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Mesquida-Veny, Francina, Del Río, José Antonio, Hervera, Arnau, (2021). Macrophagic and microglial complexity after neuronal injury Progress in Neurobiology , 101970

Central nervous system (CNS) injuries do not heal properly in contrast to normal tissue repair, in which functional recovery typically occurs. The reason for this dichotomy in wound repair is explained in part by macrophage and microglial malfunction, affecting both the extrinsic and intrinsic barriers to appropriate axonal regeneration. In normal healing tissue, macrophages promote the repair of injured tissue by regulating transitions through different phases of the healing response. In contrast, inflammation dominates the outcome of CNS injury, often leading to secondary damage. Therefore, an understanding of the molecular mechanisms underlying this dichotomy is critical to advance in neuronal repair therapies. Recent studies highlight the plasticity and complexity of macrophages and microglia beyond the classical view of the M1/M2 polarization paradigm. This plasticity represents an in vivo continuous spectrum of phenotypes with overlapping functions and markers. Moreover, macrophage and microglial plasticity affect many events essential for neuronal regeneration after injury, such as myelin and cell debris clearance, inflammation, release of cytokines, and trophic factors, affecting both intrinsic neuronal properties and extracellular matrix deposition. Until recently, this complexity was overlooked in the translation of therapies modulating these responses for the treatment of neuronal injuries. However, recent studies have shed important light on the underlying molecular mechanisms of this complexity and its transitions and effects on regenerative events. Here we review the complexity of macrophages and microglia after neuronal injury and their roles in regeneration, as well as the underlying molecular mechanisms, and we discuss current challenges and future opportunities for treatment.

Keywords: Neuronal injury, Neuroinflammation, Macrophages, Microglia, Chemokines and cytokines, Regeneration

Abdelrahman, F., Easwaran, M., Daramola, O. I., Ragab, S., Lynch, S., Oduselu, T. J., Khan, F. M., Ayobami, A., Adnan, F., Torrents, E., Sanmukh, S., El-Shibiny, A., (2021). Phage-encoded endolysins Antibiotics 10, (2), 1-31

Due to the global emergence of antibiotic resistance, there has been an increase in research surrounding endolysins as an alternative therapeutic. Endolysins are phage-encoded enzymes, utilized by mature phage virions to hydrolyze the cell wall from within. There is significant evidence that proves the ability of endolysins to degrade the peptidoglycan externally without the assistance of phage. Thus, their incorporation in therapeutic strategies has opened new options for therapeutic application against bacterial infections in the human and veterinary sectors, as well as within the agricultural and biotechnology sectors. While endolysins show promising results within the laboratory, it is important to document their resistance, safety, and immunogenicity for in-vivo application. This review aims to provide new insights into the synergy between endolysins and antibiotics, as well as the formulation of endolysins. Thus, it provides crucial information for clinical trials involving endolysins. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords: Antibiotic resistance, Bacteriophages, Endolysin

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

Mas, S., Torro, A., Bec, N., Fernández, L., Erschov, G., Gongora, C., Larroque, C., Martineau, P., de Juan, A., Marco, S., (2019). Use of physiological information based on grayscale images to improve mass spectrometry imaging data analysis from biological tissues Analytica Chimica Acta 1074, 69-79

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

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

Gouveia, Virgínia M., Rizzello, Loris, Nunes, Claudia, Poma, Alessandro, Ruiz-Perez, Lorena, Oliveira, António, Reis, Salette, Battaglia, Giuseppe, (2019). Macrophage targeting pH responsive polymersomes for glucocorticoid therapy Pharmaceutics 11, (11), 614

Glucocorticoid (GC) drugs are the cornerstone therapy used in the treatment of inflammatory diseases. Here, we report pH responsive poly(2-methacryloyloxyethyl phosphorylcholine)–poly(2-(diisopropylamino)ethyl methacrylate) (PMPC–PDPA) polymersomes as a suitable nanoscopic carrier to precisely and controllably deliver GCs within inflamed target cells. The in vitro cellular studies revealed that polymersomes ensure the stability, selectivity and bioavailability of the loaded drug within macrophages. At molecular level, we tested key inflammation-related markers, such as the nuclear factor-κB, tumour necrosis factor-α, interleukin-1β, and interleukin-6. With this, we demonstrated that pH responsive polymersomes are able to enhance the anti-inflammatory effect of loaded GC drug. Overall, we prove the potential of PMPC–PDPA polymersomes to efficiently promote the inflammation shutdown, while reducing the well-known therapeutic limitations in GC-based therapy.

Keywords: Inflammation, Macrophages, Glucocorticoid, Polymersomes

Hervera, A., De Virgiliis, F., Palmisano, I., Zhou, L., Tantardini, E., Kong, G., Hutson, T., Danzi, M. C., Perry, R. B. T., Santos, C. X. C., Kapustin, A. N., Fleck, R. A., Del Río, J. A., Carroll, T., Lemmon, V., Bixby, J. L., Shah, A. M., Fainzilber, M., Di Giovanni, S., (2018). Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons Nature Cell Biology 20, (3), 307-319

Reactive oxygen species (ROS) contribute to tissue damage and remodelling mediated by the inflammatory response after injury. Here we show that ROS, which promote axonal dieback and degeneration after injury, are also required for axonal regeneration and functional recovery after spinal injury. We find that ROS production in the injured sciatic nerve and dorsal root ganglia requires CX3CR1-dependent recruitment of inflammatory cells. Next, exosomes containing functional NADPH oxidase 2 complexes are released from macrophages and incorporated into injured axons via endocytosis. Once in axonal endosomes, active NOX2 is retrogradely transported to the cell body through an importin-β1–dynein-dependent mechanism. Endosomal NOX2 oxidizes PTEN, which leads to its inactivation, thus stimulating PI3K–phosporylated (p-)Akt signalling and regenerative outgrowth. Challenging the view that ROS are exclusively involved in nerve degeneration, we propose a previously unrecognized role of ROS in mammalian axonal regeneration through a NOX2–PI3K–p-Akt signalling pathway.

Keywords: Adult neurogenesis, Endocytosis, Exocytosis, Monocytes and macrophages, Stress signalling

Vaca, R., Aranda, J., (2014). Approximating coupler curves using strip trees Advanced Numerical Methods II 11th World Congress on Computational Mechanics (WCCM XI) 5th European Conference on Computational Mechanics (ECCM V) 6th European Conference on Computational Fluid Dynamics (ECFD VI) , CIMNE (Barcelona, Spain) , 1-2

For the mechanisms considered under the title linkages, coupler curve is the path traced by one of the point on the coupler link considered as an output of the mechanism which is joined to a fixed link. The equation of the coupler curve generated can be obtained solving a set of equations which describes distance constancy between all points of a mechanism and this coupler curve is the eliminant of these equations. The proposal to this work is to approximate coupler curves using strip trees.

Keywords: Coupler curves, Strip tress, Distance geometry, Affine arithmetics, Planar linkages

Valente, T., Gella, A., Fernàndez-Busquets, X., Unzeta, M., Durany, N., (2010). Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer's disease and diabetes mellitus Neurobiology of Disease , 37, (1), 67-76

It has been extensively reported that diabetes mellitus (DM) patients have a higher risk of developing Alzheimer's disease (AD). but a mechanistic connection between both pathologies has not been provided so far Carbohydrate-derived advanced glycation endproducts (AGEs) have been implicated in the chronic complications of DM and have been reported to play an important role in the pathogenesis of AD. The earliest histopathological manifestation of AD is the apparition of extracellular aggregates of the amyloid beta peptide (A beta). To investigate possible correlations between AGEs and A beta aggregates with both pathologies. we have performed an immuhistochemical study in human post-mortem samples of AD, AD with diabetes (ADD). diabetic and nondemented controls ADD brains showed increased number of A beta dense plaques and receptor for AGEs (RACE)-positive and Tau-positive cells, higher AGEs levels and major microglial activation, compared to AD brain. Our results indicate that ADD patients present a significant increase of cell damage through a RAGE-dependent mechanism, suggesting that AGEs may promote the generation of an oxidative stress vicious cycle, which can explain the severe progression of patients with both pathologies.

Keywords: Abeta, Alzheimer's disease, Rage, Ages, Diabetes, Immunohistochemistry, Advanced glycation endproducts, Beta-amyloid peptide, End-products, Oxidative stress, Advanced glycosylation, Synaptic dysfunction, Cross-linking

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-Briones, F., Artes, J. M., Diez-Perez, I., Gorostiza, P., Sanz, F., (2009). Direct observation of the valence band edge by in situ ECSTM-ECTS in p-type Cu2O layers prepared by copper anodization Journal of Physical Chemistry C 113, (3), 1028-1036

Polycrystalline Cu2O layers have been selectively grown by electrochemical anodization of polycrystalline Cu electrodes in an alkaline medium (pH 12.85). Uniform layers with thicknesses around 100 nm have been obtained. Using electrochemical impedance spectroscopy, it was concluded that the Cu2O films behave as a p-type semiconductor. The Mott-Schottky plot gives a value for the flat band potential of U-FB = -255 mV vs silver/silver chloride electrode (SSC), an estimated carrier density N-A = 6.1 x 10(17) cm(-3), and the space charge layer width was calculated to be W-SCL = 9 nm at a band bending of 120 mV. The electronic structure of the Cu vertical bar Cu2O vertical bar electrolyte interface was for the first time probed by in situ electrochemical tunneling spectroscopy. The use of in situ electrochemical scanning tunneling microscopy allows us to directly observed the valence band edge and determine its position against the absolute energy scale to be E-VB = -4.9 eV. Finally, we constructed a quantitative electronic diagram of the Cu vertical bar Cu2O vertical bar electrolyte interface, where the positions of the valence and conduction band edges are depicted, as well as the edge of the previously reported electronic subband.

Keywords: 0.1 m NaOH, Electrochemical tunneling spectroscopy, Cuprous-oxide films, Anodic-oxidation, Electronic-structure, Alkaline-solution, Aqueous-solution, Initial-stages, Passive film, Thin-films