monitoring Gene Expression during a Galleria mellonella Bacterial Infection Microorganisms 8, (11), 1798

Galleria mellonella larvae are an alternative in vivo model that has been extensively used to study the virulence and pathogenicity of different bacteria due to its practicality and lack of ethical constraints. However, the larvae possess intrinsic autofluorescence that obstructs the use of fluorescent proteins to study bacterial infections, hence better methodologies are needed. Here, we report the construction of a promoter probe vector with bioluminescence expression as well as the optimization of a total bacterial RNA extraction protocol to enhance the monitoring of in vivo infections. By employing the vector to construct different gene promoter fusions, variable gene expression levels were efficiently measured in G. mellonella larvae at various time points during the course of infection and without much manipulation of the larvae. Additionally, our optimized RNA extraction protocol facilitates the study of transcriptional gene levels during an in vivo infection. The proposed methodologies will greatly benefit bacterial infection studies as they can contribute to a better understanding of the in vivo infection processes and pathogen–mammalian host interactions.

Keywords: Galleria mellonella, P. aeruginosa, Hemolymph, Hemocytes, Bioluminescence, Promoter probe vector, Optimized RNA extraction, Ribonucleotide reductases


Grechuta, Klaudia, Rubio Ballester, Belén, Espín Munné, Rosa, Usabiaga Bernal, Teresa, Molina Hervás, Begoña, Mohr, Bettina, Pulvermüller, Friedemann, San Segundo, Rosa Maria, Verschure, P., (2020). Multisensory cueing facilitates naming in aphasia Journal of NeuroEngineering and Rehabilitation 17, (1), 122

Impaired naming is a ubiquitous symptom in all types of aphasia, which often adversely impacts independence, quality of life, and recovery of affected individuals. Previous research has demonstrated that naming can be facilitated by phonological and semantic cueing strategies that are largely incorporated into the treatment of anomic disturbances. Beneficial effects of cueing, whereby naming becomes faster and more accurate, are often attributed to the priming mechanisms occurring within the distributed language network.


Bach-Griera, Marc, Campo-Pérez, Víctor, Barbosa, Sandra, Traserra, Sara, Guallar-Garrido, Sandra, Moya-Andérico, Laura, Herrero-Abadía, Paula, Luquin, Marina, Rabanal, Rosa Maria, Torrents, Eduard, Julián, Esther, (2020). Mycolicibacterium brumae is a safe and non-toxic immunomodulatory agent for cancer treatment Vaccines 8, (2), 198

Intravesical Mycobacterium bovis Bacillus Calmette–Guérin (BCG) immunotherapy remains the gold-standard treatment for non-muscle-invasive bladder cancer patients, even though half of the patients develop adverse events to this therapy. On exploring BCG-alternative therapies, Mycolicibacterium brumae, a nontuberculous mycobacterium, has shown outstanding anti-tumor and immunomodulatory capabilities. As no infections due to M. brumae in humans, animals, or plants have been described, the safety and/or toxicity of this mycobacterium have not been previously addressed. In the present study, an analysis was made of M. brumae- and BCG-intravenously-infected severe combined immunodeficient (SCID) mice, M. brumae-intravesically-treated BALB/c mice, and intrahemacoelic-infected-Galleria mellonella larvae. Organs from infected mice and the hemolymph from larvae were processed to count bacterial burden. Blood samples from mice were also taken, and a wide range of hematological and biochemical parameters were analyzed. Finally, histopathological alterations in mouse tissues were evaluated. Our results demonstrate the safety and non-toxic profile of M. brumae. Differences were observed in the biochemical, hematological and histopathological analysis between M. brumae and BCG-infected mice, as well as survival curves rates and colony forming units (CFU) counts in both animal models. M. brumae constitutes a safe therapeutic biological agent, overcoming the safety and toxicity disadvantages presented by BCG in both mice and G. mellonella animal models.

Keywords: Bladder cancer, Nontuberculous mycobacteria, BCG, Safety, Galleria mellonella, Mice


Mestre, R., Cadefau, N., Hortelão, A. C., Grzelak, J., Gich, M., Roig, A., Sánchez, S., (2020). Nanorods based on mesoporous silica containing iron oxide nanoparticles as catalytic nanomotors: Study of motion dynamics ChemNanoMat 7, (2), 134-140

Self-propelled particles and, in particular, those based on mesoporous silica, have raised considerable interest due to their potential applications in the environmental and biomedical fields thanks to their biocompatibility, tunable surface chemistry and large porosity. Although spherical particles have been widely used to fabricate nano- and micromotors, not much attention has been paid to other geometries, such as nanorods. Here, we report the fabrication of self-propelled mesoporous silica nanorods (MSNRs) that move by the catalytic decomposition of hydrogen peroxide by a sputtered Pt layer, Fe2O3 nanoparticles grown within the mesopores, or the synergistic combination of both. We show that motion can occur in two distinct sub-populations characterized by two different motion dynamics, namely enhanced diffusion or directional propulsion, especially when both catalysts are used. These results open up the possibility of using MSNRs as chassis for the fabrication of self-propelled particles for the environmental or biomedical fields

Keywords: Mesoporous silica, Nanomotors, Nanorods, Porous materials, Self-propulsion


Kyndiah, Adrica, Checa, Martí, Leonardi, Francesca, Millan-Solsona, Ruben, Di Muzio, Martina, Tanwar, Shubham, Fumagalli, Laura, Mas-Torrent, Marta, Gomila, Gabriel, (2020). Nanoscale mapping of the conductivity and interfacial capacitance of an electrolyte-gated organic field-effect transistor under operation Advanced Functional Materials , (), 2008032

Probing nanoscale electrical properties of organic semiconducting materials at the interface with an electrolyte solution under externally applied voltages is key in the field of organic bioelectronics. It is demonstrated that the conductivity and interfacial capacitance of the active channel of an electrolyte-gated organic field‐effect transistor (EGOFET) under operation can be probed at the nanoscale using scanning dielectric microscopy in force detection mode in liquid environment. Local electrostatic force versus gate voltage transfer characteristics are obtained on the device and correlated with the global current–voltage transfer characteristics of the EGOFET. Nanoscale maps of the conductivity of the semiconducting channel show the dependence of the channel conductivity on the gate voltage and its variation along the channel due to the space charge limited conduction. The maps reveal very small electrical heterogeneities, which correspond to local interfacial capacitance variations due to an ultrathin non-uniform insulating layer resulting from a phase separation in the organic semiconducting blend. Present results offer insights into the transduction mechanism at the organic semiconductor/electrolyte interfaces at scales down to ≈100 nm, which can bring substantial optimization of organic electronic devices for bioelectronic applications such as electrical recording on excitable cells or label-free biosensing.


Sala-Jarque, Julia, Mesquida-Veny, Francina, Badiola-Mateos, Maider, Samitier, Josep, Hervera, Arnau, del Río, José Antonio, (2020). Neuromuscular activity induces paracrine signaling and triggers axonal regrowth after injury in microfluidic lab-on-chip devices Cells 9, (2), 302

Peripheral nerve injuries, including motor neuron axonal injury, often lead to functional impairments. Current therapies are mostly limited to surgical intervention after lesion, yet these interventions have limited success in restoring functionality. Current activity-based therapies after axonal injuries are based on trial-error approaches in which the details of the underlying cellular and molecular processes are largely unknown. Here we show the effects of the modulation of both neuronal and muscular activity with optogenetic approaches to assess the regenerative capacity of cultured motor neuron (MN) after lesion in a compartmentalized microfluidic-assisted axotomy device. With increased neuronal activity, we observed an increase in the ratio of regrowing axons after injury in our peripheral-injury model. Moreover, increasing muscular activity induces the liberation of leukemia inhibitory factor and glial cell line-derived neurotrophic factor in a paracrine fashion that in turn triggers axonal regrowth of lesioned MN in our 3D hydrogel cultures. The relevance of our findings as well as the novel approaches used in this study could be useful not only after axotomy events but also in diseases affecting MN survival.

Keywords: Neuromuscular junction, Microfluidics, Axotomy, Paracrine signaling


Alcon, Clara, Manzano-Muñoz, Albert, Montero, Joan, (2020). A new CDK9 inhibitor on the block to treat hematologic malignancies Clinical Cancer Research 26, (4), 761-763

CDK9-specific inhibition with AZD4573 impairs cancer-promoting gene expression such as MCL-1 and has been proven effective in hematologic malignancies preclinical models. This new clinical candidate should be further explored in the clinic not only as a monotherapy but also in combination with BH3 mimetics to prevent treatment resistance.


Diaz-Lucena, Daniela, Escaramis, G., Villar-Piqué, Anna, Hermann, Peter, Schmitz, Matthias, Varges, Daniela, Santana, Isabel, del Rio, José Antonio, Martí, E., Ferrer, Isidre, Baldeiras, I., Zerr, Inga, Llorens, Franc, (2020). A new tetra-plex fluorimetric assay for the quantification of cerebrospinal fluid β-amyloid42, total-tau, phospho-tau and α-synuclein in the differential diagnosis of neurodegenerative dementia Journal of Neurology 267, (9), 2567-2581

Background: Differential diagnosis of neurodegenerative dementia is currently supported by biomarkers including cerebrospinal fluid (CSF) tests. Among them, CSF total-tau (t-tau), phosphorylated tau (p-tau) and β-amyloid42 (Aβ42) are considered core biomarkers of neurodegeneration. In the present work, we hypothesize that simultaneous assessment of these biomarkers together with CSF α-synuclein (α-syn) will significantly improve the differential diagnostic of Alzheimer's disease and other dementias. To that aim, we characterized the analytical and clinical performance of a new tetra-plex immunoassay that simultaneously quantifies CSF Aβ42, t-tau, p-tau and α-syn in the differential diagnosis of neurodegenerative dementia. Methods: Biomarkers' concentrations were measured in neurological controls (n = 38), Alzheimer's disease (n = 35), Creutzfeldt-Jakob disease (n = 37), vascular dementia (n = 28), dementia with Lewy bodies/Parkinson's disease dementia (n = 27) and frontotemporal dementia (n = 34) using the new tetra-plex assay and established single-plex assays. Biomarker's performance was evaluated and diagnostic accuracy in the discrimination of diagnostic groups was determined using partial least squares discriminant analysis. Results: The tetra-plex assay presented accuracies similar to individual single-plex assays with acceptable analytical performance. Significant correlations were observed between tetra-plex and single-plex assays. Using partial least squares discriminant analysis, Alzheimer's disease and Creutzfeldt-Jakob disease were well differentiated, reaching high accuracies in the discrimination from the rest of diagnostic groups. Conclusions: The new tetra-plex assay coupled with multivariate analytical approaches becomes a valuable asset for the differential diagnosis of neurodegenerative dementia and related applications.

Keywords: Neurodegenerative dementia, Cerebrospinal fluid, Biomarker, Amyloid beta, Total-tau, Phospho-tau, α-Synuclein, Multiplexing


Velasco, Ferran, Fernandez-Costa, Juan M., Neves, Luisa, Ramon-Azcon, Javier, (2020). New volumetric CNT-doped Gelatin-Cellulose scaffold for skeletal muscle tissue engineering Nanoscale Advances 2, (7), 2885-2896

Currently, the fabrication of scaffolds for engineered skeletal muscle tissue is unable to reach the millimeter size. The main drawbacks are the poor nutrients diffusion, lack of internal structure to align precursor cells as well as poor mechanical and electric properties. Herein, we present a combination of gelatin-carboxymethyl cellulose materials polymerised by a cryogelation process that allowed us to reach scaffold fabrication up to millimeters size and solve the main problems related with large size muscle tissue constructs. 1) By incorporating carbon nanotubes (CNT) we can improve the electrical properties of the scaffold, thereby enhancing tissue maturation when applying an electric pulse stimulus (EPS). 2) We have fabricated an anisotropic internal three-dimensional microarchitecture pore distribution with high aligned morphology to enhance cells alignment, cell fusion and myotubes formation. With this set up, we were able to generate a fully functional skeletal muscle tissue using a combination of EPS and our doped-biocomposite scaffold and obtain a mature tissue in a millimeter scale. We also characterized pore distribution, swelling, stiffness and conductivity of the scaffold. Moreover, we proved that the cells are viable and able to fuse in a three-dimensional (3D) functional myotubes throughout the scaffold. In conclusion, we fabricate a biocompatible and customizable scaffold for 3D cell culture suitable for a wide range of application such as organ-on-a-chip, drug screening, transplantation and disease modelling.


De Matteis, Valeria, Rizzello, Loris, (2020). Noble metals and soft bio-inspired nanoparticles in retinal diseases treatment: A perspective Cells 9, (3), 679

We are witnessing an exponential increase in the use of different nanomaterials in a plethora of biomedical fields. We are all aware of how nanoparticles (NPs) have influenced and revolutionized the way we supply drugs or how to use them as therapeutic agents thanks to their tunable physico-chemical properties. However, there is still a niche of applications where NP have not yet been widely explored. This is the field of ocular delivery and NP-based therapy, which characterizes the topic of the current review. In particular, many efforts are being made to develop nanosystems capable of reaching deeper sections of the eye such as the retina. Particular attention will be given here to noble metal (gold and silver), and to polymeric nanoparticles, systems consisting of lipid bilayers such as liposomes or vesicles based on nonionic surfactant. We will report here the most relevant literature on the use of different types of NPs for an efficient delivery of drugs and bio-macromolecules to the eyes or as active therapeutic tools.

Keywords: Bio-inspired NPs, Drug delivery, Noble metals NPs, Retinal diseases


Guixé-Muntet, Sergi, Ortega-Ribera, Martí, Wang, Cong, Selicean, Sonia, Andreu, Ion, Kechagia, Jenny Z., Fondevila, Constantino, Roca-Cusachs, Pere, Dufour, Jean-François, Bosch, Jaime, Berzigotti, Annalisa, Gracia-Sancho, Jordi, (2020). Nuclear deformation mediates liver cell mechanosensing in cirrhosis JHEP Reports 2, (5), 100145

Background & AimsLiver stiffness is increased in advanced chronic liver disease (ACLD) and accurately predicts prognosis in this population. Recent data suggest that extracellular matrix stiffness per se may modulate the phenotype of liver cells. We aimed at investigating the effect of matrix stiffness on the phenotype of liver cells of rats with cirrhosis, assessing its influence on their response to antifibrotic strategies and evaluating associated molecular mechanisms.

Keywords: Chronic liver disease, Hepatocyte, HSC, LSEC, Stiffness


Brugada-Vilà , P., Cascante, A., Lázaro, M. Á., Castells-Sala, C., Fornaguera, C., Rovira-Rigau, M., Albertazzi, L., Borros, S., Fillat, C., (2020). Oligopeptide-modified poly(beta-amino ester)s-coated AdNuPARmE1A: Boosting the efficacy of intravenously administered therapeutic adenoviruses Theranostics 10, (6), 2744-2758

Oncolytic adenoviruses are used as agents for the treatment of cancer. However, their potential is limited due to the high seroprevalence of anti-adenovirus neutralizing antibodies (nAbs) within the population and the rapid liver sequestration when systemically administered. To overcome these challenges, we explored using nanoparticle formulation to boost the efficacy of systemic oncolytic adenovirus administration. Methods: Adenovirus were conjugated with PEGylated oligopeptide-modified poly(β-amino ester)s (OM-pBAEs). The resulting coated viral formulation was characterized in terms of surface charge, size, aggregation state and morphology and tested for anti-adenovirus nAbs evasion and activity in cancer cells. In vivo pharmacokinetics, biodistribution, tumor targeting, and immunogenicity studies were performed. The antitumor efficacy of the oncolytic adenovirus AdNuPARmE1A coated with OM-pBAEs (SAG101) in the presence of nAbs was evaluated in pancreatic ductal adenocarcinoma (PDAC) mouse models. Toxicity of the coated formulation was analyzed in vivo in immunocompetent mice. Results: OM-pBAEs conjugated to adenovirus and generated discrete nanoparticles with a neutral charge and an optimal size. The polymeric coating with the reporter AdGFPLuc (CPEG) showed enhanced transduction and evasion of antibody neutralization in vitro. Moreover, systemic intravenous administration of the formulation showed improved blood circulation and reduced liver sequestration, substantially avoiding activation of nAb production. OM-pBAEs coating of the oncolytic adenovirus AdNuPARmE1A (SAG101) improved its oncolytic activity in vitro and enhanced antitumor efficacy in PDAC mouse models. The coated formulation protected virions from neutralization by nAbs, as antitumor efficacy was preserved in their presence but was completely lost in mice that received the non-formulated AdNuPARmE1A. Finally, coated-AdNuPARmE1A showed reduced toxicity when high doses of the formulation were administered. Conclusions: The developed technology represents a promising improvement for future clinical cancer therapy using oncolytic adenoviruses.

Keywords: Oncolytic adenovirus, Pancreatic cancer, Poly(β-amino ester)s, Polymer-coated viral vectors, Systemic delivery


Tian, Xiaohe, Angioletti-Uberti, Stefano, Battaglia, Giuseppe, (2020). On the design of precision nanomedicines Science Advances 6, (4), eaat0919

The blood-brain barrier is made of polarized brain endothelial cells (BECs) phenotypically conditioned by the central nervous system (CNS). Although transport across BECs is of paramount importance for nutrient uptake as well as ridding the brain of waste products, the intracellular sorting mechanisms that regulate successful receptor-mediated transcytosis in BECs remain to be elucidated. Here, we used a synthetic multivalent system with tunable avidity to the low-density lipoprotein receptor–related protein 1 (LRP1) to investigate the mechanisms of transport across BECs. We used a combination of conventional and super-resolution microscopy, both in vivo and in vitro, accompanied with biophysical modeling of transport kinetics and membrane-bound interactions to elucidate the role of membrane-sculpting protein syndapin-2 on fast transport via tubule formation. We show that high-avidity cargo biases the LRP1 toward internalization associated with fast degradation, while mid-avidity augments the formation of syndapin-2 tubular carriers promoting a fast shuttling across.


Tian, Xiaohe, Leite, Diana M., Scarpa, Edoardo, Nyberg, Sophie, Fullstone, Gavin, Forth, Joe, Matias, Diana, Apriceno, Azzurra, Poma, Alessandro, Duro-Castano, Aroa, Vuyyuru, Manish, Harker-Kirschneck, Lena, Šarić, Zhang, Zhongping, Xiang, Pan, Fang, Bin, Tian, Yupeng, Luo, Lei, Rizzello, Loris, Battaglia, Giuseppe, (2020). On the shuttling across the blood-brain barrier via tubule formation: Mechanism and cargo avidity bias Science Advances 6, (48), eabc4397

The blood-brain barrier is made of polarized brain endothelial cells (BECs) phenotypically conditioned by the central nervous system (CNS). Although transport across BECs is of paramount importance for nutrient uptake as well as ridding the brain of waste products, the intracellular sorting mechanisms that regulate successful receptor-mediated transcytosis in BECs remain to be elucidated. Here, we used a synthetic multivalent system with tunable avidity to the low-density lipoprotein receptor–related protein 1 (LRP1) to investigate the mechanisms of transport across BECs. We used a combination of conventional and super-resolution microscopy, both in vivo and in vitro, accompanied with biophysical modeling of transport kinetics and membrane-bound interactions to elucidate the role of membrane-sculpting protein syndapin-2 on fast transport via tubule formation. We show that high-avidity cargo biases the LRP1 toward internalization associated with fast degradation, while mid-avidity augments the formation of syndapin-2 tubular carriers promoting a fast shuttling across.


Rustler, Karin, Gomila, Alexandre, Maleeva, Galyna, Gorostiza, Pau, Bregestovski, Piotr, König, Burkhard, (2020). Optical control of GABAA receptors with a fulgimide-based potentiator Chemistry - A European Journal 26, (56), 12722-12727

Optogenetic and photopharmacological tools to manipulate neuronal inhibition have limited efficacy and reversibility. We report the design, synthesis, and biological evaluation of Fulgazepam, a fulgimide derivative of benzodiazepine that behaves as a pure potentiator of ionotropic γ-aminobutyric acid receptors (GABA A Rs) and displays full and reversible photoswitching in vitro and in vivo. The compound enables high-resolution studies of GABAergic neurotransmission, and phototherapies based on localized, acute, and reversible neuroinhibition.


Prieto, A., Bernabeu, M., Falgenhauer, L., Chakraborty, T., Hüttener, M., Juárez, A., (2020). Overexpression of the third H-NS paralogue H-NS2 compensates fitness loss in hns mutants of the enteroaggregative Escherichia coli strain 042 Scientific Reports 10, (1), 18131

Members of the H-NS protein family play a role both in the chromosome architecture and in the regulation of gene expression in bacteria. The genomes of the enterobacteria encode an H-NS paralogue, the StpA protein. StpA displays specific regulatory properties and provides a molecular backup for H-NS. Some enterobacteria also encode third H-NS paralogues. This is the case of the enteroaggregative E. coli (EAEC) strain 042, which encodes the hns, stpA and hns2 genes. We provide in this paper novel information about the role of the H-NS2 protein in strain 042. A C > T transition in the hns2 promoter leading to increased H-NS2 expression is readily selected in hns mutants. Increased H-NS2 expression partially compensates for H-NS loss. H-NS2 levels are critical for the strain 042 fitness. Under some circumstances, high H-NS2 expression levels dictated by the mutant hns2 promoter can be deleterious. The selection of T > C revertants or of clones harboring insertional inactivations of the hns2 gene can then occur. Temperature also plays a relevant role in the H-NS2 regulatory activity. At 37 °C, H-NS2 targets a subset of the H-NS repressed genes contributing to their silencing. When temperature drops to 25 °C, the repressory ability of H-NS2 is significantly reduced. At low temperature, H-NS plays the main repressory role.


Fuentes, E., Bohá, Fuentes-Caparrós, A. M., Schweins, R., Draper, E. R., Adams, D. J., Pujals, S., Albertazzi, L., (2020). PAINT-ing fluorenylmethoxycarbonyl (Fmoc)-diphenylalanine hydrogels Chemistry - A European Journal 26, (44), 9869-9873

Self-assembly of fluorenylmethoxycarbonyl-protected diphenylalanine (FmocFF) in water is widely known to produce hydrogels. Typically, confocal microscopy is used to visualize such hydrogels under wet conditions, that is, without freezing or drying. However, key aspects of hydrogels like fiber diameter, network morphology and mesh size are sub-diffraction limited features and cannot be visualized effectively using this approach. In this work, we show that it is possible to image FmocFF hydrogels by Points Accumulation for Imaging in Nanoscale Topography (PAINT) in native conditions and without direct gel labelling. We demonstrate that the fiber network can be visualized with improved resolution (≈50 nm) both in 2D and 3D. Quantitative information is extracted such as mesh size and fiber diameter. This method can complement the existing characterization tools for hydrogels and provide useful information supporting the design of new materials.

Keywords: FmocFF, Hydrogels, Mesh size, PAINT, Super-resolution


Valenti, S., Yousefzade, O., Puiggalí, J., Macovez, R., (2020). Phase-selective conductivity enhancement and cooperativity length in PLLA/TPU nanocomposite blends with carboxylated carbon nanotubes Polymer 191, 122279

Transmission electron microscopy, temperature-modulated differential scanning calorimetry, and broadband dielectric spectroscopy were employed to characterize ternary nanocomposites consisting of carboxylated carbon nanotubes (CNT) dispersed in a blend of two immiscible polymers, poly(L,lactide) (PLLA) and thermoplastic polyurethane (TPU). The nanocomposite blends were obtained by melt-compounding of PLLA and TPU in the presence of 0.2 wt-% CNT, either in the presence or absence of a Joncryl® ADR chain extender for PLLA, leading to reactive and non-reactive melt mixed samples. In both cases, the binary PLLA/TPU blend is characterized by phase separation into submicron TPU droplets dispersed in the PLLA matrix, and displays two separate glass transition temperatures. The carbon nanotubes are present either inside the TPU phase (samples obtained without chain extender), or at their boundaries (reactive-melt mixed samples). The effect of the sub-micron confinement of the TPU component is to decrease the cooperativity length of the primary segmental relaxation of this polymer, which is accentuated by the presence of the CNT fillers. Depending on the type of sample, five or six distinct relaxations are observed by means of dielectric spectroscopy, which we are able to assign to different dielectric phenomena. Our dielectric data show that the CNT fillers do not contribute directly to the long-range charge transport in the nanocomposite blends, consistent with the nanocomposites morphology, but rather result in a shift of the Maxwell-Wagner-Sillars space-charge frequency associated with charge accumulation at the PLLA/TPU boundary. Such shift testifies to a selective conductivity enhancement of the TPU phase due to the filler.

Keywords: Conductivity enhancement, Cooperatively rearranging region, Dielectric spectroscopy, Glass transition, Maxwell-Wagner-Sillars relaxation, Nanofiller


Gomila, Alexandre M. J., Rustler, Karin, Maleeva, Galyna, Nin-Hill, Alba, Wutz, Daniel, Bautista-Barrufet, Antoni, Rovira, Xavier, Bosch, Miquel, Mukhametova, Elvira, Petukhova, Elena, Ponomareva, Daria, Mukhamedyarov, Marat, Peiretti, Franck, Alfonso-Prieto, Mercedes, Rovira, Carme, König, Burkhard, Bregestovski, Piotr, Gorostiza, Pau, (2020). Photocontrol of endogenous glycine receptors in vivo Cell Chemical Biology 27, (11), 1425-1433.e7

Glycine receptors (GlyRs) are indispensable for maintaining excitatory/inhibitory balance in neuronal circuits that control reflexes and rhythmic motor behaviors. Here we have developed Glyght, a GlyR ligand controlled with light. It is selective over other Cys-loop receptors, is active in vivo, and displays an allosteric mechanism of action. The photomanipulation of glycinergic neurotransmission opens new avenues to understanding inhibitory circuits in intact animals and to developing drug-based phototherapies.

Keywords: Glycine receptors, Photopharmacology, Optopharmacology, Inhibitory neurotransmission, CNS, Photoswitch


Camarero, N., Trapero, A., Pérez-Jiménez, A., Macia, E., Gomila-Juaneda, A., Martín-Quirós, A., Nevola, L., Llobet, A., Llebaria, A., Hernando, J., Giralt, E., Gorostiza, P., (2020). Photoswitchable dynasore analogs to control endocytosis with light Chemical Science 11, (33), 8981-8988

The spatiotemporal control of cellular dynamic processes has great fundamental interest but lacks versatile molecular tools. Dynamin is a key protein in endocytosis and an appealing target to manipulate cell trafficking using patterns of light. We have developed the first photoswitchable small-molecule inhibitors of endocytosis (dynazos), by a stepwise design of the photochromic and pharmacological properties of dynasore, a dynamin inhibitor. We have characterized their photochromism with UV-visible and transient absorption spectroscopy and their biological activity using fluorescence microscopies and flow cytometry. Dynazos are water-soluble, cell permeable, and photostable, and enable fast, single-wavelength photoswitchable inhibition of clathrin-mediated endocytosis at micromolar concentration.


Raote, Ishier, Chabanon, Morgan, Walani, Nikhil, Arroyo, Marino, Garcia-Parajo, Maria F., Malhotra, Vivek, Campelo, Felix, (2020). A physical mechanism of TANGO1-mediated bulky cargo export eLife 9, e59426

The endoplasmic reticulum (ER)-resident protein TANGO1 assembles into a ring around ER exit sites (ERES), and links procollagens in the ER lumen to COPII machinery, tethers, and ER-Golgi intermediate compartment (ERGIC) in the cytoplasm (Raote et al., 2018). Here, we present a theoretical approach to investigate the physical mechanisms of TANGO1 ring assembly and how COPII polymerization, membrane tension, and force facilitate the formation of a transport intermediate for procollagen export. Our results indicate that a TANGO1 ring, by acting as a linactant, stabilizes the open neck of a nascent COPII bud. Elongation of such a bud into a transport intermediate commensurate with bulky procollagens is then facilitated by two complementary mechanisms: (i) by relieving membrane tension, possibly by TANGO1-mediated fusion of retrograde ERGIC membranes and (ii) by force application. Altogether, our theoretical approach identifies key biophysical events in TANGO1-driven procollagen export.

Keywords: Membrane tension, Procollagen export, Secretory pathway, Membrane curvature, Membrane dynamics, Budding


Alert, R., Trepat, X., (2020). Physical models of collective cell migration Annual Review of Condensed Matter Physics 11, 77-101

Collective cell migration is a key driver of embryonic development, wound healing, and some types of cancer invasion. Here, we provide a physical perspective of the mechanisms underlying collective cell migration. We begin with a catalog of the cell-cell and cell-substrate interactions that govern cell migration, which we classify into positional and orientational interactions. We then review the physical models that have been developed to explain how these interactions give rise to collective cellular movement. These models span the subcellular to the supracellular scales, and they include lattice models, phase-field models, active network models, particle models, and continuum models. For each type of model, we discuss its formulation, its limitations, and the main emergent phenomena that it has successfully explained. These phenomena include flocking and fluid-solid transitions, as well as wetting, fingering, and mechanical waves in spreading epithelial monolayers. We close by outlining remaining challenges and future directions in the physics of collective cell migration.

Keywords: Active network models, Cellular Potts models, Continuum models, Particle models, Phase-field models, Tissue biophysics


Serrat, Neus, Guerrero-Hernández, Martina, Matas-Céspedes, Alba, Yahiaoui, Anella, Valero, Juan G., Nadeu, Ferran, Clot, Guillem, Di Re, Miriam, Corbera-Bellalta, Marc, Magnano, Laura, Rivas-Delgado, Alfredo, Enjuanes, Anna, Beà , Silvia, Cid, Maria C., Campo, ElÍas, Montero, Joan, Hodson, Daniel J., López-Guillermo, Armando, Colomer, Dolors, Tannheimer, Stacey, Pérez-Galán, Patricia, (2020). PI3Kδ inhibition reshapes follicular lymphoma–immune microenvironment cross talk and unleashes the activity of venetoclax Blood Advances 4, (17), 4217-4231

Despite idelalisib approval in relapsed follicular lymphoma (FL), a complete characterization of the immunomodulatory consequences of phosphatidylinositol 3-kinase δ (PI3Kδ) inhibition, biomarkers of response, and potential combinatorial therapies in FL remain to be established. Using ex vivo cocultures of FL patient biopsies and follicular dendritic cells (FDCs) to mimic the germinal center (n = 42), we uncovered that PI3Kδ inhibition interferes with FDC-induced genes related to angiogenesis, extracellular matrix formation, and transendothelial migration in a subset of FL samples, defining an 18-gene signature fingerprint of idelalisib sensitivity. A common hallmark of idelalisib found in all FL cases was its interference with the CD40/CD40L pathway and induced proliferation, together with the downregulation of proteins crucial for B–T-cell synapses, leading to an inefficient cross talk between FL cells and the supportive T-follicular helper cells (TFH). Moreover, idelalisib downmodulates the chemokine CCL22, hampering the recruitment of TFH and immunosupressive T-regulatory cells to the FL niche, leading to a less supportive and tolerogenic immune microenvironment. Finally, using BH3 profiling, we uncovered that FL–FDC and FL–macrophage cocultures augment tumor addiction to BCL-XL and MCL-1 or BFL-1, respectively, limiting the cytotoxic activity of the BCL-2 inhibitor venetoclax. Idelalisib restored FL dependence on BCL-2 and venetoclax activity. In summary, idelalisib exhibits a patient-dependent activity toward angiogenesis and lymphoma dissemination. In all FL cases, idelalisib exerts a general reshaping of the FL immune microenvironment and restores dependence on BCL-2, predisposing FL to cell death, providing a mechanistic rationale for investigating the combination of PI3Kδ inhibitors and venetoclax in clinical trials.


Romero-Montero, A., del Valle, L. J., Puiggalí, J., Montiel, C., García-Arrazola, R., Gimeno, M., (2020). Poly(gallic acid)-coated polycaprolactone inhibits oxidative stress in epithelial cells Materials Science and Engineering C 115, 111154

Enzymatic mediated poly (gallic acid) (PGAL), a stable multiradical polyanion with helicoidal secondary structure and high antioxidant capacity, was successfully grafted to poly(ε-caprolactone) (PCL) using UV-photo induction. PCL films were prepared with several levels of roughness and subsequently grafted with PGAL (PCL-g-PGAL). The results on the full characterization of the produced materials by mechanical tests, surface morphology, and topography, thermal and crystallographic analyses, as well as wettability and cell protection activity against oxidative stress, were adequate for tissue regeneration. The in vitro biocompatibility was then assessed with epithelial-like cells showing excellent adhesion and proliferation onto the PCL-g-PGAL films, most importantly, PCL-g-PGAL displayed a good ability to protect cell cultures on their surface against reactive oxygen species. These biomaterials can consequently be considered as novel biocompatible and antioxidant films with high-responsiveness for biomedical or tissue engineering applications.

Keywords: Antioxidant, Poly(gallic acid), Polyphenol, Radical oxygen species


Fenaroli, Federico, Robertson, James D., Scarpa, Edoardo, Gouveia, Virginia M., Di Guglielmo, Claudia, De Pace, Cesare, Elks, Philip M., Poma, Alessandro, Evangelopoulos, Dimitrios, Ortiz, Julio, Prajsnar, Tomasz K., Marriott, Helen M., Dockrell, David H., Foster, Simon J., McHugh, Timothy D., Renshaw, Stephen A., Samitier, Josep, Battaglia, Giuseppe, Rizzello, Loris, (2020). Polymersomes eradicating intracellular bacteria ACS Nano 14, (7), 8287-8298

Mononuclear phagocytes such as monocytes, tissue-specific macrophages, and dendritic cells are primary actors in both innate and adaptive immunity. These professional phagocytes can be parasitized by intracellular bacteria, turning them from housekeepers to hiding places and favoring chronic and/or disseminated infection. One of the most infamous is the bacteria that cause tuberculosis (TB), which is the most pandemic and one of the deadliest diseases, with one-third of the world’s population infected and an average of 1.8 million deaths/year worldwide. Here we demonstrate the effective targeting and intracellular delivery of antibiotics to infected macrophages both in vitro and in vivo, using pH-sensitive nanoscopic polymersomes made of PMPC–PDPA block copolymer. Polymersomes showed the ability to significantly enhance the efficacy of the antibiotics killing Mycobacterium bovis, Mycobacterium tuberculosis, and another established intracellular pathogen, Staphylococcus aureus. Moreover, they demonstrated to easily access TB-like granuloma tissues—one of the harshest environments to penetrate—in zebrafish models. We thus successfully exploited this targeting for the effective eradication of several intracellular bacteria, including M. tuberculosis, the etiological agent of human TB.


del Rio, Jose A., Ferrer, Isidre, (2020). Potential of microfluidics and lab-on-chip platforms to improve understanding of “prion-like” protein assembly and behavior Frontiers in Bioengineering and Biotechnology 8, 570692

Human aging is accompanied by a relevant increase in age-associated chronic pathologies, including neurodegenerative and metabolic diseases. The appearance and evolution of numerous neurodegenerative diseases is paralleled by the appearance of intracellular and extracellular accumulation of misfolded proteins in affected brains. In addition, recent evidence suggests that most of these amyloid proteins can behave and propagate among neural cells similarly to infective prions. In order to improve understanding of the seeding and spreading processes of these “prion-like” amyloids, microfluidics and 3D lab-on-chip approaches have been developed as highly valuable tools. These techniques allow us to monitor changes in cellular and molecular processes responsible for amyloid seeding and cell spreading and their parallel effects in neural physiology. Their compatibility with new optical and biochemical techniques and their relative availability have increased interest in them and in their use in numerous laboratories. In addition, recent advances in stem cell research in combination with microfluidic platforms have opened new humanized in vitro models for myriad neurodegenerative diseases affecting different cellular targets of the vascular, muscular, and nervous systems, and glial cells. These new platforms help reduce the use of animal experimentation. They are more reproducible and represent a potential alternative to classical approaches to understanding neurodegeneration. In this review, we summarize recent progress in neurobiological research in “prion-like” protein using microfluidic and 3D lab-on-chip approaches. These approaches are driven by various fields, including chemistry, biochemistry, and cell biology, and they serve to facilitate the development of more precise human brain models for basic mechanistic studies of cell-to-cell interactions and drug discovery.

Keywords: Lab-On-Chip, Amyloid propagation, Microfluidics, Fibril, Seeding, Spreading, Prion-like, Prionoid


Cullaro, G., Sharma, R., Trebicka, J., Cárdenas, A., Verna, E. C., (2020). Precipitants of acute-on-chronic liver failure: An opportunity for preventative measures to improve outcomes Liver Transplantation 26, (2), 283-293

Acute-on-chronic liver failure (ACLF) is a feared complication that can develop at any stage of chronic liver disease. The incidence of ACLF is increasing, leading to a significant burden to both the affected individual and health care systems. To date, our understanding of ACLF suggests that it may be initiated by precipitants such as systemic infection, alcohol use, or viral hepatitis. The prevalence of these vary significantly by geography and underlying liver disease, and these precipitants have a varying impact on patient prognosis. Herein, we present a review of our current understanding of the precipitants of ACLF, including gaps in current data and opportunities for meaningful intervention and areas of future research.


Madsen, B. S., Thiele, M., Detlefsen, S., Sørensen, M. D., Kjærgaard, M., Møller, L. S., Rasmussen, D. N., Schlosser, A., Holmskov, U., Trebicka, J., Sorensen, G. L., Krag, A., (2020). Prediction of liver fibrosis severity in alcoholic liver disease by human microfibrillar-associated protein 4 Liver International 40, (7), 1701-1712

Background: Alcoholic liver disease (ALD) is a public health concern that is the cause of half of all cirrhosis-related deaths. Early detection of fibrosis, ideally in the precirrhotic stage, is a key strategy for improving ALD outcomes and for preventing progression to cirrhosis. Previous studies identified the blood-borne marker human microfibrillar-associated protein 4 (MFAP4) as a biomarker for detection of hepatitis C virus (HCV)-related fibrosis. Aim: To evaluate the diagnostic accuracy of MFAP4 to detect ALD-induced fibrosis. Method: We performed a prospective, liver biopsy-controlled study involving 266 patients with prior or current alcohol overuse. Patients were split into a training and a validation cohort. Results: MFAP4 was present in fibrotic hepatic tissue and serum MFAP4 levels increased with fibrosis grade. The area under the receiver operating characteristic curve (AUROC) for detection of cirrhosis was 0.91 (95% CI 0.85-0.96) in the training cohort and 0.91 (95% CI 0.79-1.00) in the validation cohort. For detection of advanced fibrosis, the AUROC was 0.88 (95% CI 0.81-0.94) in the training cohort and 0.92 (95% CI 0.83-1.00) in the validation cohort. The diagnostic accuracy did not differ between MFAP4 and the enhanced liver fibrosis (ELF) test or transient elastography (TE) in an intention-to-diagnose analysis. MFAP4 did not predict hepatic decompensation in a time-to-decompensation analysis in a subgroup of patients with cirrhosis. Conclusion: MFAP4 is a novel biomarker that can detect ALD-related fibrosis with high accuracy.

Keywords: Biomarker, Cirrhosis, Extracellular matrix protein, Liver biopsy, Non-invasive testing


Hall, Jocelin Isabel, Lozano, Manuel, Estrada-Petrocelli, Luis, Birring, Surinder, Turner, Richard, (2020). The present and future of cough counting tools Journal of Thoracic Disease 12, (9), 5207-5223

The widespread use of cough counting tools has, to date, been limited by a reliance on human input to determine cough frequency. However, over the last two decades advances in digital technology and audio capture have reduced this dependence. As a result, cough frequency is increasingly recognised as a measurable parameter of respiratory disease. Cough frequency is now the gold standard primary endpoint for trials of new treatments for chronic cough, has been investigated as a marker of infectiousness in tuberculosis (TB), and used to demonstrate recovery in exacerbations of chronic obstructive pulmonary disease (COPD). This review discusses the principles of automatic cough detection and summarises key currently and recently used cough counting technology in clinical research. It additionally makes some predictions on future directions in the field based on recent developments. It seems likely that newer approaches to signal processing, the adoption of techniques from automatic speech recognition, and the widespread ownership of mobile devices will help drive forward the development of real-time fully automated ambulatory cough frequency monitoring over the coming years. These changes should allow cough counting systems to transition from their current status as a niche research tool in chronic cough to a much more widely applicable method for assessing, investigating and understanding respiratory disease.

Keywords: Cough, Cough monitor, Cough frequency


Vodovotz, Y., Barnard, N., Hu, F. B., Jakicic, J., Lianov, L., Loveland, D., Buysse, D., Szigethy, E., Finkel, T., Sowa, G., Verschure, P., Williams, K., Sanchez, E., Dysinger, W., Maizes, V., Junker, C., Phillips, E., Katz, D., Drant, S., Jackson, R. J., Trasande, L., Woolf, S., Salive, M., South-Paul, J., States, S. L., Roth, L., Fraser, G., Stout, R., Parkinson, M. D., (2020). Prioritized research for the prevention, treatment, and reversal of chronic disease: recommendations from the lifestyle medicine research summit Frontiers in Medicine 7, 585744

Declining life expectancy and increasing all-cause mortality in the United States have been associated with unhealthy behaviors, socioecological factors, and preventable disease. A growing body of basic science, clinical research, and population health evidence points to the benefits of healthy behaviors, environments and policies to maintain health and prevent, treat, and reverse the root causes of common chronic diseases. Similarly, innovations in research methodologies, standards of evidence, emergence of unique study cohorts, and breakthroughs in data analytics and modeling create new possibilities for producing biomedical knowledge and clinical translation. To understand these advances and inform future directions research, The Lifestyle Medicine Research Summit was convened at the University of Pittsburgh on December 4–5, 2019. The Summit's goal was to review current status and define research priorities in the six core areas of lifestyle medicine: plant-predominant nutrition, physical activity, sleep, stress, addictive behaviors, and positive psychology/social connection. Forty invited subject matter experts (1) reviewed existing knowledge and gaps relating lifestyle behaviors to common chronic diseases, such as cardiovascular disease, diabetes, many cancers, inflammatory- and immune-related disorders and other conditions; and (2) discussed the potential for applying cutting-edge molecular, cellular, epigenetic and emerging science knowledge and computational methodologies, research designs, and study cohorts to accelerate clinical applications across all six domains of lifestyle medicine. Notably, federal health agencies, such as the Department of Defense and Veterans Administration have begun to adopt “whole-person health and performance” models that address these lifestyle and environmental root causes of chronic disease and associated morbidity, mortality, and cost. Recommendations strongly support leveraging emerging research methodologies, systems biology, and computational modeling in order to accelerate effective clinical and population solutions to improve health and reduce societal costs. New and alternative hierarchies of evidence are also be needed in order to assess the quality of evidence and develop evidence-based guidelines on lifestyle medicine. Children and underserved populations were identified as prioritized groups to study. The COVID-19 pandemic, which disproportionately impacts people with chronic diseases that are amenable to effective lifestyle medicine interventions, makes the Summit's findings and recommendations for future research particularly timely and relevant.

Keywords: Chronic disease, Epigenetics, In silico modeling, Inflammation, Lifestyle medicine, Nutrition, Physical activity, Research methodologies


Borgheti-Cardoso, L. N., San Anselmo, M., Lantero, E., Lancelot, A., Serrano, J. L., Hernández-Ainsa, S., Fernàndez-Busquets, X., Sierra, T., (2020). Promising nanomaterials in the fight against malaria Journal of Materials Chemistry B 8, (41), 9428-9448

For more than one hundred years, several treatments against malaria have been proposed but they have systematically failed, mainly due to the occurrence of drug resistance in part resulting from the exposure of the parasite to low drug doses. Several factors are behind this problem, including (i) the formidable barrier imposed by the Plasmodium life cycle with intracellular localization of parasites in hepatocytes and red blood cells, (ii) the adverse fluidic conditions encountered in the blood circulation that affect the interaction of molecular components with target cells, and (iii) the unfavorable physicochemical characteristics of most antimalarial drugs, which have an amphiphilic character and can be widely distributed into body tissues after administration and rapidly metabolized in the liver. To surpass these drawbacks, rather than focusing all efforts on discovering new drugs whose efficacy is quickly decreased by the parasite's evolution of resistance, the development of effective drug delivery carriers is a promising strategy. Nanomaterials have been investigated for their capacity to effectively deliver antimalarial drugs at local doses sufficiently high to kill the parasites and avoid drug resistance evolution, while maintaining a low overall dose to prevent undesirable toxic side effects. In recent years, several nanostructured systems such as liposomes, polymeric nanoparticles or dendrimers have been shown to be capable of improving the efficacy of antimalarial therapies. In this respect, nanomaterials are a promising drug delivery vehicle and can be used in therapeutic strategies designed to fight the parasite both in humans and in the mosquito vector of the disease. The chemical analyses of these nanomaterials are essential for the proposal and development of effective anti-malaria therapies. This review is intended to analyze the application of nanomaterials to improve the drug efficacy on different stages of the malaria parasites in both the human and mosquito hosts.


Palacio, F., Fonollosa, J., Burgués, J., Gomez, J. M., Marco, S., (2020). Pulsed-temperature metal oxide gas sensors for microwatt power consumption IEEE Access 8, 70938-70946

Metal Oxide (MOX) gas sensors rely on chemical reactions that occur efficiently at high temperatures, resulting in too-demanding power requirements for certain applications. Operating the sensor under a Pulsed-Temperature Operation (PTO), by which the sensor heater is switched ON and OFF periodically, is a common practice to reduce the power consumption. However, the sensor performance is degraded as the OFF periods become larger. Other research works studied, generally, PTO schemes applying waveforms to the heater with time periods of seconds and duty cycles above 20%. Here, instead, we explore the behaviour of PTO sensors working under aggressive schemes, reaching power savings of 99% and beyond with respect to continuous heater stimulation. Using sensor sensitivity and the limit of detection, we evaluated four Ultra Low Power (ULP) sensors under different PTO schemes exposed to ammonia, ethylene, and acetaldehyde. Results show that it is possible to operate the sensors with total power consumption in the range of microwatts. Despite the aggressive power reduction, sensor sensitivity suffers only a moderate decline and the limit of detection may degrade up to a factor five. This is, however, gas-dependent and should be explored on a case-by-case basis since, for example, the same degradation has not been observed for ammonia. Finally, the run-in time, i.e., the time required to get a stable response immediately after switching on the sensor, increases when reducing the power consumption, from 10 minutes to values in the range of 10–20 hours for power consumptions smaller than 200 microwatts.

Keywords: Robot sensing systems, Temperature sensors, Heating systems, Gas detectors, Power demand, Sensitivity, Electronic nose, gas sensors, low-power operation, machine olfaction, pulsed-temperature operation, temperature modulation


Gavín, Rosalina, Lidón, Laia, Ferrer, Isidre, del Río, José Antonio, (2020). The quest for cellular prion protein functions in the aged and neurodegenerating brain Cells 9, (3), 591

Cellular (also termed ‘natural’) prion protein has been extensively studied for many years for its pathogenic role in prionopathies after misfolding. However, neuroprotective properties of the protein have been demonstrated under various scenarios. In this line, the involvement of the cellular prion protein in neurodegenerative diseases other than prionopathies continues to be widely debated by the scientific community. In fact, studies on knock-out mice show a vast range of physiological functions for the protein that can be supported by its ability as a cell surface scaffold protein. In this review, we first summarize the most commonly described roles of cellular prion protein in neuroprotection, including antioxidant and antiapoptotic activities and modulation of glutamate receptors. Second, in light of recently described interaction between cellular prion protein and some amyloid misfolded proteins, we will also discuss the molecular mechanisms potentially involved in protection against neurodegeneration in pathologies such as Alzheimer’s, Parkinson’s, and Huntington’s diseases.

Keywords: Prion, Tau, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Neuroprotection


Kocere, A., Resseguier, J., Wohlmann, J., Skjeldal, F. M., Khan, S., Speth, M., Dal, N. J. K., Ng, M. Y. W., Alonso-Rodriguez, N., Scarpa, E., Rizzello, L., Battaglia, G., Griffiths, G., Fenaroli, F., (2020). Real-time imaging of polymersome nanoparticles in zebrafish embryos engrafted with melanoma cancer cells: Localization, toxicity and treatment analysis EBioMedicine 58, 102902

Background: The developing zebrafish is an emerging tool in nanomedicine, allowing non-invasive live imaging of the whole animal at higher resolution than is possible in the more commonly used mouse models. In addition, several transgenic fish lines are available endowed with selected cell types expressing fluorescent proteins; this allows nanoparticles to be visualized together with host cells. Methods: Here, we introduce the zebrafish neural tube as a robust injection site for cancer cells, excellently suited for high resolution imaging. We use light and electron microscopy to evaluate cancer growth and to follow the fate of intravenously injected nanoparticles. Findings: Fluorescently labelled mouse melanoma B16 cells, when injected into this structure proliferated rapidly and stimulated angiogenesis of new vessels. In addition, macrophages, but not neutrophils, selectively accumulated in the tumour region. When injected intravenously, nanoparticles made of Cy5-labelled poly(ethylene glycol)-block-poly(2-(diisopropyl amino) ethyl methacrylate) (PEG-PDPA) selectively accumulated in the neural tube cancer region and were seen in individual cancer cells and tumour associated macrophages. Moreover, when doxorubicin was released from PEG-PDPA, in a pH dependant manner, these nanoparticles could strongly reduce toxicity and improve the treatment outcome compared to the free drug in zebrafish xenotransplanted with mouse melanoma B16 or human derived melanoma cells. Interpretation: The zebrafish has the potential of becoming an important intermediate step, before the mouse model, for testing nanomedicines against patient-derived cancer cells.


Trebicka, J., Gu, W., Ibañez-Samaniego, L., Hernández-Gea, V., Pitarch, C., Garcia, E., Procopet, B., Giráldez, Á, Amitrano, L., Villanueva, C., Thabut, D., Silva-Junior, G., Martinez, J., Genescà , J., Bureau, C., Llop, E., Laleman, W., Palazon, J. M., Castellote, J., Rodrigues, S., Gluud, L., Ferreira, C. N., Barcelo, R., Cañete, N., Rodríguez, M., Ferlitsch, A., Mundi, J. L., Gronbaek, H., Hernández-Guerra, M., Sassatelli, R., Dell'Era, A., Senzolo, M., Abraldes, J. G., Romero-Gómez, M., Zipprich, A., Casas, M., Masnou, H., Primignani, M., Weiss, E., Catalina, M. V., Erasmus, H. P., Uschner, F. E., Schulz, M., Brol, M. J., Praktiknjo, M., Chang, J., Krag, A., Nevens, F., Calleja, J. L., Robic, M. A., Conejo, I., Albillos, A., Rudler, M., Alvarado, E., Guardascione, M. A., Tantau, M., Bosch, J., Torres, F., Pavesi, M., Garcia-Pagán, J. C., Jansen, C., Bañares, R., (2020). Rebleeding and mortality risk are increased by ACLF but reduced by pre-emptive TIPS Journal of Hepatology 73, (5), 1082-1091

Background & Aims: The relationship between acute-on-chronic liver failure (ACLF) and acute variceal bleeding (AVB) is poorly understood. Specifically, the prevalence and prognosis of ACLF in the context of AVB is unclear, while the role of transjugular intrahepatic portosystemic shunt (TIPS) in the management in patients with ACLF has not been described to date. Methods: A multicenter, international, observational study was conducted in 2,138 patients from 34 centers between 2011 and 2015. ACLF was defined and graded according to the EASL-CLIF consortium definition. Placement of pre-emptive TIPS (pTIPS) was based on individual center policy. Patients were followed-up for 1 year, until death or liver transplantation. Cox regression and competing risk models (Gray's test) were used to identify independent predictors of rebleeding or mortality. Results: At admission, 380/2,138 (17.8%) patients had ACLF according to EASL-CLIF criteria (grade 1: 38.7%; grade 2: 39.2%; grade 3: 22.1%). The 42-day rebleeding (19% vs. 10%; p <0.001) and mortality (47% vs. 10%; p <0.001) rates were higher in patients with ACLF and increased with ACLF grades. Of note, the presence of ACLF was independently associated with rebleeding and mortality. pTIPS placement improved survival in patients with ACLF at 42 days and 1 year. This effect was also observed in propensity score matching analysis of 66 patients with ACLF, of whom 44 received pTIPs and 22 did not. Conclusions: This large multicenter international real-life study identified ACLF at admission as an independent predictor of rebleeding and mortality in patients with AVB. Moreover, pTIPS was associated with improved survival in patients with ACLF and AVB. Lay summary: Acute variceal bleeding is a deadly complication of liver cirrhosis that results from severe portal hypertension. This study demonstrates that the presence of acute-on-chronic liver failure (ACLF) is the strongest predictor of mortality in patients with acute variceal bleeding. Importantly, patients with ACLF and acute variceal (re)bleeding benefit from pre-emptive (early) placement of a transjugular intrahepatic portosystemic shunt.

Keywords: Acute variceal bleeding, Acute-on-chronic liver failure, Cirrhosis, Rebleeding


Torres, S., Abdullah, Z., Brol, M. J., Hellerbrand, C., Fernandez, M., Fiorotto, R., Klein, S., Königshofer, P., Liedtke, C., Lotersztajn, S., Nevzorova, Y. A., Schierwagen, R., Reiberger, T., Uschner, F. E., Tacke, F., Weiskirchen, R., Trebicka, J., (2020). Recent advances in practical methods for liver cell biology: A short overview International Journal of Molecular Sciences 21, (6), 2027

Molecular and cellular research modalities for the study of liver pathologies have been tremendously improved over the recent decades. Advanced technologies offer novel opportunities to establish cell isolation techniques with excellent purity, paving the path for 2D and 3D microscopy and high-throughput assays (e.g., bulk or single-cell RNA sequencing). The use of stem cell and organoid research will help to decipher the pathophysiology of liver diseases and the interaction between various parenchymal and non-parenchymal liver cells. Furthermore, sophisticated animal models of liver disease allow for the in vivo assessment of fibrogenesis, portal hypertension and hepatocellular carcinoma (HCC) and for the preclinical testing of therapeutic strategies. The purpose of this review is to portray in detail novel in vitro and in vivo methods for the study of liver cell biology that had been presented at the workshop of the 8th meeting of the European Club for Liver Cell Biology (ECLCB-8) in October of 2018 in Bonn, Germany.

Keywords: Fibrogenesis, Hepatic stellate cells, Hepatocellular cancer, In vitro models, Steatosis


Lanzalaco, S., Fabregat, G., Muñoz-Galan, H., Cabrera, J., Muñoz-Pascual, X., Llorca, J., Alemán, C., (2020). Recycled low-density polyethylene for noninvasive glucose monitoring: A proposal for plastic recycling that adds technological value ACS Sustainable Chemistry and Engineering 8, (33), 12554-12560

In this work, we present a successful strategy to convert recycled LDPE films, which usually end up in landfills or leak into the environment, into an advanced biomedical product. More specifically, LDPE films for food packaging have been treated with atmosphere corona discharge plasma for electrochemical detection of glucose. Enzyme-functionalized sensors manufactured using such recycled materials, which act as a mediator capable of electrocommunicating with the glucose oxidase (GOx) enzyme, are able to detect glucose concentrations in sweat and are fully compatible with the levels of such bioanalytes in both healthy and diabetic patients. Covalent immobilization of the GOx enzyme on the plasma-treated LDPE films has been successfully performed using the carbodiimide method, as proved by X-ray photoelectron spectroscopy. Then, the electronic communication between the deeply buried active site of the GOx and the reactive excited species formed at the surface of the plasma-treated LDPE has been demonstrated by linear sweep voltammetry. Finally, cyclic voltammetry in artificial sweat has been used to show that the LDPE-functionalized sensor has a linear response in the concentration of range of 50 μM to 1 mM with a limit of detection of 375 μA·μM–1·cm–2. Comparison of the performance of sensors prepared using recycled (i.e. with additives) and pristine (i.e. without additives) LDPE indicates that the utilization of the former does not require any pretreatment to eliminate additives. The present strategy demonstrates a facile approach for recycling LDPE waste into a high value-added product, which will potentially pave the way for the treatment of plastic waste in the future. Noninvasive glucose sensors based on recycled LDPE may play a crucial role in monitoring diabetes in underdeveloped regions.

Keywords: Biosensors, Diabetes monitoring, High-value recycling, Plasma treatment, Sweat sensors


Vidal, L., Kampleitner, C., Krissian, S., Brennan, M. Á, Hoffmann, O., Raymond, Y., Maazouz, Y., Ginebra, M. P., Rosset, P., Layrolle, P., (2020). Regeneration of segmental defects in metatarsus of sheep with vascularized and customized 3D-printed calcium phosphate scaffolds Scientific Reports 10, (1), 7068

Although autografts are considered to be the gold standard treatment for reconstruction of large bone defects resulting from trauma or diseases, donor site morbidity and limited availability restrict their use. Successful bone repair also depends on sufficient vascularization and to address this challenge, novel strategies focus on the development of vascularized biomaterial scaffolds. This pilot study aimed to investigate the feasibility of regenerating large bone defects in sheep using 3D-printed customized calcium phosphate scaffolds with or without surgical vascularization. Pre-operative computed tomography scans were performed to visualize the metatarsus and vasculature and to fabricate customized scaffolds and surgical guides by 3D printing. Critical-sized segmental defects created in the mid-diaphyseal region of the metatarsus were either left empty or treated with the 3D scaffold alone or in combination with an axial vascular pedicle. Bone regeneration was evaluated 1, 2 and 3 months post-implantation. After 3 months, the untreated defect remained non-bridged while the 3D scaffold guided bone regeneration. The presence of the vascular pedicle further enhanced bone formation. Histology confirmed bone growth inside the porous 3D scaffolds with or without vascular pedicle inclusion. Taken together, this pilot study demonstrated the feasibility of precised pre-surgical planning and reconstruction of large bone defects with 3D-printed personalized scaffolds.


Ferrer, I., Zelaya, M. V., Aguiló García, M., Carmona, M., López-González, I., Andrés-Benito, P., Lidón, L., Gavín, R., Garcia-Esparcia, P., del Rio, J. A., (2020). Relevance of host tau in tau seeding and spreading in tauopathies Brain Pathology 30, (2), 298-318

Human tau seeding and spreading occur following intracerebral inoculation of brain homogenates obtained from tauopathies in transgenic mice expressing natural or mutant tau, and in wild-type (WT) mice. The present study was geared to learning about the patterns of tau seeding, the cells involved and the characteristics of tau following intracerebral inoculation of homogenates from primary age-related tauopathy (PART: neuronal 4Rtau and 3Rtau), aging-related tau astrogliopathy (ARTAG: astrocytic 4Rtau) and globular glial tauopathy (GGT: 4Rtau with neuronal deposits and specific tau inclusions in astrocytes and oligodendrocytes). For this purpose, young and adult WT mice were inoculated unilaterally in the hippocampus or in the lateral corpus callosum with sarkosyl-insoluble fractions from PART, ARTAG and GGT cases, and were killed at variable periods of three to seven months. Brains were processed for immunohistochemistry in paraffin sections. Tau seeding occurred in the ipsilateral hippocampus and corpus callosum and spread to the septal nuclei, periventricular hypothalamus and contralateral corpus callosum, respectively. Tau deposits were mainly found in neurons, oligodendrocytes and threads; the deposits were diffuse or granular, composed of phosphorylated tau, tau with abnormal conformation and 3Rtau and 4Rtau independently of the type of tauopathy. Truncated tau at the aspartic acid 421 and ubiquitination were absent. Tau deposits had the characteristics of pre-tangles. A percentage of intracellular tau deposits co-localized with active (phosphorylated) tau kinases p38 and ERK 1/2. Present study shows that seeding and spreading of human tau into the brain of WT mice involves neurons and glial cells, mainly oligodendrocytes, thereby supporting the idea of a primary role of oligodendrogliopathy, together with neuronopathy, in the progression of tauopathies. In addition, it suggests that human tau inoculation modifies murine tau metabolism with the production and deposition of 3Rtau and 4Rtau, and by activation of specific tau kinases in affected cells.

Keywords: Aging-related tau astrogliopathy, Globular glial tauopathy, Primary age-related tauopathy, Seeding, Spreading, Tau, Tauopathies


Rodríguez-Pereira, Cristina, Lagunas, Anna, Casanellas, Ignasi, Vida, Yolanda, Pérez-Inestrosa, Ezequiel, Andrades, José A., Becerra, José, Samitier, Josep, Blanco, Francisco J., Magalhães, Joana, (2020). RGD-dendrimer-poly(L-lactic) acid nanopatterned substrates for the early chondrogenesis of human mesenchymal stromal cells derived from osteoarthritic and healthy donors Materials 13, (10), 2247

Aiming to address a stable chondrogenesis derived from mesenchymal stromal cells (MSCs) to be applied in cartilage repair strategies at the onset of osteoarthritis (OA), we analyzed the effect of arginine–glycine–aspartate (RGD) density on cell condensation that occurs during the initial phase of chondrogenesis. For this, we seeded MSC-derived from OA and healthy (H) donors in RGD-dendrimer-poly(L-lactic) acid (PLLA) nanopatterned substrates (RGD concentrations of 4 × 10−9, 10−8, 2.5 × 10−8, and 10−2 w/w), during three days and compared to a cell pellet conventional three-dimensional culture system. Molecular gene expression (collagens type-I and II–COL1A1 and COL2A1, tenascin-TNC, sex determining region Y-box9-SOX9, and gap junction protein alpha 1–GJA1) was determined as well as the cell aggregates and pellet size, collagen type-II and connexin 43 proteins synthesis. This study showed that RGD-tailored first generation dendrimer (RGD-Cys-D1) PLLA nanopatterned substrates supported the formation of pre-chondrogenic condensates from OA- and H-derived human bone marrow-MSCs with enhanced chondrogenesis regarding the cell pellet conventional system (presence of collagen type-II and connexin 43, both at the gene and protein level). A RGD-density dependent trend was observed for aggregates size, in concordance with previous studies. Moreover, the nanopatterns’ had a higher effect on OA-derived MSC morphology, leading to the formation of bigger and more compact aggregates with improved expression of early chondrogenic markers.

Keywords: Cell condensation, Gap junctions, RGD-density, Chondrogenic differentiation, Osteoarthritis


M Leite, D., Matias, D., Battaglia, G., (2020). The role of BAR proteins and the glycocalyx in brain endothelium transcytosis Cells 9, (12), 2685

Within the brain, endothelial cells lining the blood vessels meticulously coordinate the transport of nutrients, energy metabolites and other macromolecules essential in maintaining an appropriate activity of the brain. While small molecules are pumped across specialised molecular transporters, large macromolecular cargos are shuttled from one side to the other through membrane-bound carriers formed by endocytosis on one side, trafficked to the other side and released by exocytosis. Such a process is collectively known as transcytosis. The brain endothelium is recognised to possess an intricate vesicular endosomal network that mediates the transcellular transport of cargos from blood-to-brain and brain-to-blood. However, mounting evidence suggests that brain endothelial cells (BECs) employ a more direct route via tubular carriers for a fast and efficient transport from the blood to the brain. Here, we compile the mechanism of transcytosis in BECs, in which we highlight intracellular trafficking mediated by tubulation, and emphasise the possible role in transcytosis of the Bin/Amphiphysin/Rvs (BAR) proteins and glycocalyx (GC)-a layer of sugars covering BECs, in transcytosis. Both BAR proteins and the GC are intrinsically associated with cell membranes and involved in the modulation and shaping of these membranes. Hence, we aim to summarise the machinery involved in transcytosis in BECs and highlight an uncovered role of BAR proteins and the GC at the brain endothelium.

Keywords: BAR proteins, Blood-brain barrier, Endothelium, Glycocalyx, Transcytosis, Tubulation


Schierwagen, R., Uschner, F. E., Ortiz, C., Torres, S., Brol, M. J., Tyc, O., Gu, W., Grimm, C., Zeuzem, S., Plamper, A., Pfeifer, P., Zimmer, S., Welsch, C., Schaefer, L., Rheinwalt, K. P., Clària, J., Arroyo, V., Trebicka, J., Klein, S., (2020). The role of macrophage-inducible C-type lectin in different stages of chronic liver disease Frontiers in Immunology 11, 1352

The macrophage-inducible C-type lectin (mincle) is part of the innate immune system and acts as a pattern recognition receptor for pathogen-associated molecular patterns (PAMPS) and damage-associated molecular patterns (DAMPs). Ligand binding induces mincle activation which consequently interacts with the signaling adapter Fc receptor, SYK, and NF-kappa-B. There is also evidence that mincle expressed on macrophages promotes intestinal barrier integrity. However, little is known about the role of mincle in hepatic fibrosis, especially in more advanced disease stages. Mincle expression was measured in human liver samples from cirrhotic patients and donors collected at liver transplantation and in patients undergoing bariatric surgery. Human results were confirmed in rodent models of cirrhosis and acute-on-chronic liver failure (ACLF). In these models, the role of mincle was investigated in liver samples as well as in peripheral blood monocytes (PBMC), tissues from the kidney, spleen, small intestine, and heart. Additionally, mincle activation was stimulated in experimental non-alcoholic steatohepatitis (NASH) by treatment with mincle agonist trehalose-6,6-dibehenate (TDB). In human NASH, mincle is upregulated with increased collagen production. In ApoE deficient mice fed high-fat western diet (NASH model), mincle activation significantly increases hepatic collagen production. In human cirrhosis, mincle expression is also significantly upregulated. Furthermore, mincle expression is associated with the stage of chronic liver disease. This could be confirmed in rat models of cirrhosis and ACLF. ACLF was induced by LPS injection in cirrhotic rats. While mincle expression and downstream signaling via FC receptor gamma, SYK, and NF-kappa-B are upregulated in the liver, they are downregulated in PBMCs of these rats. Although mincle expressed on macrophages might be beneficial for intestinal barrier integrity, it seems to contribute to inflammation and fibrosis once the intestinal barrier becomes leaky in advanced stages of chronic liver disease.

Keywords: ACLF, Bacterial translocation, Fibrosis, Inflammation, NASH


Pose, E., Napoleone, L., Amin, A., Campion, D., Jimenez, C., Piano, S., Roux, O., Uschner, F. E., de Wit, K., Zaccherini, G., Alessandria, C., Angeli, P., Bernardi, M., Beuers, U., Caraceni, P., Durand, F., Mookerjee, R. P., Trebicka, J., Vargas, V., Andrade, R. J., Carol, M., Pich, J., Ferrero, J., Domenech, G., Llopis, M., Torres, F., Kamath, P. S., Abraldes, J. G., Solà, E., Ginès, P., (2020). Safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial The Lancet Gastroenterology and Hepatology 5, (1), 31-41

Background Statins have beneficial effects on intrahepatic circulation and decrease portal hypertension and rifaximin modulates the gut microbiome and might prevent bacterial translocation in patients with cirrhosis. Therefore, this drug combination might be of therapeutic benefit in patients with decompensated cirrhosis. However, there is concern regarding the safety of statins in patients with decompensated cirrhosis. We assessed the safety of two different doses of simvastatin, in combination with rifaximin, in patients with decompensated cirrhosis. Methods We did a double-blind, randomised, placebo-controlled, phase 2 trial in patients with decompensated cirrhosis and moderate-to-severe liver failure from nine university hospitals in six European countries (Italy, France, Holland, Germany, the UK, and Spain). Patients older than 18 years with Child-Pugh class B or C disease were eligible. We randomly assigned patients (1:1:1) to receive either simvastatin 40 mg/day plus rifaximin 1200 mg/day, simvastatin 20 mg/day plus rifaximin 1200 mg/day, or placebo of both medications for 12 weeks. Randomisation was stratified according to Child-Pugh class (B vs C) and restricted using blocks of multiples of three. The primary endpoint was development of liver or muscle toxicity, as defined by changes in liver aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), alkaline phosphastase, and creatine kinase. The study is registered with the European Union Clinical Trials Register, 2016-004499-23, and with ClinicalTrials.gov, NCT03150459. Findings The study recruitment period was between July 28, 2017, and Jan 2, 2018. Follow-up finished on March 12, 2018. 50 patients were randomly assigned to simvastatin 40 mg/day plus rifaximin 1200 mg/day (n=18), simvastatin 20 mg/day plus rifaximin 1200 mg/day (n=16), or placebo of both medications (n=16). Six patients (two from each group) were excluded. Therefore, the full analysis set included 44 patients (16 in the simvastatin 40 mg/day plus rifaximin 1200 mg/day group, 14 in the simvastatin 20 mg/day plus rifaximin mg/day group, and 14 in the placebo group). After a safety analyses when the first ten patients completed treatment, treatment was stopped prematurely in the simvastatin 40 mg/day plus rifaximin group due to recommendations by the data safety monitoring board. Patients in the simvastatin 40 mg/day plus rifaximin group showed a significant increase in AST and ALT compared with the placebo group (mean differences between the groups at the end of treatment for AST 130 IU/L [95% CI 54 to 205; p=0·0009] and for ALT 61 IU/L [22 to 100; p=0·0025]. We observed no significant differences at 12 weeks in AST and ALT between the simvastatin 20 mg/day plus rifaximin and placebo group (for AST −14 IU/L [–91 to 64; p=0·728] and for ALT −8 IU/L [–49 to 33; p=0·698]). We observed no significant differences in alkaline phosphatase between the the simvastatin 40 mg/day plus rifaximin or the simvastatin 20 mg/day plus rifaximin groups compared with placebo. Patients in the simvastatin 40 mg/day plus rifaximin group showed an increase in creatine kinase at the end of treatment compared with patients in the placebo group (1009 IU/L [208 to 1809]; p=0·014). We observed no significant changes in creatine kinase in the simvastatin 20 mg/day plus rifaximin group (4·2 IU/L [–804 to 813]; p=0·992). Three (19%) patients in the simvastatin 40 mg/day group developed liver and muscle toxicity consistent with rhabdomyolysis. The number of patients who stopped treatment because of adverse events was significantly higher in the simvastatin 40 mg/day plus rifaximin group (nine [56%] of 16 patients) compared with the other two groups (two [14%] of 14 for both groups; p=0·017). There were no serious unexpected adverse reactions reported during the study. Interpretation Treatment with simvastatin 40 mg/day plus rifaximin in patients with decompensated cirrhosis was associated with a significant increase in adverse events requiring treatment withdrawal, particularly rhabdomyolysis, compared with simvastatin 20 mg/day plus rifaximin. We recommend simvastatin 20 mg/day as the dose to be used in studies investigating the role of statins in patients with decompensated cirrhosis.


Kaang, Byung Kwon, Mestre, Rafael, Kang, Dong-Chang, Sánchez, Samuel, Kim, Dong-Pyo, (2020). Scalable and integrated flow synthesis of triple-responsive nano-motors via microfluidic Pickering emulsification Applied Materials Today 21, 100854

Artificial micro-/nano-motors are tiny machines as newly emerging tools capable of achieving numerous tasks. In principle, the self-phoretic motions require asymmetric structures in geometry and chemistry. However, conventional production techniques suffered from complex and time consuming multi-step process in low uniformity, and difficult to endow multi-functions into motors. This work disclosed a continuous-flow synthesis of triple-responsive (thermophoretic, chemical and magnetic movement) nano-motors (m-SiO2/Fe3O4-Pdop/Pt) via microfluidic Pickering emulsification in a process of integrated and scalable manner. The droplet microfluidic process allows efficient self-assembly of the silica nanoparticles surrounding the spherical interface of resin droplet, rendering excellent Pickering efficiency and reproducibility, and followed by anisotropic decoration of polydopamine (Pdop) and Pt catalyst in a serial flow process. The obtained Janus nanoparticles reveal double- or triple-responsive self-propulsions with synergic mobility by combining thermophoresis powered by light, catalytic driven motion in H2O2 or magnetic movement by magnet. Further, a non-metallic polydopamine based thermophoretic motion as well as an automated nano-cleaner for rapid water purification by dye removal are convincingly functioned. Finally, this novel integrated flow strategy proves a scalable manufacturing production (> 0.7 g hr−1) of the nano-motors using inexpensive single microreactor, fulfilling quantitative and qualitative needs for versatile applications.

Keywords: Microfluidics Pickering emulsions, Triple-responsive motor, Adsorbent


Xu, D., Wang, Y., Liang, C., You, Y., Sanchez, S., Ma, X., (2020). Self-propelled micro/nanomotors for on-demand biomedical cargo transportation Small 16, (27), 1902464

Micro/nanomotors (MNMs) are miniaturized machines that can perform assigned tasks at the micro/nanoscale. Over the past decade, significant progress has been made in the design, preparation, and applications of MNMs that are powered by converting different sources of energy into mechanical force, to realize active movement and fulfill on-demand tasks. MNMs can be navigated to desired locations with precise controllability based on different guidance mechanisms. A considerable research effort has gone into demonstrating that MNMs possess the potential of biomedical cargo loading, transportation, and targeted release to achieve therapeutic functions. Herein, the recent advances of self-propelled MNMs for on-demand biomedical cargo transportation, including their self-propulsion mechanisms, guidance strategies, as well as proof-of-concept studies for biological applications are presented. In addition, some of the major challenges and possible opportunities of MNMs are identified for future biomedical applications in the hope that it may inspire future research.

Keywords: Biomedical applications, Cargo transportation, Guidance strategies, Micro/nanomotors, Self-propulsion


De Corato, Marco, Arqué, Xavier, Patiño, Tania, Arroyo, Marino, Sánchez, Samuel, Pagonabarraga, Ignacio, (2020). Self-propulsion of active colloids via ion release: Theory and experiments Physical Review Letters 124, (10), 108001

We study the self-propulsion of a charged colloidal particle that releases ionic species using theory and experiments. We relax the assumptions of thin Debye length and weak nonequilibrium effects assumed in classical phoretic models. This leads to a number of unexpected features that cannot be rationalized considering the classic phoretic framework: an active particle can reverse the direction of motion by increasing the rate of ion release and can propel even with zero surface charge. Our theory predicts that there are optimal conditions for self-propulsion and a novel regime in which the velocity is insensitive to the background electrolyte concentration. The theoretical results quantitatively capture the salt-dependent velocity measured in our experiments using active colloids that propel by decomposing urea via a surface enzymatic reaction.


Moghimiardekani, A., Molina, B. G., Enshaei, H., del Valle, L. J., Pérez-Madrigal, M. M., Estrany, F., Alemán, C., (2020). Semi-interpenetrated hydrogels-microfibers electroactive assemblies for release and real-time monitoring of drugs Macromolecular Bioscience 20, (7), 2000074

Simultaneous drug release and monitoring using a single polymeric platform represents a significant advance in the utilization of biomaterials for therapeutic use. Tracking drug release by real-time electrochemical detection using the same platform is a simple way to guide the dosage of the drug, improve the desired therapeutic effect, and reduce the adverse side effects. The platform developed in this work takes advantage of the flexibility and loading capacity of hydrogels, the mechanical strength of microfibers, and the capacity of conducting polymers to detect the redox properties of drugs. The engineered platform is prepared by assembling two spin-coated layers of poly-γ-glutamic acid hydrogel, loaded with poly(3,4-ethylenedioxythiophene) (PEDOT) microparticles, and separated by a electrospun layer of poly-ε-caprolactone microfibers. Loaded PEDOT microparticles are used as reaction nuclei for the polymerization of poly(hydroxymethyl-3,4-ethylenedioxythiophene) (PHMeDOT), that semi-interpenetrate the whole three layered system while forming a dense network of electrical conduction paths. After demonstrating its properties, the platform is loaded with levofloxacin and its release monitored externally by UV–vis spectroscopy and in situ by using the PHMeDOT network. In situ real-time electrochemical monitoring of the drug release from the engineered platform holds great promise for the development of multi-functional devices for advanced biomedical applications.

Keywords: Biosensors, Conducting polymers, Drug delivery, Poly-γ-glutamic acid, Poly-ε-caprolactone


Sierra, J., Marrugo-Ramírez, J., Rodriguez-Trujillo, R., Mir, M., Samitier, J., (2020). Sensor-integrated microfluidic approaches for liquid biopsies applications in early detection of cancer Sensors 20, (5), 1317

Cancer represents one of the conditions with the most causes of death worldwide. Common methods for its diagnosis are based on tissue biopsies—the extraction of tissue from the primary tumor, which is used for its histological analysis. However, this technique represents a risk for the patient, along with being expensive and time-consuming and so it cannot be frequently used to follow the progress of the disease. Liquid biopsy is a new cancer diagnostic alternative, which allows the analysis of the molecular information of the solid tumors via a body fluid draw. This fluid-based diagnostic method displays relevant advantages, including its minimal invasiveness, lower risk, use as often as required, it can be analyzed with the use of microfluidic-based platforms with low consumption of reagent, and it does not require specialized personnel and expensive equipment for the diagnosis. In recent years, the integration of sensors in microfluidics lab-on-a-chip devices was performed for liquid biopsies applications, granting significant advantages in the separation and detection of circulating tumor nucleic acids (ctNAs), circulating tumor cells (CTCs) and exosomes. The improvements in isolation and detection technologies offer increasingly sensitive and selective equipment’s, and the integration in microfluidic devices provides a better characterization and analysis of these biomarkers. These fully integrated systems will facilitate the generation of fully automatized platforms at low-cost for compact cancer diagnosis systems at an early stage and for the prediction and prognosis of cancer treatment through the biomarkers for personalized tumor analysis.

Keywords: Cancer, Circulant tumor cells (CTC), Circulant tumor DNA (ctDNA), Exosomes, Liquid biopsy, Microfluidic, Sensors


Alcon, Clara, Manzano-Muñoz, Albert, Prada, Estela, Mora, Jaume, Soriano, Aroa, Guillén, Gabriela, Gallego, Soledad, Roma, Josep, Samitier, Josep, Villanueva, Alberto, Montero, Joan, (2020). Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance Cell Death & Disease 11, (8), 634

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood and adolescence. Refractory/relapsed RMS patients present a bad prognosis that combined with the lack of specific biomarkers impairs the development of new therapies. Here, we utilize dynamic BH3 profiling (DBP), a functional predictive biomarker that measures net changes in mitochondrial apoptotic signaling, to identify anti-apoptotic adaptations upon treatment. We employ this information to guide the use of BH3 mimetics to specifically inhibit BCL-2 pro-survival proteins, defeat resistance and avoid relapse. Indeed, we found that BH3 mimetics that selectively target anti-apoptotic BCL-xL and MCL-1, synergistically enhance the effect of clinically used chemotherapeutic agents vincristine and doxorubicin in RMS cells. We validated this strategy in vivo using a RMS patient-derived xenograft model and observed a reduction in tumor growth with a tendency to stabilization with the sequential combination of vincristine and the MCL-1 inhibitor S63845. We identified the molecular mechanism by which RMS cells acquire resistance to vincristine: an enhanced binding of BID and BAK to MCL-1 after drug exposure, which is suppressed by subsequently adding S63845. Our findings validate the use of DBP as a functional assay to predict treatment effectiveness in RMS and provide a rationale for combining BH3 mimetics with chemotherapeutic agents to avoid tumor resistance, improve treatment efficiency, and decrease undesired secondary effects.


Benz, F., Bogen, A., Praktiknjo, M., Jansen, C., Meyer, C., Wree, A., Demir, M., Loosen, S., Vucur, M., Schierwagen, R., Tacke, F., Trebicka, J., Roderburg, C., (2020). Serum levels of bone sialoprotein correlate with portal pressure in patients with liver cirrhosis PLoS ONE 15, (4), e0231701

Liver cirrhosis represents the common end-stage of chronic liver diseases regardless of its etiology. Patients with compensated disease are mostly asymptomatic, however, progression to a decompensated disease stage is common. The available stratification strategies are often unsuitable to identify patients with a higher risk for disease progression and a limited prognosis. SIBLINGs, soluble glycophosphoproteins, are secreted into the blood by immune-cells. While osteopontin, the most prominent member of the SIBLINGs family, has been repeatedly associated with liver cirrhosis, data on the diagnostic and/or prognostic value of bone sialoprotein (BSP) are scarce and partly inconclusive. In this study, we analyzed the diagnostic and prognostic potential of circulating BSP in comparison to other standard laboratory markers in a large cohort of patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt (TIPS). Serum levels of BSP were similar in patients with different disease stages and were not indicative for prognosis. Interestingly, BSP serum levels did correlate inversely with portal pressure, as well as its surrogates such as platelet count, the portal vein cross-sectional area and correlated positively with the portal venous velocity. In summary, our data highlight that BSP might represent a previously unrecognized marker for portal hypertension in patients with liver cirrhosis.


Torner, M., Mangal, A., Scharnagl, H., Jansen, C., Praktiknjo, M., Queck, A., Gu, W., Schierwagen, R., Lehmann, J., Uschner, F. E., Graf, C., Strassburg, C. P., Fernandez, J., Stojakovic, T., Woitas, R., Trebicka, J., (2020). Sex specificity of kidney markers to assess prognosis in cirrhotic patients with TIPS Liver International 40, (1), 186-193

Background & Aims: Renal function assessed by creatinine is a key prognostic factor in cirrhotic patients. However, creatinine is influenced by several factors, rendering interpretation difficult in some situations. This is especially important in early stages of renal dysfunction where renal impairment might not be accompanied by an increase in creatinine. Other parameters, such as cystatin C (CysC) and beta‐trace protein (BTP), have been evaluated to fill this gap. However, none of these studies have considered the role of the patient's sex. The present study analysed CysC and BTP to evaluate their prognostic value and differentiate them according to sex. Patients and methods: CysC and BTP were measured in 173 transjugular intrahepatic portosystemic shunt (TIPS)-patients from the NEPTUN-STUDY(NCT03628807) and analysed their relationship with mortality and sex. Propensity score for age, MELD, etiology and TIPS indication was used. Results: Cystatin C and BTP showed excellent correlations with creatinine values at baseline and follow-up. CysC was an independent predictor of overall mortality (HR = 1.66(1.33-2.06)) with an AUC of 0.75 and identified a cut-off of 1.55 mg/L in the whole cohort. Interestingly, CysC was significantly lower in females, also after propensity score matching. In males, the only independent predictor was the creatinine level (HR = 1.54(1.25-1.58)), while in females CysC levels independently predicted mortality (HR = 3.17(1.34-7.52)). Conclusion: This study demonstrates for the first time that in TIPS-patients creatinine predicts mortality in males better than in females, whereas CysC is a better predictor of mortality in females. These results may influence future clinical decisions on therapeutic options for example, allocation for liver transplantation in TIPS-patients.

Keywords: Beta-trace protein, Cirrhosis, Cystatin C, Portal hypertension, Renal function


Cremonese, C., Schierwagen, R., Uschner, F. E., Torres, S., Tyc, O., Ortiz, C., Schulz, M., Queck, A., Kristiansen, G., Bader, M., Sauerbruch, T., Weiskirchen, R., Walther, T., Trebicka, J., Klein, S., (2020). Short-term western diet aggravates non-alcoholic fatty liver disease (NAFLD) with portal hypertension in TGR(mREN2)27 rats International Journal of Molecular Sciences 21, (9), 3308

Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity. Especially, the development of fibrosis and portal hypertension in NAFLD patients requires treatment. Transgenic TGR(mREN2)27 rats overexpressing mouse renin spontaneously develop NAFLD with portal hypertension but without obesity. This study investigated the additional role of obesity in this model on the development of portal hypertension and fibrosis. Obesity was induced in twelve-week old TGR(mREN2)27 rats after receiving Western diet (WD) for two or four weeks. Liver fibrosis was assessed using standard techniques. Hepatic expression of transforming growth factor-β1 (TGF-β1), collagen type Iα1, α-smooth muscle actin, and the macrophage markers Emr1, as well as the chemoattractant Ccl2, interleukin-1β (IL1β) and tumor necrosis factor-α (TNFα) were analyzed. Assessment of portal and systemic hemodynamics was performed using the colored microsphere technique. As expected, WD induced obesity and liver fibrosis as confirmed by Sirius Red and Oil Red O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were increased during feeding of WD, indicating infiltration of macrophages into the liver, even though this increase was statistically not significant for the EGF module-containing mucin-like receptor (Emr1) mRNA expression levels. Of note, portal pressure increased with the duration of WD compared to animals that received a normal chow. Besides obesity, WD feeding increased systemic vascular resistance reflecting systemic endothelial and splanchnic vascular dysfunction. We conclude that transgenic TGR(mREN2)27 rats are a suitable model to investigate NAFLD development with liver fibrosis and portal hypertension. Tendency towards elevated expression of Emr1 is associated with macrophage activity point to a significant role of macrophages in NAFLD pathogenesis, probably due to a shift of the renin–angiotensin system towards a higher activation of the classical pathway. The hepatic injury induced by WD in TGR(mREN2)27 rats is suitable to evaluate different stages of fibrosis and portal hypertension in NAFLD with obesity.

Keywords: ADGRE1, EMR1, F4/80, Immunity, Liver fibrosis, Macrophage, NAFLD, Portal hypertension, TGR(mREN2)27, Western diet


Sanz-Fraile, H., Amoros, S., Mendizabal, I., Galvez-Monton, C., Prat-Vidal, C., Bayes-Genis, A., Navajas, D., Farre, R., Otero, J., (2020). Silk-reinforced collagen hydrogels with raised multiscale stiffness for mesenchymal cells 3D culture Tissue Engineering - Part A 26, (5-6), 358-370

Type I collagen hydrogels are of high interest in tissue engineering. With the evolution of 3D bioprinting technologies, a high number of collagen-based scaffolds have been reported for the development of 3D cell cultures. A recent proposal was to mix collagen with silk fibroin derived from Bombyx mori silkworm. Nevertheless, due to the difficulties in the preparation and the characteristics of the protein, several problems such as phase separation and collagen denaturation appear during the procedure. Therefore, the common solution is to diminish the concentration of collagen although in that way the most biologically relevant component is reduced. In this study, we present a new, simple, and effective method to develop a collagen-silk hybrid hydrogel with high collagen concentration and with increased stiffness approaching that of natural tissues, which could be of high interest for the development of cardiac patches for myocardial regeneration and for preconditioning of mesenchymal stem cells (MSCs) to improve their therapeutic potential. Sericin in the silk was preserved by using a physical solubilizing procedure that results in a preserved fibrous structure of type I collagen, as shown by ultrastructural imaging. The macro- and micromechanical properties of the hybrid hydrogels measured by tensile stretch and atomic force microscopy, respectively, showed a more than twofold stiffening than the collagen-only hydrogels. Rheological measurements showed improved printability properties for the developed biomaterial. The suitability of the hydrogels for 3D cell culture was assessed by 3D bioprinting bone marrow-derived MSCs cultured within the scaffolds. The result was a biomaterial with improved printability characteristics that better resembled the mechanical properties of natural soft tissues while preserving biocompatibility owing to the high concentration of collagen. In this study, we report the development of silk microfiber-reinforced type I collagen hydrogels for 3D bioprinting and cell culture. In contrast with previously reported studies, a novel physical method allowed the preservation of the silk sericin protein. Hydrogels were stable, showed no phase separation between the biomaterials, and they presented improved printability. An increase between two- and threefold of the multiscale stiffness of the scaffolds was achieved with no need of using additional crosslinkers or complex methods, which could be of high relevance for cardiac patches development and for preconditioning mesenchymal stem cells (MSCs) for therapeutic applications. We demonstrate that bone marrow-derived MSCs can be effectively bioprinted and 3D cultured within the stiffened structures.

Keywords: 3D bioprinting, Collagen, Hydrogel, Mesenchymal cells, Multiscale mechanics, Silk


Molina, B. G., Bendrea, A. D., Lanzalaco, S., Franco, L., Cianga, L., del Valle, L. J., Puiggali, J., Turon, P., Armelin, E., Cianga, I., Alemán, C., (2020). Smart design for a flexible, functionalized and electroresponsive hybrid platform based on poly(3,4-ethylenedioxythiophene) derivatives to improve cell viability Journal of Materials Chemistry B 8, (38), 8864-8877

Development of smart functionalized materials for tissue engineering has attracted significant attention in recent years. In this work we have functionalized a free-standing film of isotactic polypropylene (i-PP), a synthetic polymer that is typically used for biomedical applications (e.g. fabrication of implants), for engineering a 3D all-polymer flexible interface that enhances cell proliferation by a factor of ca. three. A hierarchical construction process consisting of three steps was engineered as follows: (1) functionalization of i-PP by applying a plasma treatment, resulting in i-PPf; (2) i-PPf surface coating with a layer of polyhydroxymethy-3,4-ethylenedioxythiophene nanoparticles (PHMeEDOT NPs) by in situ chemical oxidative polymerization of HMeEDOT; and (3) deposition on the previously activated and PHMeEDOT NPs coated i-PP film (i-PPf/NP) of a graft conjugated copolymer, having a poly(3,4-ethylenedioxythiophene) (PEDOT) backbone, and randomly distributed short poly(ε-caprolactone) (PCL) side chains (PEDOT-g-PCL), as a coating layer of ∼9 μm in thickness. The properties of the resulting bioplatform, which can be defined as a robust macroscopic composite coated with a “molecular composite”, were investigated in detail, and both adhesion and proliferation of two human cell lines have been evaluated, as well. The results demonstrate that the incorporation of the PEDOT-g-PCL layer significantly improves cell attachment and cell growth not only when compared to i-PP but also with respect to the same platform coated with only PEDOT, constructed in a similar manner, as a control.


De Corato, M., Pagonabarraga, I., Abdelmohsen, L. K. E. A., Sánchez, S., Arroyo, M., (2020). Spontaneous polarization and locomotion of an active particle with surface-mobile enzymes Physical Review Fluids 5, (12), 122001

We examine a mechanism of locomotion of active particles whose surface is uniformly coated with mobile enzymes. The enzymes catalyze a reaction that drives phoretic flows but their homogeneous distribution forbids locomotion by symmetry. We find that the ability of the enzymes to migrate over the surface combined with self-phoresis can lead to a spontaneous symmetry-breaking instability whereby the homogeneous distribution of enzymes polarizes and the particle propels. The instability is driven by the advection of enzymes by the phoretic flows and occurs above a critical Péclet number. The transition to polarized motile states occurs via a supercritical or subcritical pitchfork bifurcations, the latter of which enables hysteresis and coexistence of uniform and polarized states.

Keywords: Biomimetic & bio-inspired materials, Locomotion, Surface-driven phase separation


López-Carral, Héctor, Grechuta, Klaudia, Verschure, P., (2020). Subjective ratings of emotive stimuli predict the impact of the COVID-19 quarantine on affective states PLoS ONE PLOS ONE , 15, (8), e0237631

The COVID-19 crisis resulted in a large proportion of the world’s population having to employ social distancing measures and self-quarantine. Given that limiting social interaction impacts mental health, we assessed the effects of quarantine on emotive perception as a proxy of affective states. To this end, we conducted an online experiment whereby 112 participants provided affective ratings for a set of normative images and reported on their well-being during COVID-19 self-isolation. We found that current valence ratings were significantly lower than the original ones from 2015. This negative shift correlated with key aspects of the personal situation during the confinement, including working and living status, and subjective well-being. These findings indicate that quarantine impacts mood negatively, resulting in a negatively biased perception of emotive stimuli. Moreover, our online assessment method shows its validity for large-scale population studies on the impact of COVID-19 related mitigation methods and well-being.


Maleeva, Galyna, Nin-Hill, Alba, Rustler, Karin, Petukhova, Elena, Ponomareva, Daria, Mukhametova, Elvira, Gomila-Juaneda, Alexandre, Wutz, Daniel, Alfonso-Prieto, Mercedes, König, Burkhard, Gorostiza, Pau, Bregestovski, Piotr, (2020). Subunit-specific photocontrol of glycine receptors by azobenzene-nitrazepam photoswitcher eneuro 8, (1), 0294-20

Photopharmacology is a unique approach that through a combination of photochemistry methods and advanced life science techniques allows the study and control of specific biological processes, ranging from intracellular pathways to brain circuits. Recently, a first photochromic channel blocker of anion-selective GABAA receptors, Azo-NZ1, has been described. In the present study using patch-clamp technique in heterologous system and in mice brain slices, site-directed mutagenesis and molecular modelling we provide evidence of the interaction of Azo-NZ1 with glycine receptors (GlyRs) and determine the molecular basis of this interaction. Glycinergic synaptic neurotransmission determines an important inhibitory drive in the vertebrate nervous system and plays a crucial role in the control of neuronal circuits in the spinal cord and brain stem. GlyRs are involved in locomotion, pain sensation, breathing and auditory function, as well as in the development of such disorders as hyperekplexia, epilepsy and autism. Here we demonstrate that Azo-NZ1 blocks in a UV dependent manner the activity of alpha2 GlyRs (GlyR2), while being barely active on alpha1 GlyRs (GlyR1). The site of Azo-NZ1 action is in the chloride-selective pore of GlyR at the 2’ position of transmembrane helix 2 and amino acids forming this site determine the difference in Azo-NZ1 blocking activity between GlyR2 and GlyR1. This subunit specific modulation is also shown on motoneurons of brainstem slices from neonatal mice that switch during development from expressing "foetal" GlyR2 to "adult" GlyR1 receptors. Significance Statement Photochromic molecules are becoming widely used for studying and modulating various biological processes. Successful application of these compounds, whose activity can be controlled with light, potentially provides a promising tool for future therapeutic approaches. The main advantage of such compounds is their precise spatial and temporal selectivity, a property that favours specific drug action and diminishes their side effects. In the present study, we describe in detail the interaction of the novel azobenzene-nitrazepam-based photochromic compound (Azo-NZ1) with glycine receptors (GlyRs) and determine its subunit-specific blocking activity in the Cl-selective pore of GlyRs. This compound offers a new strategy for specific control of glycinergic circuits and stepping stone for design of new GlyR-active drugs.

Keywords: Brain slices, Glycine receptors, Hypoglossal motoneurons, Molecular modelling, Patch-clamp, Photopharmacology


Puigbò, J. Y., Arsiwalla, X. D., González-Ballester, M. A., Verschure, P., (2020). Switching operation modes in the neocortex via cholinergic neuromodulation Molecular Neurobiology 57, (1), 139-149

In order to deal with the uncertainty in the world, our brains need to be able to flexibly switch between the exploration of new sensory representations and exploitation of previously acquired ones. This requires forming accurate estimations of what and how much something is expected. While modeling has allowed for the development of several ways to form predictions, how the brain could implement those is still under debate. Here, we recognize acetylcholine as one of the main neuromodulators driving learning based on uncertainty, promoting the exploration of new sensory representations. We identify its interactions with cortical inhibitory interneurons and derive a biophysically grounded computational model able to capture and learn from uncertainty. This model allows us to understand inhibition beyond gain control by suggesting that different interneuron subtypes either encode predictions or estimate their uncertainty, facilitating detection of unexpected cues. Moreover, we show how acetylcholine-like neuromodulation uniquely interacts with global and local sources of inhibition, disrupting perceptual certainty and promoting the rapid acquisition of new perceptual cues. Altogether, our model proposes that cortical acetylcholine favors sensory exploration over exploitation in a cortical microcircuit dedicated to estimating sensory uncertainty.


De Coen, R., Nuhn, L., Perera, C., Arista-Romero, M., Risseeuw, M. D. P., Freyn, A., Nachbagauer, R., Albertazzi, L., Van Calenbergh, S., Spiegel, D. A., Peterson, B. R., De Geest, B. G., (2020). Synthetic rhamnose glycopolymer cell-surface receptor for endogenous antibody recruitment Biomacromolecules 21, (2), 793-802

Synthetic materials capable of engineering the immune system are of great relevance in the fight against cancer to replace or complement the current monoclonal antibody and cell therapy-based immunotherapeutics. Here, we report on antibody recruiting glycopolymers (ARGPs). ARGPs consist of polymeric copies of a rhamnose motif, which can bind endogenous antirhamnose antibodies present in human serum. As a proof-of-concept, we have designed ARGPs with a lipophilic end group that efficiently inserts into cell-surface membranes. We validate the specificity of rhamnose to attract antibodies from human serum to the target cell surface and demonstrate that ARGPs outperform an analogous small-molecule compound containing only one single rhamnose motif. The ARGP concept opens new avenues for the design of potent immunotherapeutics that mark target cells for destruction by the immune system through antibody-mediated effector functions.


Lidón, Laia, Vergara, Cristina, Ferrer, Isidro, Hernández, Félix, Ávila, Jesús, del Rio, Jose A., Gavín, Rosalina, (2020). Tau protein as a new regulator of cellular prion protein transcription Molecular Neurobiology 57, (10), 4170-4186

Cellular prion protein (PrPC) is largely responsible for transmissible spongiform encephalopathies (TSEs) when it becomes the abnormally processed and protease resistant form PrPSC. Physiological functions of PrPC include protective roles against oxidative stress and excitotoxicity. Relevantly, PrPC downregulates tau levels, whose accumulation and modification are a hallmark in the advance of Alzheimer's disease (AD). In addition to the accumulation of misfolded proteins, in the initial stages of AD-affected brains display both increased reactive oxygen species (ROS) markers and levels of PrPC. However, the factors responsible for the upregulation of PrPC are unknown. Thus, the aim of this study was to uncover the different molecular actors promoting PrPC overexpression. In order to mimic early stages of AD, we used β-amyloid-derived diffusible ligands (ADDLs) and tau cellular treatments, as well as ROS generation, to elucidate their particular roles in human PRNP promoter activity. In addition, we used specific chemical inhibitors and site-specific mutations of the PRNP promoter sequence to analyze the contribution of the main transcription factors involved in PRNP transcription under the analyzed conditions. Our results revealed that tau is a new modulator of PrPC expression independently of ADDL treatment and ROS levels. Lastly, we discovered that the JNK/c-jun-AP-1 pathway is involved in increased PRNP transcription activity by tau but not in the promoter response to ROS.

Keywords: Alzheimer’s disease, Cellular prion protein, Promoter, Tau, Tauopathies


Maiti, B., Abramov, A., Franco, L., Puiggalí, J., Enshaei, H., Alemán, C., Díaz, D. D., (2020). Thermoresponsive shape-memory hydrogel actuators made by phototriggered click chemistry Advanced Functional Materials 30, (24), 2001683

This article describes the design and synthesis of a new series of hydrogel membranes composed of trialkyne derivatives of glycerol ethoxylate and bisphenol A diazide (BA-diazide) or diazide-terminated PEG600 monomer via a Cu(I)-catalyzed photoclick reaction. The water-swollen hydrogel membranes display thermoresponsive actuation and their lower critical solution temperature (LCST) values are determined by differential scanning calorimetry. Glycerol ethoxylate moiety serves as the thermoresponsive component and hydrophilic part, while the azide-based component acts as the hydrophobic comonomer and most likely provides a critical hydrophobic/hydrophilic balance contributing also to the significant mechanical strength of the membranes. These hydrogels exhibit a reversible shape-memory effect in response to temperature through a defined phase transition. The swelling and deswelling behavior of the membranes are systematically examined. Due to the click nature of the reaction, easy availability of azide and alkyne functional-monomers, and the polymer architecture, the glass transition temperature (Tg) is easily controlled through monomer design and crosslink density by varying the feed ratio of different monomers. The mechanical properties of the membranes are studied by universal tensile testing measurements. Moreover, the hydrogels show the ability to absorb a dye and release it in a controlled manner by applying heat below and above the LCST.

Keywords: Hydrogels, Membranes, Photoclick, Polymers, Shape-memory, Thermoresponsive


Monferrer, Ezequiel, Martínn-Vañó, Susana, Carretero, Aitor, Garcíaa-Lizarribar, Andrea, Burgos-Panadero, Rebeca, Navarro, Samuel, Samitier, Josep, Noguera, Rosa, (2020). A three-dimensional bioprinted model to evaluate the effect of stiffness on neuroblastoma cell cluster dynamics and behavior Scientific Reports 10, (1), 6370

Three-dimensional (3D) bioprinted culture systems allow to accurately control microenvironment components and analyze their effects at cellular and tissue levels. The main objective of this study was to identify, quantify and localize the effects of physical-chemical communication signals between tumor cells and the surrounding biomaterial stiffness over time, defining how aggressiveness increases in SK-N-BE(2) neuroblastoma (NB) cell line. Biomimetic hydrogels with SK-N-BE(2) cells, methacrylated gelatin and increasing concentrations of methacrylated alginate (AlgMA 0%, 1% and 2%) were used. Young’s modulus was used to define the stiffness of bioprinted hydrogels and NB tumors. Stained sections of paraffin-embedded hydrogels were digitally quantified. Human NB and 1% AlgMA hydrogels presented similar Young´s modulus mean, and orthotopic NB mice tumors were equally similar to 0% and 1% AlgMA hydrogels. Porosity increased over time; cell cluster density decreased over time and with stiffness, and cell cluster occupancy generally increased with time and decreased with stiffness. In addition, cell proliferation, mRNA metabolism and antiapoptotic activity advanced over time and with stiffness. Together, this rheological, optical and digital data show the potential of the 3D in vitro cell model described herein to infer how intercellular space stiffness patterns drive the clinical behavior associated with NB patients.

Keywords: Biomaterials - cells, Paediatric cancer


Hakimi, O., Krallinger, M., Ginebra, M. P., (2020). Time to kick-start text mining for biomaterials Nature Reviews Materials 5, (8), 553-556

The rapidly expanding biomaterials data are challenging to organize. Text mining systems are powerful tools that automatically extract and integrate information in large textual collections. As text mining leaps forward by leveraging deep-learning approaches, it is time to address the most pressing biomaterials information and data processing needs.


Vidal, E., Torres, D., Guillem-Marti, J., Scionti, G., Manero, J. M., Ginebra, M. P., Rodríguez, D., Rupérez, E., (2020). Titanium scaffolds by direct ink writing: Fabrication and functionalization to guide osteoblast behavior Metals 10, (9), 1156

Titanium (Ti) and Ti alloys have been used for decades for bone prostheses due to its mechanical reliability and good biocompatibility. However, the high stiffness of Ti implants and the lack of bioactivity are pending issues that should be improved to minimize implant failure. The stress shielding effect, a result of the stiffness mismatch between titanium and bone, can be reduced by introducing a tailored structural porosity in the implant. In this work, porous titanium structures were produced by direct ink writing (DIW), using a new Ti ink formulation containing a thermosensitive hydrogel. A thermal treatment was optimized to ensure the complete elimination of the binder before the sintering process, in order to avoid contamination of the titanium structures. The samples were sintered in argon atmosphere at 1200 °C, 1300 °C or 1400 °C, resulting in total porosities ranging between 72.3% and 77.7%. A correlation was found between the total porosity and the elastic modulus of the scaffolds. The stiffness and yield strength were similar to those of cancellous bone. The functionalization of the scaffold surface with a cell adhesion fibronectin recombinant fragment resulted in enhanced adhesion and spreading of osteoblastic-like cells, together with increased alkaline phosphatase expression and mineralization.

Keywords: Direct ink writing, Osseointegration, Recombinant protein, Thermoresponsive binder, Titanium, Titanium scaffold


Praktiknjo, M., Simón-Talero, M., Römer, J., Roccarina, D., Martínez, J., Lampichler, K., Baiges, A., Low, G., Llop, E., Maurer, M. H., Zipprich, A., Triolo, M., Maleux, G., Fialla, A. D., Dam, C., Vidal-González, J., Majumdar, A., Picón, C., Toth, D., Darnell, A., Abraldes, J. G., López, M., Jansen, C., Chang, J., Schierwagen, R., Uschner, F., Kukuk, G., Meyer, C., Thomas, D., Wolter, K., Strassburg, C. P., Laleman, W., La Mura, V., Ripoll, C., Berzigotti, A., Calleja, J. L., Tandon, P., Hernandez-Gea, V., Reiberger, T., Albillos, A., Tsochatzis, E. A., Krag, A., Genescà , J., Trebicka, J., (2020). Total area of spontaneous portosystemic shunts independently predicts hepatic encephalopathy and mortality in liver cirrhosis Journal of Hepatology 72, (6), 1140-1150

Background & Aims: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that the presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, the presence of >1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcomes in patients with liver cirrhosis. Methods: In this retrospective international multicentric study, CT scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. One-year survival was the primary endpoint and acute decompensation (oHE, variceal bleeding, ascites) was the secondary endpoint. Results: A total of 301 patients (169 male) were included in the training cohort. Thirty percent of all patients presented with >1 SPSS. A TSA cut-off of 83 mm2 was used to classify patients with small or large TSA (S-/L-TSA). Patients with L-TSA presented with higher model for end-stage liver disease score (11 vs. 14) and more commonly had a history of oHE (12% vs. 21%, p <0.05). During follow-up, patients with L-TSA experienced more oHE episodes (33% vs. 47%, p <0.05) and had lower 1-year survival than those with S-TSA (84% vs. 69%, p <0.001). Multivariate analysis identified L-TSA (hazard ratio 1.66; 95% CI 1.02–2.70, p <0.05) as an independent predictor of mortality. An independent multicentric validation cohort of 607 patients confirmed that patients with L-TSA had lower 1-year survival (77% vs. 64%, p <0.001) and more oHE development (35% vs. 49%, p <0.001) than those with S-TSA. Conclusion: This study suggests that TSA >83 mm2 increases the risk for oHE and mortality in patients with cirrhosis. Our results support the clinical use of TSA/SPSS for risk stratification and decision-making in the management of patients with cirrhosis. Lay summary: The prevalence of spontaneous portosystemic shunts (SPSS) is higher in patients with more advanced chronic liver disease. The presence of more than 1 SPSS is common in advanced chronic liver disease and is associated with the development of hepatic encephalopathy. This study shows that total cross-sectional SPSS area (rather than diameter of the single largest SPSS) predicts survival in patients with advanced chronic liver disease. Our results support the clinical use of total cross-sectional SPSS area for risk stratification and decision-making in the management of SPSS.

Keywords: ACLF, Acute decompensation, Acute-on-chronic liver failure, Ascites, Cirrhosis, Computed tomography, Hepatic encephalopathy, Liver, Portal hypertension, Spontaneous portosystemic shunt, SPSS, TIPS


Lanzalaco, S., Turon, P., Weis, C., Mata, C., Planas, E., Alemán, C., Armelin, E., (2020). Toward the new generation of surgical meshes with 4D response: Soft, dynamic, and adaptable Advanced Functional Materials 30, (36), 2004145

Herein, a facile approach toward transforming a 2D polypropylene flexible mesh material into a 4D dynamic system is presented. The versatile platform, composed by a substrate of knitted fibers of isotactic polypropylene (iPP) mesh and a coating of thermosensitive poly(N‐isopropylacrylamide‐co‐N,N’‐methylene bis(acrylamide) (PNIPAAm‐co‐MBA) hydrogel, covalently bonded to the mesh surface, after cold‐plasma surface treatment and radical polymerization, is intended to undergo variations in its geometry via its reversible folding/unfolding behavior. The study is the first to trace the 3D movement of a flat surgical mesh, intended to repair hernia defects, under temperature and humidity control. An infrared thermographic camera and an optical microscope are used to evaluate the macroscopic and microscopic structure stimulus response. The presence of the PP substrate and the distribution of the gel surrounding the PP threads, affect both the PNIPAAM gel expansion/contraction as well as the time of folding/unfolding response. Furthermore, PP‐g‐PNIPAAm meshes show an increase in the bursting strength of ≈16% with respect to the uncoated mesh, offering a strongest and adaptable system for its future implantation in human body. The findings reported offer unprecedented application possibilities in the biomedical field.

Keywords: Dynamic devices, Polypropylene meshes, Surgical implants, Thermosensitive hydrogels


Cilloni, Daniela, Petiti, Jessica, Campia, Valentina, Podestà , Marina, Squillario, Margherita, Montserrat, Nuria, Bertaina, Alice, Sabatini, Federica, Carturan, Sonia, Berger, Massimo, Saglio, Francesco, Bandini, Giuseppe, Bonifazi, Francesca, Fagioli, Franca, Moretta, Lorenzo, Saglio, Giuseppe, Verri, Alessandro, Barla, Annalisa, Locatelli, Franco, Frassoni, Francesco, (2020). Transplantation induces profound changes in the transcriptional asset of hematopoietic stem cells: Identification of specific signatures using machine learning techniques Journal of Clinical Medicine 9, (6), 1670

During the phase of proliferation needed for hematopoietic reconstitution following transplantation, hematopoietic stem/progenitor cells (HSPC) must express genes involved in stem cell self-renewal. We investigated the expression of genes relevant for self-renewal and expansion of HSPC (operationally defined as CD34+ cells) in steady state and after transplantation. Specifically, we evaluated the expression of ninety-one genes that were analyzed by real-time PCR in CD34+ cells isolated from (i) 12 samples from umbilical cord blood (UCB); (ii) 15 samples from bone marrow healthy donors; (iii) 13 samples from bone marrow after umbilical cord blood transplant (UCBT); and (iv) 29 samples from patients after transplantation with adult hematopoietic cells. The results show that transplanted CD34+ cells from adult cells acquire an asset very different from transplanted CD34+ cells from cord blood. Multivariate machine learning analysis (MMLA) showed that four specific gene signatures can be obtained by comparing the four types of CD34+ cells. In several, but not all cases, transplanted HSPC from UCB overexpress reprogramming genes. However, these remarkable changes do not alter the commitment to hematopoietic lineage. Overall, these results reveal undisclosed aspects of transplantation biology.

Keywords: Hematopoietic stem/progenitor cell, Cord blood, Stem cell transplantation


Scarpa, E., de Pace, C., Joseph, A. S., de Souza, S. C., Poma, A., Liatsi-Douvitsa, E., Contini, C., de Matteis, V., Samitier, J., Battaglia, G., Rizzello, L., (2020). Tuning cell behavior with nanoparticle shape PLoS ONE 15, (11), e0240197

We investigated how the shape of polymeric vesicles, made by the exact same material, impacts the replication activity and metabolic state of both cancer and non-cancer cell types. First, we isolated discrete geometrical structures (spheres and tubes) from a heterogeneous sample using density-gradient centrifugation. Then, we characterized the cellular internalization and the kinetics of uptake of both types of polymersomes in different cell types (either cancer or non-cancer cells). We also investigated the cellular metabolic response as a function of the shape of the structures internalized and discovered that tubular vesicles induce a significant decrease in the replication activity of cancer cells compared to spherical vesicles. We related this effect to the significant up-regulation of the tumor suppressor genes p21 and p53 with a concomitant activation of caspase 3/7. Finally, we demonstrated that combining the intrinsic shape-dependent effects of tubes with the delivery of doxorubicin significantly increases the cytotoxicity of the system. Our results illustrate how the geometrical conformation of nanoparticles could impact cell behavior and how this could be tuned to create novel drug delivery systems tailored to specific biomedical application.


Andrzejak, R. G., Ruzzene, G., Schöll, E., Omelchenko, I., (2020). Two populations of coupled quadratic maps exhibit a plentitude of symmetric and symmetry broken dynamics Chaos 30, (3), 033125

We numerically study a network of two identical populations of identical real-valued quadratic maps. Upon variation of the coupling strengths within and across populations, the network exhibits a rich variety of distinct dynamics. The maps in individual populations can be synchronized or desynchronized. Their temporal evolution can be periodic or aperiodic. Furthermore, one can find blends of synchronized with desynchronized states and periodic with aperiodic motions. We show symmetric patterns for which both populations have the same type of dynamics as well as chimera states of a broken symmetry. The network can furthermore show multistability by settling to distinct dynamics for different realizations of random initial conditions or by switching intermittently between distinct dynamics for the same realization. We conclude that our system of two populations of a particularly simple map is the most simple system that can show this highly diverse and complex behavior, which includes but is not limited to chimera states. As an outlook to future studies, we explore the stability of two populations of quadratic maps with a complex-valued control parameter. We show that bounded and diverging dynamics are separated by fractal boundaries in the complex plane of this control parameter.


Trepat, X., (2020). When cellular forces became visible Nature Reviews Molecular Cell Biology 21, (5), 253

Rodriguez, J., Schulz, S., Voss, A., Giraldo, B. F., (2020). Cardiorespiratory and vascular variability analysis to classify patients with ischemic and dilated cardiomyopathy* Engineering in Medicine & Biology Society (EMBC) 42nd Annual International Conference of the IEEE , IEEE (Montreal, Canada) , 2764-2767

Heart diseases are the leading cause of death in developed countries. Ascertaining the etiology of cardiomyopathies is still a challenge. The objective of this study was to classify cardiomyopathy patients through cardio, respiratory and vascular variability analysis, considering the vascular activity as the input and output of the baroreflex response. Forty-one cardiomyopathy patients (CMP) classified as ischemic (ICM, 24 patients) and dilated (DCM, 17 patients) were analyzed. Thirty-nine elderly control subjects (CON) were used as reference. From the electrocardiographic, respiratory flow, and blood pressure signals, following temporal series were extracted: beat-to-beat intervals (BBI), total respiratory cycle time series (TT), and end– systolic (SBP) and diastolic (DBP) blood pressure amplitudes, respectively. Three-dimensional representation of the cardiorespiratory and vascular activities was characterized geometrically, by fitting a polygon that contains 95% of data, and by statistical descriptive indices. The best classifiers were used to build support vector machine models. The optimal model to classify ICM versus DCM patients achieved 92.7% accuracy, 94.1% sensitivity, and 91.7% specificity. When comparing CMP patients and CON subjects, the best model achieved 86.2% accuracy, 82.9% sensitivity, and 89.7% specificity. These results suggest a limited ability of cardiac and respiratory systems response to regulate the vascular variability in these patients.

Keywords: Time series analysis, Support vector machines, Blood pressure, Sensitivity, Indexes, Electrocardiography, Kernel


Amil, Adrián F., Puigbó, J.-Y., Verschure, P., (2020). Cholinergic control of chaos and evidence sensitivity in a neocortical model of perceptual decision-making Biomimetic and Biohybrid Systems 9th International Conference, Living Machines 2020 (Lecture Notes in Computer Science) , Springer International Publishing (Freiburg, Germany) 12413, 92-96

Perceptual decision-making in the brain is commonly modeled as a competition among tuned cortical populations receiving stimulation according to their perceptual evidence. However, the contribution of evidence on the decision-making process changes through time. In this regard, the mechanisms controlling the sensitivity to perceptual evidence remain unknown. Here we explore this issue by using a biologically constrained model of the neocortex performing a dual-choice perceptual discrimination task. We combine mutual and global GABAergic inhibition, which are differentially regulated by acetylcholine (ACh), a neuromodulator linked to enhanced stimulus discriminability. We find that, while mutual inhibition determines the phase-space separation between two stable attractors representing each stimulus, global inhibition controls the formation of a chaotic attractor in-between the two, effectively protecting the weakest stimulus. Hence, under low ACh levels, where global inhibition dominates, the decision-making process is chaotic and less determined by the difference between perceptual evidences. On the contrary, under high ACh levels, where mutual inhibition dominates, the network becomes very sensitive to small differences between stimuli. Our results are in line with the putative role of ACh in enhanced stimulus discriminability and suggest that ACh levels control the sensitivity to sensory inputs by regulating the amount of chaos.

Keywords: Acetylcholine, Cortical model, Decision-making, Chaos


Solà-Soler, J., Giraldo, B. F., (2020). Comparison of ECG-eerived respiration estimation methods on healthy subjects in function of recording site and subject position and gender Engineering in Medicine & Biology Society (EMBC) 42nd Annual International Conference of the IEEE , IEEE (Montreal, Canada) , 2650-2653

Respiration rate can be assessed by analyzing respiratory changes of the electrocardiogram (ECG). Several methods can be applied to derive the respiratory signal from the ECG (EDR signal). In this study, four EDR estimation methods based on QRS features were analyzed. A database with 44 healthy subjects (16 females) in supine and sitting positions was analyzed. Respiratory flow and ECG recordings on leads I, II, III and a Chest lead was studied. A QR slope-based method, an RS slope-based method, an QRS angle-based method and an QRS area-based method were applied. Their performance was evaluated by the correlation coefficient with the reference respiratory volume signal. Significantly higher correlation coefficients in the range r = 0.77 – 0.86 were obtained with the Chest lead for all methods. The EDR estimation method based on the QRS angle provided the highest similarity with the volume signal for all recording leads and subject positions. We found no statistically significant differences according to gender or subject position.Clinical Relevance— This work analyzes the EDR signal from four electrocardiographic leads to obtain the respiratory signal and contributes to a simplified analysis of respiratory activity.

Keywords: Electrocardiography, Lead, Estimation, Correlation coefficient, Databases, Heart, Correlation


Blancas, Maria, Valero, Cristina, Mura, Anna, Vouloutsi, Vasiliki, Verschure, P., (2020). "CREA": An inquiry-based methodology to teach robotics to children Robotics in Education International Conference on Robotics in Education (RiE) , Springer International Publishing (Vienna, Austria) Advances in Intelligent Systems and Computing (AISC, volume 1023), 45-51

Learning programming and robotics offers the opportunity to practice problem-solving, creativity, and team-work and it provides important competencies to train for the 21st century. However, programming can be challenging, and children may encounter difficulties in learning the syntax or using the coding environment. To address this issue, we have developed a methodology for teaching programming, design and robotics based on inquiry-based learning and hands-on oriented activities together with visual programming. We have applied and evaluated this new methodology within the extracurricular activity of an international elementary school in Barcelona. Our findings showed acquisition and learning of technical language, understanding of electronics devices, understanding the mapping of coding into action via the robot’s behavior. This suggests that our approach is a valid and effective teaching methodology for the instructional design of robotics and programming.

Keywords: Educational technology, Instructional design, Robotics


Guerrero, O., Verschure, P., (2020). Distributed adaptive control: An ideal cognitive architecture candidate for managing a robotic recycling plant Biomimetic and Biohybrid Systems 9th International Conference, Living Machines 2020 (Lecture Notes in Computer Science) , Springer International Publishing (Freiburg, Germany) 12413, 153-164

In the past decade, society has experienced notable growth in a variety of technological areas. However, the Fourth Industrial Revolution has not been embraced yet. Industry 4.0 imposes several challenges which include the necessity of new architectural models to tackle the uncertainty that open environments represent to cyber-physical systems (CPS). Waste Electrical and Electronic Equipment (WEEE) recycling plants stand for one of such open environments. Here, CPSs must work harmoniously in a changing environment, interacting with similar and not so similar CPSs, and adaptively collaborating with human workers. In this paper, we support the Distributed Adaptive Control (DAC) theory as a suitable Cognitive Architecture for managing a recycling plant. Specifically, a recursive implementation of DAC (between both single-agent and large-scale levels) is proposed to meet the expected demands of the European Project HR-Recycler. Additionally, with the aim of having a realistic benchmark for future implementations of the recursive DAC, a micro-recycling plant prototype is presented.

Keywords: Cognitive architecture, Distributed Adaptive Control, Recycling plant, Navigation, Motor control, Human-Robot Interaction


Romero, D., Jané, R., (2020). Hypoxia-induced effects on ECG depolarization by time warping analysis during recurrent obstructive apnea Engineering in Medicine & Biology Society (EMBC) 42nd Annual International Conference of the IEEE , IEEE (Montreal, Canada) , 2626-2629

In this work, we evaluated a non-linear approach to estimate morphological variations in ECG depolarization, in the context of intermittent hypoxia (IH). Obstructive apnea sequences were provoked for 15 minutes in anesthetized Sprague-Dawley rats, alternating with equal periods of normal breathing, in a recurrent obstructive sleep apnea (OSA) model. Each apnea episode lasted 15 s, while the frequency used for each sequence was randomly selected. Average heartbeats obtained before the start and at the end of each episode, were delineated to extract only the QRS wave. Then, the segmented QRS waves were non-linearly aligned using the dynamic time warping (DWT) algorithm. Morphological QRS changes in both the amplitude and temporal domains were estimated from this alignment procedure. The hypoxic and basal segments were analyzed using ECG (lead I) recordings acquired during the experiment. To assess the effects of IH over time, the changes relative to the basal QRS wave were determined, in the intervals prior to each successive events until the end of the experiment. The results showed a progressive increase in the amplitude and time-domain morphological markers of the QRS wave along the experiment, which were strongly correlated with the changes in traditional QRS markers (r ≈ 0.9). Significant changes were found between pre-apnea and hypoxic measures only for the time-domain analysis (p<0.001), probably due to the short duration of the simulated apnea episodes.Clinical relevance Increased variability in ECG depolarization morphology during recurrent hypoxic episodes would be closely related to the expression of cardiovascular dysfunction in OSA patients.

Keywords: Electrocardiography, Rats, Heart rate variability, Sleep apnea, Protocols, Heuristic algorithms


Freire, Ismael T., Urikh, D., Arsiwalla, X. D., Verschure, P., (2020). Machine morality: From harm-avoidance to human-robot cooperation Biomimetic and Biohybrid Systems 9th International Conference, Living Machines 2020 (Lecture Notes in Computer Science) , Springer International Publishing (Freiburg, Germany) 12413, 116-127

We present a new computational framework for modeling moral decision-making in artificial agents based on the notion of ‘Machine Morality as Cooperation’. This framework integrates recent advances from cross-disciplinary moral decision-making literature into a single architecture. We build upon previous work outlining cognitive elements that an artificial agent would need for exhibiting latent morality, and we extend it by providing a computational realization of the cognitive architecture of such an agent. Our work has implications for cognitive and social robotics. Recent studies in human neuroimaging have pointed to three different decision-making processes, Pavlovian, model-free and model-based, that are defined by distinct neural substrates in the brain. Here, we describe how computational models of these three cognitive processes can be implemented in a single cognitive architecture by using the distributed and hierarchical organization proposed by the DAC theoretical framework. Moreover, we propose that a pro-social drive to cooperate exists at the Pavlovian level that can also bias the rest of the decision system, thus extending current state-of-the-art descriptive models based on harm-aversion.

Keywords: Morality, Moral decision-making, Computational models, Cognitive architectures, Cognitive robotics, Human-robot interaction


Estrada-Petrocelli, L., Jané, R., Torres, A., (2020). Neural respiratory drive estimation in respiratory sEMG with cardiac arrhythmias Engineering in Medicine & Biology Society (EMBC) 42nd Annual International Conference of the IEEE , IEEE (Montreal, Canada) , 2748-2751

Neural respiratory drive as measured by the electromyography allows the study of the imbalance between the load on respiratory muscles and its capacity. Surface respiratory electromyography (sEMG) is a non-invasive tool used for indirectly assessment of NRD. It also provides a way to evaluate the level and pattern of respiratory muscle activation. The prevalence of electrocardiographic activity (ECG) in respiratory sEMG signals hinders its proper evaluation. Moreover, the occurrence of abnormal heartbeats or cardiac arrhythmias in respiratory sEMG measures can make even more challenging the NRD estimation. Respiratory sEMG can be evaluated using the fixed sample entropy (fSampEn), a technique which is less affected by cardiac artefacts. The aim of this work was to investigate the performance of the fSampEn, the root mean square (RMS) and the average rectified value (ARV) on respiratory sEMG signals with supraventricular arrhythmias (SVA) for NRD estimation. fSampEn, ARV and RMS parameters increased as the inspiratory load increased during the test. fSampEn was less influenced by ECG with SVAs for the NRD estimation showing a greater response to respiratory sEMG, reflected with a higher percentage increase with increasing load (228 % total increase, compared to 142 % and 135 % for ARV and RMS, respectively).

Keywords: Electrocardiography, Muscles, Electrodes, Estimation, Band-pass filters, Electromyography, Heart beat


Lozano-García, M., Nuhic, J., Moxham, J., Rafferty, G. F., Jolley, C. J., Jané, R., (2020). Performance evaluation of fixed sample entropy for lung sound intensity estimation Engineering in Medicine & Biology Society (EMBC) 42nd Annual International Conference of the IEEE , IEEE (Montreal, Canada) , 2740-2743

Lung sound (LS) signals are often contaminated by impulsive artifacts that complicate the estimation of lung sound intensity (LSI) using conventional amplitude estimators. Fixed sample entropy (fSampEn) has proven to be robust to cardiac artifacts in myographic respiratory signals. Similarly, fSampEn is expected to be robust to artifacts in LS signals, thus providing accurate LSI estimates. However, the choice of fSampEn parameters depends on the application and fSampEn has not previously been applied to LS signals. This study aimed to perform an evaluation of the performance of the most relevant fSampEn parameters on LS signals, and to propose optimal fSampEn parameters for LSI estimation. Different combinations of fSampEn parameters were analyzed in LS signals recorded in a heterogeneous population of healthy subjects and chronic obstructive pulmonary disease patients during loaded breathing. The performance of fSampEn was assessed by means of its cross-covariance with flow signals, and optimal fSampEn parameters for LSI estimation were proposed.

Keywords: Large scale integration, Lung, Estimation, Entropy, Loading, Robustness, Diseases


Wang, S., Hu, Y., Burgués, J., Marco, S., Liu, S.-L., (2020). Prediction of gas concentration using gated recurrent neural networks 2nd IEEE International Conference on Artificial Intelligence Circuits and Systems (AICAS) , IEEE (Genova, Italy) , 178-182

Low-cost gas sensors allow for large-scale spatial monitoring of air quality in the environment. However they require calibration before deployment. Methods such as multivariate regression techniques have been applied towards sensor calibration. In this work, we propose instead, the use of deep learning methods, particularly, recurrent neural networks for predicting the gas concentrations based on the outputs of these sensors. This paper presents a first study of using Gated Recurrent Unit (GRU) neural network models for gas concentration prediction. The GRU networks achieve on average, a 44.69% and a 25.17% RMSE improvement in concentration prediction on a gas dataset when compared with Support Vector Regression (SVR) and Multilayer Perceptron (MLP) models respectively. With the current advances in deep network hardware accelerators, these networks can be combined with the sensors for a compact embedded system suitable for edge applications.

Keywords: Robot sensing systems, Predictive models, Logic gates, Gas detectors, Training, Temperature measurement, Support vector machines


Romero, D., Lázaro, J., Jané, R., Laguna, P., Bailón, R., (2020). A quaternion-based approach to estimate respiratory rate from the vectorcardiogram Computers in Cardiology (CinC) 2020 Computing in Cardiology , IEEE (Rimini, Italy) 47, 1-4

A novel ECG-derived respiration (EDR) approach is presented to efficiently estimate the respiratory rate. It combines spatial rotations and magnitude variations of the heart's electrical vector due to respiration. Orthogonal leads X, Y and Z from 10 volunteers were analyzed during a tilt table test. The largest vector magnitude (VM) within each QRS loop was assessed, and its 3D coordinates were converted into unit quaternion qb. Angular distances between these quaternions and the axes of the reference coordinate system, θ x , θ y and θ z , were then computed as EDR signals to track their relative variations caused by respiration. The respiratory rate was estimated on the spectrum of individual EDR signals obtained from the angular distances and VM time-series, but also on EDR signals obtained by principal component analysis (PCA). Relative errors (eR) to the reference respiratory signal exhibited relatively low values. The combination of EDR signals' spectrum {θ X ,θ Y, θ Z , VM} (eR=0.63±4.15%) and individual signals derived from θ X (e R =0.46±8.22%) and PCA (eR=0.36±6.58%) achieved the overall best results. The proposed method represents a computationally efficient alternative to other EDR approaches, but its robustness should be further investigated. The method could be enhanced if combined with other features tracking morphological changes induced by respiration.

Keywords: Heart, Three-dimensional displays, Quaternions, Robustness, Computational efficiency, Cardiology, Principal component analysis


Blanco-Almazan, D., Romero, D., Groenendaal, W., Lijnen, L., Smeets, C., Ruttens, D., Catthoor, F., Jané, R., (2020). Relationship between heart rate recovery and disease severity in chronic obstructive pulmonary disease patients Computers in Cardiology (CinC) 2020 Computing in Cardiology , IEEE (Rimini, Italy) 47, 1-4

Chronic obstructive pulmonary disease (COPD) patients exhibit impaired autonomic control which can be assessed by heart rate variability analysis. The study aims to evaluate the cardiac autonomic responses of COPD patients after completing a conventional six-minute walk test (6MWT). Fifty COPD patients were included in the study, for which an ECG signal (lead II) was acquired by a wearable device, before, during, and after the test. We used the heart rate (HR) time-series to assess the heart rate dynamic during recovery. The heart rate recovery (HRR) marker was evaluated every 5 s after the 6MWT and showed different dynamic trends among severity groups. We compared the HRR among patient groups classified according to the GOLD standard. Significantly larger normalized HRR values (nHRR) were found in mild COPD patients (n=23, GOLD={1,2}; nHRR 1 =14.B±7.5 %, nHRR 2 =18.6±8.1 %) compared to those with more disease severity (n=23, GOLD={3,4}; nHRR 1 =9.3±5.8 %, p=0.002; and nHRR 2 = 13.7±6.7%, p=0.041). The largest differences were observed around the first 30 s of the recovery phase (nHRR=10.8±6.6 % vs. nHRR=5.6±4 % p=0.001). Our results showed a slower recovery for the severest patients, suggesting that cardiac parameters like the ones we propose here, may provide valuable information for a better characterization of COPD severity.

Keywords: Pulmonary diseases, Wearable computers, Electrocardiography, Market research, Cardiology, Heart rate variability


Lozano-García, M., Davidson, C. M., Prieto-Ramón, C., Moxham, J., Rafferty, G. F., Jolley, C. J., Jané, R., (2020). Spatial distribution of normal lung sounds in healthy individuals under varied inspiratory load and flow conditions Engineering in Medicine & Biology Society (EMBC) 42nd Annual International Conference of the IEEE , IEEE (Montreal, Canada) , 2744-2747

Respiratory sounds yield pertinent information about respiratory function in both health and disease. Normal lung sound intensity is a characteristic that correlates well with airflow and it can therefore be used to quantify the airflow changes and limitations imposed by respiratory diseases. The dual aims of this study are firstly to establish whether previously reported asymmetries in normal lung sound intensity are affected by varying the inspiratory threshold load or the airflow of respiration, and secondly to investigate whether fixed sample entropy can be used as a valid measure of lung sound intensity. Respiratory sounds were acquired from twelve healthy individuals using four contact microphones on the posterior skin surface during an inspiratory threshold loading protocol and a varying airflow protocol. The spatial distribution of the normal lung sounds intensity was examined. During the protocols explored here the normal lung sound intensity in the left and right lungs in healthy populations was found to be similar, with asymmetries of less than 3 dB. This agrees with values reported in other studies. The fixed sample entropy of the respiratory sound signal was also calculated and compared with the gold standard root mean square representation of lung sound intensity showing good agreement.


Vouloutsi, V., Chesson, A., Blancas, M., Guerrero, O., Verschure, P., (2020). The use of social sensorimotor contingencies in humanoid robots Biomimetic and Biohybrid Systems 9th International Conference, Living Machines 2020 (Lecture Notes in Computer Science) , Springer International Publishing (Freiburg, Germany) 12413, 378-389

This pilot study investigates the role of social sensorimotor contingencies as exhibited from a humanoid robot to allow mutual understanding and social entrainment in a group social activity. The goal is to evaluate whether sensorimotor contingencies can lead to transparent and understandable interactions while we explore the dimension of personality. We propose the task of taking a selfie with a robot and a group of humans as the benchmark to evaluate the social sensorimotor contingencies displayed. We have constructed two models of interaction with an introverted and extroverted robot. We also seek to address the gap in research in context and personality of social sensorimotor contingencies in HRI and contribute to the field of personality in social robotics by determining what type of behaviour of the robot attracts certain personalities in humans in group settings. Although the sample size was small, and there were no significant differences between conditions, results suggest that the expression of sensorimotor contingencies can lead to successful coupling and interactions.

Keywords: Human-robot interaction, Personality, Social robots, Social sensorimotor contingencies


De Pace, Cesare, Marchello, Gabriele, Perez, Lorena Ruiz, Battaglia, Giuseppe, (2020). Brownian tomography of biomolecules and soft polymer assemblies Microscopy and Microanalysis Microscopy and Microanalysis 2020 , Cambridge University Press (Virtual) 26, (S2), 1024-1025

One of the most powerful techniques for structural determination is electron microscopy (EM), which is able to achieve imaging at atomic resolution. However, EM requires keeping the beam under high vacuum to avoid undesired scattering in the electron path. This drawback leads to solidification techniques (such as controlled drying cryogenic techniques), which may alter the microstructure and chemical nature of the sample. The mesoscopic structure of biological and soft specimens is controlled by the presence of their media. Fast vitrification overcame these drawbacks; yet, cryogenic TEM works on static snapshots and does not allow the observation of dynamic events.


Abasolo, Ibane, Seras-Franzoso, Joaquin, Díaz-Riascos, Zamira Vanessa, Corchero, José Luis, González, Patricia, García-Aranda, Natalia, Mandaña, Monica, Riera, Roger, Boullosa, Ana, Mancilla, Sandra, Grayston, Alba, Moltó-Abad, Marc, Garcia-Fruitós, Elena, Mendoza, Rosa, Pintos-Morell, Guillem, Albertazzi, Lorenzo, Rosell, Anna, Casas, Josefina, Villaverde, Antonio, Schwartz, Simó, (2020). Extracellular vesicles increase the enzymatic activity of lysosomal proteins and improve the efficacy of enzyme replacement therapy in Fabry disease Molecular Genetics and Metabolism 16th Annual Research Meeting of the WORLDSymposium , Elsevier (Orlando, USA) 129, (2), S16

Mencattini, A., Di Giuseppe, D., D'Orazio, M., Rizzuto, V., Manu Pereira, M. M., Colomba Comes, M., Lopez-Martinez, M. J., Samitier, J., Martinelli, E., (2020). A microfluidic device for shape measurement in red blood cells (RBCs) IEEE International Workshop on Medical Measurement and Applications (MEMEA) , IEEE (Bari, Italy) , 1-5

Modern optical sensors coupled with time-lapse microscopy devices and dedicated software tools allow the miniaturization of laboratories for biological experiments leading to the Organ-On-Chip (OoC) framework. OoCs allow performing massive measurements on a large number of cells under the assumption of reproducibility conditions, permitting to investigate the cell dynamics in terms of motility and shape changes over time. In this work, we present the OoC platform used in a preliminary study of the Rare Haemolytic Anaemia (RHA) disease, a group of rare diseases characterized by haemolysis, which is the premature loss of red blood cells (RBCs). Preliminary results demonstrate the effectiveness of shape measurement for the diagnosis of RHA.

Keywords: Anaemia diagnosis, Cell tracking, Plasticity measurement, Time-lapse microscopy


Nin-Hill, Alba, Maleeva, Galyna, Gomila-Juaneda, Alexandre, Wutz, Daniel, Rustler, Karin, Bautista-Barrufet, Antoni, Rovira, Xavier, Bosch, Miquel, Scholze, Petra, Peiretti, Franck, Rovira, Carme, König, Burkhard, Gorostiza, Pau, Bregestovski, Piotr, Prieto, Mercedes Alfonso, (2020). Photomodulation of inhibitory neurotransmission. Insights from molecular modeling Biophysical Journal Biophysical Society 64th Annual Meeting , CellPress (San Diego (USA)) 118, (3), 325a-326a

Photoswitches are molecules that change their conformation with light of specific wavelength. These light-regulated molecules can be designed to target ion channels, thus providing a unique tool for precise spatial and temporal control of ion channel functioning. Recently, we have applied a multidisciplinary approach to design, synthesize and functionally characterize two of such photoswitches, azo-NZ1 [Maleeva et al. Br. J. Pharmacol. 2019] and Glyght [Gomila-Juaneda et al. BioRxiv 2019], targeting GABA and glycine receptors, respectively. Using homology modeling and molecular docking, we have provided a molecular explanation of the light-dependent effect of these two photoswitchable ligands, as observed in in vitro electrophysiology experiments and in vivo tadpole behavioral assays. Azo-NZ1 is composed of a nitrazepam moiety merged to an azobenzene photoisomerizable group, yet it has an inhibitory effect on GABA A receptors under visible light and also inhibits benzodiazepine-insensitive GABA C (rho2) receptors. Molecular modeling, combined with electrophysiology and mutagenesis experiments, shows that addition of the sulfonyl azobenzene unexpectedly converts the ligand into a pore blocker. Glyght is also an azobenzene-containing benzodiazepine, yet it acts selectively on glycine receptors as a negative modulator and its inhibitory action increases under UV light. Molecular modeling suggests that Glyght binds to a novel allosteric site located at the interface between the extracellular and transmembrane domains. The two aforementioned photoswitches pave the way towards photomanipulation of inhibitory (gabaergic and glycinergic) neurotransmission, with potential applications in understanding inhibitory circuits in intact animals and in development of drug-based phototherapies


Winkler, Pamina, Campelo, Felix, Giannotti, Marina, García-Parajo, María, (2020). Planar plasmonic antenna arrays resolve transient nanoscopic heterogeneities in biological membranes Single Molecule Spectroscopy and Superresolution Imaging XIII SPIE BiOS 2020 , SPIE (San Francisco, USA) 11246, 112460F

We introduce an innovative design of planar plasmonic nanogap antenna arrays and demonstrate its potential to study the spatiotemporal organization of mimetic biological membranes at the nanoscale. We exploit our novel nanogap antenna platform with different nanogap sizes (10-45 nm) combined with fluorescence correlation spectroscopy to reveal the existence of nanoscopic domains in mimetic biological membranes. Our approach takes advantage of the highly enhanced and confined excitation light provided by the antennas together with their extreme planarity to investigate membrane regions as small as 10 nm in size with microsecond temporal resolution. We first demonstrate the ultra-high confinement of photonic antennas on biological membranes. Moreover, we show that cholesterol slows down the diffusion of individual fluorescent molecules embedded in the lipid bilayer, consistent with the formation of nanoscopic domains enriched by cholesterol. Incorporation of hyaluronic acid (HA) to the ternary lipid mixture further slows down molecular diffusion, suggesting a synergistic effect of cholesterol and HA on the dynamic partitioning of mimetic biological membranes.


Almici, Enrico, Caballero, David, Montero, Joan, Samitier, Josep, (2020). 3D neuroblastoma in vitro models using engineered cell-derived matrices Biomaterials for 3D Tumor Modeling (ed. Kundu, Subhas C., Reis, Rui L.), Elsevier (Amsterdam, Netherlands) , 107-130

Neuroblastoma (NB) is a malignant tumor that affects the peripheral nervous system and represents one of the most frequent cancers in infants. Its prognosis is poor in older patients and the presence of genetic abnormalities. Metastasis is often present at the time of diagnosis, making treatment more intensive and unsuccessful. Poor prognosis and variable treatment efficacy require a better understanding of the underlying biology. Evidence has shown that the tumor microenvironment is the characteristic of tumor malignancy and progression. A more highly differentiated tissue phenotype represents a positive prognostic marker, while the tumoral tissue is characterized by a distinct composition and morphology of the extracellular matrix (ECM). In this chapter, we discuss the application of decellularized cell-derived matrices (CDMs) to model in vitro the morphology of the ECM encountered in histological hallmarks of NB patients. This technique allows for the in vitro reproduction of the fine structure and composition of native microenvironments. Because of recent advances in culture systems and decellularization techniques, it is possible to engineer CDM composition and microarchitecture to produce differentiated models of tissue niches. The final goal is to repopulate the “scaffold” with malignant NB cells for drug screening and target discovery applications, studying the impact of patient-inspired tissues on signaling, migration, and tissue remodeling.

Keywords: Neuroblastoma, Cancer, Bioengineering, Tumor microenvironment, Cell-derived matrices, Decellularization


Rahman, Abdel, Ganesh, Swapnil, Torrents, Eduard, Jahan, Nusrat, Wedyan, Moh'd Ali, Qaisi, Ali M., Al-Tawaha, Abdelrazzaq, (2020). Algal viruses Applied Plant Virology (ed. Awasthi, L. P.), Academic Press (London, UK) Advances, Detection, and Antiviral Strategies, 237-246

In marine ecosystems, the algae community is abundant and plays an important role in the food web. On the other hand, algal viruses have different advantages and disadvantages depending on the properties, such as applications of algal viruses in the advancement of molecular biology and for enhancement of biofuel production. Many environmental factors affecting growth and development of algae and virus such as temperature, salinity, ultraviolet radiation, photosynthetic active radiation, nutrients, inorganic particles, organic particles, CO2 concentration, and pH.

Keywords: Algal viruses, Biofuel production, Nutrients


Conti, S., Kato, T., Park, D., Sahai, E., Trepat, X., Labernadie, A., (2020). CAFs and cancer cells co-migration in 3D spheroid invasion assay Methods in Molecular Biology (ed. Campbell, K., Thevenea, E.), Humana Press (New York, USA) 2179, 243-256

In many solid tumors, collective cell invasion prevails over single-cell dissemination strategies. Collective modes of invasion often display specific front/rear cellular organization, where invasive leader cells arise from cancer cell populations or the tumor stroma. Collective invasion involves coordinated cellular movements which require tight mechanical crosstalk through specific combinations of cell–cell interactions and cell–matrix adhesions. Cancer Associated Fibroblasts (CAFs) have been recently reported to drive the dissemination of epithelial cancer cells through ECM remodeling and direct intercellular contact. However, the cooperation between tumor and stromal cells remains poorly understood. Here we present a simple spheroid invasion assay to assess the role of CAFs in the collective migration of epithelial tumor cells. This method enables the characterization of 3D spheroid invasion patterns through live cell fluorescent labeling combined with spinning disc microscopy. When embedded in extracellular matrix, the invasive strands of spheroids can be tracked and leader/follower organization of CAFs and cancer cells can be quantified.

Keywords: 3D spheroid invasion, Cancer associated fibroblasts, Collective migration, Epithelial cancer cells, Leader/follower cells


Otero, J., Navajas, D., Alcaraz, J., (2020). Characterization of the elastic properties of extracellular matrix models by atomic force microscopy Methods in Cell Biology (ed. Caballero, David, Kundu, Subhas C., Reis, Rui L.), Academic Press (Cambridge, USA) 156, 59-83

Tissue elasticity is a critical regulator of cell behavior in normal and diseased conditions like fibrosis and cancer. Since the extracellular matrix (ECM) is a major regulator of tissue elasticity and function, several ECM-based models have emerged in the last decades, including in vitro endogenous ECM, decellularized tissue ECM and ECM hydrogels. The development of such models has urged the need to quantify their elastic properties particularly at the nanometer scale, which is the relevant length scale for cell-ECM interactions. For this purpose, the versatility of atomic force microscopy (AFM) to quantify the nanomechanical properties of soft biomaterials like ECM models has emerged as a very suitable technique. In this chapter we provide a detailed protocol on how to assess the Young's elastic modulus of ECM models by AFM, discuss some of the critical issues, and provide troubleshooting guidelines as well as illustrative examples of AFM measurements, particularly in the context of cancer.

Keywords: 3D ECM hydrogels, Atomic force microscopy, Decellularized tissue, Elastic modulus, Endogenous ECM, Extracellular matrix


Almici, Enrico, Caballero, David, Montero, Joan, Samitier, Josep, (2020). Engineering cell-derived matrices with controlled 3D architectures for pathophysiological studies Methods in Cell Biology (ed. Caballero, David, Kundu, Subhas C., Reis, Rui Luís), Academic Press (Cambridge, USA) 156, 161-183

The composition and architecture of the extracellular matrix (ECM) and their dynamic alterations, play an important regulatory role on numerous cellular processes. Cells embedded in 3D scaffolds show phenotypes and morphodynamics reminiscent of the native scenario. This is in contrast to flat environments, where cells display artificial phenotypes. The structural and biomolecular properties of the ECM are critical in regulating cell behavior via mechanical, chemical and topological cues, which induce cytoskeleton rearrangement and gene expression. Indeed, distinct ECM architectures are encountered in the native stroma, which depend on tissue type and function. For instance, anisotropic geometries are associated with ECM degradation and remodeling during tumor progression, favoring tumor cell invasion. Overall, the development of innovative in vitro ECM models of the ECM that reproduce the structural and physicochemical properties of the native scenario is of upmost importance to investigate the mechanistic determinants of tumor dissemination. In this chapter, we describe an extremely versatile technique to engineer three-dimensional (3D) matrices with controlled architectures for the study of pathophysiological processes in vitro. To this aim, a confluent culture of “sacrificial” fibroblasts was seeded on top of microfabricated guiding templates to induce the 3D ECM growth with specific isotropic or anisotropic architectures. The resulting matrices, and cells seeded on them, recapitulated the structure, composition, phenotypes and morphodynamics typically found in the native scenario. Overall, this method paves the way for the development of in vitro ECMs for pathophysiological studies with potential clinical relevance.

Keywords: Extracellular matrix, Cell-derived matrix, 3D model, Biomimicry, Anisotropy


Said Al-Tawaha, A.R.M., Singh, S., Singh, V., Kafeel, U., Naikoo, M.I., Kumari, A., Amanullah, I., Al-Tawaha, A.R., Qaisi, A.M., Khanum, S., Thangadurai, D, Sangeetha, J., Islam, S., Etesami, H., Kerkoub, N., Amrani, A., Labidi, Z., Maaref, H., Nasri, H., Sanmukh, S.G., Torrents, E. , (2020). Improving water use efficiency and nitrogen use efficiency in rice through breeding and genomics approaches Rice Research for Quality Improvement: Genomics and Genetic Engineering (ed. Roychoudhury, A.), Springer (Singapore, Singapore) Volume 2: Nutrient Biofortification and Herbicide and Biotic Stress Resistance in Rice, 307-337

Rice is a staple food of more than half of the world’s population; more than 3.5 billion inhabitants depend on rice for obtaining 20% of their daily calorie intake. Nitrogen is the most important for crop growth and yield potential. Indeed, nitrogen is essential to stimulate tillering, leaf growth, photosynthesis, and protein synthesis. Significant achievements have recently been observed at the molecular level in nitrogen use efficiency and water use efficiency in plants. In this chapter we will discuss the following issue: (i) definition of both nitrogen use efficiency and water use efficiency, (ii) genes responsible for nitrogen use efficiency and water use efficiency, (iii) best ways for improving water and nutrient use efficiency in rice, and (iv) optimizing nitrogen options for improving water and nitrogen use efficiency of rice under different water regimes.

Keywords: Rice, Water use efficiency, Nitrogen use efficiency, Breeding, Genomics approaches


Redondo-Morata, Lorena, Losada-Pérez, Patricia, Giannotti, Marina Inés, (2020). Lipid bilayers: Phase behavior and nanomechanics Current Topics in Membranes (ed. Levitan, Irena, Trache, Andreea), Academic Press (Berlin, Germany) 86, 1-55

Lipid membranes are involved in many physiological processes like recognition, signaling, fusion or remodeling of the cell membrane or some of its internal compartments. Within the cell, they are the ultimate barrier, while maintaining the fluidity or flexibility required for a myriad of processes, including membrane protein assembly. The physical properties of in vitro model membranes as model cell membranes have been extensively studied with a variety of techniques, from classical thermodynamics to advanced modern microscopies. Here we review the nanomechanics of solid-supported lipid membranes with a focus in their phase behavior. Relevant information obtained by quartz crystal microbalance with dissipation monitoring (QCM-D) and atomic force microscopy (AFM) as complementary techniques in the nano/mesoscale interface is presented. Membrane morphological and mechanical characterization will be discussed in the framework of its phase behavior, phase transitions and coexistence, in simple and complex models, and upon the presence of cholesterol.

Keywords: Lipid phase behavior, Phase transition, Phase coexistence, Nanomechanics, Thermodynamics, Atomic force microscopy (AFM), Quartz crystal microbalance with dissipation monitoring (QCM-D)


Haick, H., Vishinking, R., di Natale, C., Marco, S., (2020). Sensor Systems Breathborne Biomarkers and the Human Volatilome (ed. Beauchamp, J., Davis, C., Pleil, J.), Elsevier (Amsterdam, The Netherlands) , 201-202

Vouloutsi, Vasiliki, Mura, Anna, Tauber, F., Speck, T., Prescott, T. J., Verschure, P., (2020). Biomimetic and Biohybrid Systems 9th International Conference, Living Machines 2020, Freiburg, Germany, July 28–30, 2020, Proceedings , Springer, Cham (Lausanne, Switzerland) 12413, 1-428

This book constitutes the proceedings of the )th International Conference on Biomimetic and Biohybrid Systems, Living Machines 2020, held in Freiburg, Germany, in July 2020. Due to COVID-19 pandemic the conference was held virtually. The 32 full and 7 short papers presented in this volume were carefully reviewed and selected from 45 submissions. They deal with research on novel life-like technologies inspired by the scientific investigation of biological systems, biomimetics, and research that seeks to interface biological and artificial systems to create biohybrid systems.

Keywords: Artificial intelligence, Soft robotics, Biomimetics, Insect navigation, Synthetic nervous system, Computer vision, Bio-inspired materials, Visual homing, Locomotion+, Image processing, Intelligent robots, Human-robot interaction, Machine learning, Snake robot, Mobile robots, Robotic systems, Drosophila, Robots, Sensors, Signal processing