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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 on-line publication

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.

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

Martinez-Hernandez, Uriel, Vouloutsi, Vasiliki, Mura, Anna, Mangan, Michael, Asada, Minoru, Prescott, T. J., Verschure, P., (2019). Biomimetic and Biohybrid Systems 8th International Conference, Living Machines 2019, Nara, Japan, July 9–12, 2019, Proceedings , Springer, Cham (Lausanne, Switzerland) 11556, 1-384

This book constitutes the proceedings of the 8th International Conference on Biomimetic and Biohybrid Systems, Living Machines 2019, held in Nara, Japan, in July 2019. The 26 full and 16 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, Biomimetics, Computer architecture, Human robot interaction, Human-Computer Interaction (HCI), Humanoid robot, Image processing, Learning algorithms, Mobile robots, Multipurpose robots, Neural networks, Quadruped robots, Reinforcement learning, Robot learning, Robotics, Robots, Sensor, Sensors, Swarm robotics, User interfaces

Matera, Carlo, Gomila-Juaneda, Alexandre, Camarero, Núria, Libergoli, Michela, Soler, Concepció, Gorostiza, Pau, (2018). A photoswitchable antimetabolite for targeted photoactivated chemotherapy Journal of the American Chemical Society 140, (46), 15764-15773

The efficacy and tolerability of systemically administered anticancer agents are limited by their off-target effects. Precise spatiotemporal control over their cytotoxic activity would allow improving chemotherapy treatments, and light-regulated drugs are well suited to this purpose. We have developed phototrexate, the first photoswitchable inhibitor of the human dihydrofolate reductase (DHFR), as a photochromic analog of methotrexate, a widely prescribed chemotherapeutic drug to treat cancer and psoriasis. Quantification of the light-regulated DHFR enzymatic activity, cell proliferation, and in vivo effects in zebrafish show that phototrexate behaves as a potent antifolate in its photoactivated cis configuration, and that it is nearly inactive in its dark-relaxed trans form. Thus, phototrexate constitutes a proof-of-concept to design light-regulated cytotoxic small molecules, and a step forward to develop targeted anticancer photochemotherapies with localized efficacy and reduced adverse effects.

Keywords: Photopharmacology, Photodynamic therapy, Antiproliferative, Arthritis, Psoriasis, Nanomedicine

Quiliano, Miguel, Pabón, Adriana, Moles, Ernest, Bonilla-Ramirez, Leonardo, Fabing, Isabelle, Fong, Kim Y., Nieto-Aco, Diego A., Wright, David W., Pizarro, Juan C., Vettorazzi, Ariane, López de Cerain, Adela, Deharo, Eric, Fernàndez-Busquets, Xavier, Garavito, Giovanny, Aldana, Ignacio, Galiano, Silvia, (2018). Structure-activity relationship of new antimalarial 1-aryl-3-susbtituted propanol derivatives: Synthesis, preliminary toxicity profiling, parasite life cycle stage studies, target exploration, and targeted delivery European Journal of Medicinal Chemistry 152, 489-514

Design, synthesis, structure-activity relationship, cytotoxicity studies, in silico drug-likeness, genotoxicity screening, and in vivo studies of new 1-aryl-3-substituted propanol derivatives led to the identification of nine compounds with promising in vitro (55, 56, 61, 64, 66, and 70–73) and in vivo (66 and 72) antimalarial profiles against Plasmodium falciparum and Plasmodium berghei. Compounds 55, 56, 61, 64, 66 and 70–73 exhibited potent antiplasmodial activity against chloroquine-resistant strain FCR-3 (IC50s < 0.28 μM), and compounds 55, 56, 64, 70, 71, and 72 showed potent biological activity in chloroquine-sensitive and multidrug-resistant strains (IC50s < 0.7 μM for 3D7, D6, FCR-3 and C235). All of these compounds share appropriate drug-likeness profiles and adequate selectivity indexes (77 < SI < 184) as well as lack genotoxicity. In vivo efficacy tests in a mouse model showed compounds 66 and 72 to be promising candidates as they exhibited significant parasitemia reductions of 96.4% and 80.4%, respectively. Additional studies such as liver stage and sporogony inhibition, target exploration of heat shock protein 90 of P. falciparum, targeted delivery by immunoliposomes, and enantiomer characterization were performed and strongly reinforce the hypothesis of 1-aryl-3-substituted propanol derivatives as promising antimalarial compounds.

Keywords: Antiplasmodial, Antimalarial, Arylamino alcohol, Multi-stage activity, Hsp90, Enantiomer separation

Agusil, Juan Pablo, Torras, Núria, Duch, Marta, Esteve, Jaume, Pérez-García, Lluïsa, Samitier, Josep, Plaza, José A., (2017). Highly anisotropic suspended planar-array chips with multidimensional sub-micrometric biomolecular patterns Advanced Functional Materials 27, 1605912

Suspended planar-array (SPA) chips embody millions of individual miniaturized arrays to work in extremely small volumes. Here, the basis of a robust methodology for the fabrication of SPA silicon chips with on-demand physical and chemical anisotropies is demonstrated. Specifically, physical traits are defined during the fabrication process with special focus on the aspect ratio, branching, faceting, and size gradient of the final chips. Additionally, the chemical attributes augment the functionality of the chips with the inclusion of complete coverage or patterns of selected biomolecules on the surface of the chips with contact printing techniques, offering an extremely high versatility, not only with the choice of the pattern shape and distribution but also in the choice of biomolecular inks to pattern. This approach increases the miniaturization of printed arrays in 3D structures by two orders of magnitude compared to those previously demonstrated. Finally, functional micrometric and sub-micrometric patterned features are demonstrated with an antibody binding assay with the recognition of the printed spots with labeled antibodies from solution. The selective addition of physical and chemical attributes on the suspended chips represents the basis for future biomedical assays performed within extremely small volumes.

Keywords: Microcontact printing, Microparticles, Molecular multiplexing, Polymer pen lithography, Silicon chip technology

Wills, C. R., Malandrino, A., Van Rijsbergen, M., Lacroix, D., Ito, K., Noailly, J., (2016). Simulating the sensitivity of cell nutritive environment to composition changes within the intervertebral disc Journal of the Mechanics and Physics of Solids 90, 108-123

Altered nutrition in the intervertebral disc affects cell viability and can generate catabolic cascades contributing to extracellular matrix (ECM) degradation. Such degradation is expected to affect couplings between disc mechanics and nutrition, contributing to accelerate degenerative processes. However, the relation of ECM changes to major biophysical events within the loaded disc remains unclear. A L4-L5 disc finite element model including the nucleus (NP), annulus (AF) and endplates was used and coupled to a transport-cell viability model. Solute concentrations and cell viability were evaluated along the mid-sagittal plane path. A design of experiment (DOE) was performed. DOE parameters corresponded to AF and NP biochemical tissue measurements in discs with different degeneration grades. Cell viability was not affected by any parameter combinations defined. Nonetheless, the initial water content was the parameter that affected the most the solute contents, especially glucose. Calculations showed that altered NP composition could negatively affect AF cell nutrition. Results suggested that AF and NP tissue degeneration are not critical to nutrition-related cell viability at early-stage of disc degeneration. However, small ECM degenerative changes may alter significantly disc nutrition under mechanical loads. Coupling disc mechano-transport simulations and enzyme expression studies could allow identifying spatiotemporal sequences related to tissue catabolism.

Keywords: Cell nutrition, Finite element analysis, Intervertebral disc degeneration, Multiphysics, Tissue composition

Hernansanz, A., Casals, A., Amat, J., (2015). A multi-robot cooperation strategy for dexterous task oriented teleoperation Robotics and Autonomous Systems , 68, 156-172

The use of multiple robots working cooperatively in a redundant way offers new possibilities in the execution of complex tasks in dynamic workspaces. The aim of this work is to increase the range of applicability of teleoperated systems by means of the automatic cooperation of multiple slave robots which, controlled by a human operator, act as if they were a unique robot: a Multi-Robot Cooperation Platform for Task-Oriented Teleoperation, MRCP. From the human operator commands, this robotic platform, the MRCP, dynamically selects the most suitable slave robot and manages, when necessary, a task transfer from one robot to another in order to achieve a smooth execution of teleoperated tasks. The result of the proposed methodology is an improved teleoperated system in terms of reachable workspace (volume, manoeuvrability and accessibility) and dexterity, thus widening its range of applicability. This approach allows human operators to focus their attention on the ongoing task more than on the teleoperated robots.

Keywords: Multi-robot cooperation, Single-operator-multiple-robot, Task-oriented teleoperation

Fumagalli, L., Edwards, Martin Andrew, Gomila, G., (2014). Quantitative electrostatic force microscopy with sharp silicon tips Nanotechnology 25, (49), 495701 (9)

Electrostatic force microscopy (EFM) probes are typically coated in either metal (radius ~ 30 nm) or highly-doped diamond (radius ~ 100 nm). Highly-doped silicon probes, which offer a sharpened and stable tip apex (radius ~ 1–10 nm) and are usually used only in standard atomic force microscopy, have been recently shown to allow enhanced lateral resolution in quantitative EFM and its application for dielectric constant measurement. Here we present the theoretical modelling required to quantitatively interpret the electrostatic force between these sharpened tips and samples. In contrast to a sphere-capped cone geometry used to describe metal/diamond-coated tips, modelling a sharpened silicon tip requires a geometry comprised of a cone with two different angles. Theoretical results are supported by experimental measurements of metallic substrates and ~10 nm radius dielectric nanoparticles. This work is equally applicable to EFM and other electrical scanned probe techniques, where it allows quantifying electrical properties of nanomaterials and 3D nano-objects with higher resolution.

Keywords: AFM, Dielectric constant, EFM, Dielectrics, Nanoparticles, Sharp tips

Harder, A., Walhorn, V., Dierks, T., Fernàndez-Busquets, X., Anselmetti, D., (2010). Single-molecule force spectroscopy of cartilage aggrecan self-adhesion Biophysical Journal , 99, (10), 3498-3504

We investigated self-adhesion between highly negatively charged aggrecan macromolecules extracted from bovine cartilage extracellular matrix by performing atomic force microscopy (AFM) imaging and single-molecule force spectroscopy (SMFS) in saline solutions. By controlling the density of aggrecan molecules on both the gold substrate and the gold-coated tip surface at submonolayer densities, we were able to detect and quantify the Ca2+-dependent homodimeric interaction between individual aggrecan molecules at the single-molecule level. We found a typical nonlinear sawtooth profile in the AFM force-versus-distance curves with a molecular persistence length of I-p = 0.31 +/- 0.04 nm. This is attributed to the stepwise dissociation of individual glycosaminoglycan (GAG) side chains in aggrecans, which is very similar to the known force fingerprints of other cell adhesion proteoglycan systems. After studying the GAG-GAG dissociation in a dynamic, loading-rate-dependent manner (dynamic SMFS) and analyzing the data according to the stochastic Bell-Evans model for a thermally activated decay of a metastable state under an external force, we estimated for the single glycan interaction a mean lifetime of tau = 7.9 +/- 4.9 s and a reaction bond length of x(beta) = 0.31 +/- 0.08 nm. Whereas the x(beta)-value compares well with values from other cell adhesion carbohydrate recognition motifs in evolutionary distant marine sponge proteoglycans, the rather short GAG interaction lifetime reflects high intermolecular dynamics within aggrecan complexes, which may be relevant for the viscoelastic properties of cartilage tissue.

Keywords: Bovine nasal cartilage, Articular-cartilage, Sinorhizobium-meliloti, Proteoglycan, Microscopy, DNA, Macromolecules, Binding, Protein, Glycosaminoglycans

Caballero, D., Villanueva, G., Plaza, J. A., Mills, C. A., Samitier, J., Errachid, A., (2010). Sharp high-aspect-ratio AFM tips fabricated by a combination of deep reactive ion etching and focused ion beam techniques Journal of Nanoscience and Nanotechnology , 10, (1), 497-501

The shape and dimensions of an atomic force microscope tip are crucial factors to obtain high resolution images at the nanoscale. When measuring samples with narrow trenches, inclined sidewalls near 90 or nanoscaled structures, standard silicon atomic force microscopy (AFM) tips do not provide satisfactory results. We have combined deep reactive ion etching (DRIE) and focused ion beam (FIB) lithography techniques in order to produce probes with sharp rocket-shaped silicon AFM tips for high resolution imaging. The cantilevers were shaped and the bulk micromachining was performed using the same DRIE equipment. To improve the tip aspect ratio we used FIB nanolithography technique. The tips were tested on narrow silicon trenches and over biological samples showing a better resolution when compared with standard AFM tips, which enables nanocharacterization and nanometrology of high-aspect-ratio structures and nanoscaled biological elements to be completed, and provides an alternative to commercial high aspect ratio AFM tips.

Keywords: Atomic-Force Microscope, Carbon nanotube tips, Probes, Roughness, Cells, Microfabrication, Calibration, Surfaces

Correa, L. S., Laciar, E., Mut, V., Giraldo, B. F., Torres, A., (2010). Multi-parameter analysis of ECG and Respiratory Flow signals to identify success of patients on weaning trials Engineering in Medicine and Biology Society (EMBC) 32nd Annual International Conference of the IEEE , IEEE (Buenos Aires, Argentina) -----, 6070-6073

Statistical analysis, power spectral density, and Lempel Ziv complexity, are used in a multi-parameter approach to analyze four temporal series obtained from the Electrocardiographic and Respiratory Flow signals of 126 patients on weaning trials. In which, 88 patients belong to successful group (SG), and 38 patients belong to failure group (FG), i.e. failed to maintain spontaneous breathing during trial. It was found that mean values of cardiac inter-beat and breath durations give higher values for SG than for FG; Kurtosis coefficient of the spectrum of the rapid shallow breathing index is higher for FG; also Lempel Ziv complexity mean values associated with the respiratory flow signal are bigger for FG. Patients were then classified with a pattern recognition neural network, obtaining 80% of correct classifications (81.6% for FG and 79.5% for SG).

Keywords: Electrocardiography, Medical signal processing, Neural nets, Pattern recognition, Pneumodynamics, Signal classification, Statistical analysis, ECG, Kurtosis coefficient, Lempel Ziv complexity, Breath durations, Cardiac interbeat durations, Electrocardiography, Multiparameter analysis, Pattern recognition neural network, Power spectral density, Respiratory flow signals, Signal classification, Spontaneous breathing, Statistical analysis, Weaning trials

Estrada, L., Santamaria, J., Isetta, V., Iranzo, A., Navajas, D., Farre, R., (2010). Validation of an EEG-based algorithm for automatic detection of sleep onset in the multiple sleep latency test Proceedings of the World Congress on Engineering 2010 World Congress on Engineering 2010 , IAENG (International Association of Engineers) (London, UK) 1, 1-3

The Multiple Sleep Latency Test (MSLT) is a standard test to objectively evaluate patients with excessive daytime sleepiness. Sleep onset latencies are determined by visual analysis, which is costly and time-consuming. The aim of this study was to implement and test a single automatic algorithm to detect the sleep onset in the MSLT on the basis of electroencephalographic (EEG) signals. The designed algorithm computed the relative EEG spectral powers in the occipital area and detected the sleep onset corresponding to the intersection point between the lower and alpha frequencies. The algorithm performance was evaluated by comparing the sleep latencies computed automatically by the algorithm and by a sleep specialist using MSLT recordings from a total of 19 patients (95 naps). The mean difference in sleep latency between the two methods was 0.025 min and the limits of agreement were ± 2.46 min (Bland-Altman analysis). Moreover, the intra-class correlation coefficient showed a considerable inter-rater reliability (0.90). The algorithm accurately detected the sleep onset in the MSLT. The devised algorithm can be a useful tool to support and speed up the sleep specialist’s work in routine clinical MSLT assessment.

Keywords: Automatic Algorithm, Drowsiness, Electroencephalography, Multiple Sleep Latency Test, Polysomnography, Sleep onset

Gramse, G., Casuso, I., Toset, J., Fumagalli, L., Gomila, G., (2009). Quantitative dielectric constant measurement of thin films by DC electrostatic force microscopy Nanotechnology 20, (39), 395702

A simple method to measure the static dielectric constant of thin films with nanometric spatial resolution is presented. The dielectric constant is extracted from DC electrostatic force measurements with the use of an accurate analytical model. The method is validated here on thin silicon dioxide films (8 nm thick, dielectric constant approximately 4) and purple membrane monolayers (6 nm thick, dielectric constant approximately 2), providing results in excellent agreement with those recently obtained by nanoscale capacitance microscopy using a current-sensing approach. The main advantage of the force detection approach resides in its simplicity and direct application on any commercial atomic force microscope with no need of additional sophisticated electronics, thus being easily available to researchers in materials science, biophysics and semiconductor technology.

Keywords: Roscopy, Membrane, Tip, Polarizability, Polarization, Resolution, Nanotubes, Charge

Gomila, G., Toset, J., Fumagalli, L., (2008). Nanoscale capacitance microscopy of thin dielectric films Journal of Applied Physics 104, (2), 8

We present an analytical model to interpret nanoscale capacitance microscopy measurements on thin dielectric films. The model displays a logarithmic dependence on the tip-sample distance and on the film thickness-dielectric constant ratio and shows an excellent agreement with finite-element numerical simulations and experimental results on a broad range of values. Based on these results, we discuss the capabilities of nanoscale capacitance microscopy for the quantitative extraction of the dielectric constant and the thickness of thin dielectric films at the nanoscale.

Keywords: AFM, Thickness, Tip