by Keyword: Mechanism

Andrés-Benito, Pol, Flores, África, Busquet-Areny, Sara, Carmona, Margarita, Ausín, Karina, Cartas-Cejudo, Paz, Lachén-Montes, Mercedes, Del Rio, José Antonio, Fernández-Irigoyen, Joaquín, Santamaría, Enrique, Ferrer, Isidro, (2023). Deregulated Transcription and Proteostasis in Adult mapt Knockout Mouse International Journal Of Molecular Sciences 24, 6559-6559

Transcriptomics and phosphoproteomics were carried out in the cerebral cortex of B6.Cg-Mapttm1(EGFP)Klt (tau knockout: tau-KO) and wild-type (WT) 12 month-old mice to learn about the effects of tau ablation. Compared with WT mice, tau-KO mice displayed reduced anxiety-like behavior and lower fear expression induced by aversive conditioning, whereas recognition memory remained unaltered. Cortical transcriptomic analysis revealed 69 downregulated and 105 upregulated genes in tau-KO mice, corresponding to synaptic structures, neuron cytoskeleton and transport, and extracellular matrix components. RT-qPCR validated increased mRNA levels of col6a4, gabrq, gad1, grm5, grip2, map2, rab8a, tubb3, wnt16, and an absence of map1a in tau-KO mice compared with WT mice. A few proteins were assessed with Western blotting to compare mRNA expression with corresponding protein levels. Map1a mRNA and protein levels decreased. However, β-tubulin III and GAD1 protein levels were reduced in tau-KO mice. Cortical phosphoproteomics revealed 121 hypophosphorylated and 98 hyperphosphorylated proteins in tau-KO mice. Deregulated phosphoproteins were categorized into cytoskeletal (n = 45) and membrane proteins, including proteins of the synapses and vesicles, myelin proteins, and proteins linked to membrane transport and ion channels (n = 84), proteins related to DNA and RNA metabolism (n = 36), proteins connected to the ubiquitin-proteasome system (UPS) (n = 7), proteins with kinase or phosphatase activity (n = 21), and 22 other proteins related to variegated pathways such as metabolic pathways, growth factors, or mitochondrial function or structure. The present observations reveal a complex altered brain transcriptome and phosphoproteome in tau-KO mice with only mild behavioral alterations.

JTD Keywords: computational platform, conformational-changes, cytoskeleton, disease, expression, isoforms, mechanisms, mice, phosphoproteomics, phosphorylation, synapse, tauopathies, transcriptomics, Tau-ko, Tau-protein

Ortiz, Cristina, Klein, Sabine, Reul, Winfried H., Magdaleno, Fernando, Gröschl, Stefanie, Dietrich, Peter, Schierwagen, Robert, Uschner, Frank E., Torres, Sandra, Hieber, Christoph, Meier, Caroline, Kraus, Nico, Tyc, Olaf, Brol, Maximilian, Zeuzem, Stefan, Welsch, Christoph, Poglitsch, Marco, Hellerbrand, Claus, Alfonso-Prieto, Mercedes, Mira, Fabio, Keller, Ulrich auf dem, Tetzner, Anja, Moore, Andrew, Walther, Thomas, Trebicka, Jonel, (2023). Neprilysin-dependent neuropeptide Y cleavage in the liver promotes fibrosis by blocking NPY-receptor 1 Cell Reports 42, 112059

Sanmukh, Swapnil Ganesh, Admella, Joana, Moya-Andérico, Laura, Fehér, Tamás, Arévalo-Jaimes, Betsy Verónica, Blanco-Cabra, Núria, Torrents, Eduard, (2023). Accessing the In Vivo Efficiency of Clinically Isolated Phages against Uropathogenic and Invasive Biofilm-Forming Escherichia coli Strains for Phage Therapy Cells 12, 344

Escherichia coli is one of the most common members of the intestinal microbiota. Many of its strains are associated with various inflammatory infections, including urinary or gut infections, especially when displaying antibiotic resistance or in patients with suppressed immune systems. According to recent reports, the biofilm-forming potential of E. coli is a crucial factor for its increased resistance against antibiotics. To overcome the limitations of using antibiotics against resistant E. coli strains, the world is turning once more towards bacteriophage therapy, which is becoming a promising candidate amongst the current personalized approaches to target different bacterial infections. Although matured and persistent biofilms pose a serious challenge to phage therapy, they can still become an effective alternative to antibiotic treatment. Here, we assess the efficiency of clinically isolated phages in phage therapy against representative clinical uropathogenic and invasive biofilm-forming E. coli strains. Our results demonstrate that irrespective of host specificity, bacteriophages producing clear plaques with a high burst size, and exhibiting depolymerizing activity, are good candidates against biofilm-producing E. coli pathogens as verified from our in vitro and in vivo experiments using Galleria mellonella where survival was significantly increased for phage-therapy-treated larvae.

JTD Keywords: antibiotic resistance, assay, bacteriophage, bacteriophages, biofilm-forming potential, infection, inflammatory infections, mechanisms, Galleria-mellonella, Intestinal microflora

Júnior, Constança, Ulldemolins, Anna, Narciso, Maria, Almendros, Isaac, Farré, Ramon, Navajas, Daniel, López, Javier, Eroles, Mar, Rico, Felix, Gavara, Núria, (2023). Multi-Step Extracellular Matrix Remodelling and Stiffening in the Development of Idiopathic Pulmonary Fibrosis International Journal Of Molecular Sciences 24, 1708

The extracellular matrix (ECM) of the lung is a filamentous network composed mainly of collagens, elastin, and proteoglycans that provides structural and physical support to its populating cells. Proliferation, migration and overall behaviour of those cells is greatly determined by micromechanical queues provided by the ECM. Lung fibrosis displays an aberrant increased deposition of ECM which likely changes filament organization and stiffens the ECM, thus upregulating the profibrotic profile of pulmonary cells. We have previously used AFM to assess changes in the Young’s Modulus (E) of the ECM in the lung. Here, we perform further ECM topographical, mechanical and viscoelastic analysis at the micro- and nano-scale throughout fibrosis development. Furthermore, we provide nanoscale correlations between topographical and elastic properties of the ECM fibres. Firstly, we identify a softening of the ECM after rats are instilled with media associated with recovery of mechanical homeostasis, which is hindered in bleomycin-instilled lungs. Moreover, we find opposite correlations between fibre stiffness and roughness in PBS- vs bleomycin-treated lung. Our findings suggest that changes in ECM nanoscale organization take place at different stages of fibrosis, with the potential to help identify pharmacological targets to hinder its progression.

JTD Keywords: atomic force microscopy, cells, deposition, idiopathic pulmonary fibrosis, mechanisms, mechanosensing, membranes, micromechanical properties, pathogenesis, stiffness, tissues, viscoelasticity, Extracellular matrix, Induced lung fibrosis

Wang, ZH, Klingner, A, Magdanz, V, Hoppenreijs, MW, Misra, S, Khalil, ISM, (2023). Flagellar Propulsion of Sperm Cells Against a Time-Periodic Interaction Force Advanced Biology 7, 2200210

Sperm cells undergo complex interactions with external environments, such as a solid-boundary, fluid flow, as well as other cells before arriving at the fertilization site. The interaction with the oviductal epithelium, as a site of sperm storage, is one type of cell-to-cell interaction that serves as a selection mechanism. Abnormal sperm cells with poor swimming performance, the major cause of male infertility, are filtered out by this selection mechanism. In this study, collinear bundles, consisting of two sperm cells, generate propulsive thrusts along opposite directions and allow to observe the influence of cell-to-cell interaction on flagellar wave-patterns. The developed elasto-hydrodynamic model demonstrates that steric and adhesive forces lead to highly symmetrical wave-pattern and reduce the bending amplitude of the propagating wave. It is measured that the free cells exhibit a mean flagellar curvature of 6.4 +/- 3.5 rad mm(-1) and a bending amplitude of 13.8 +/- 2.8 rad mm(-1). After forming the collinear bundle, the mean flagellar curvature and bending amplitude are decreased to 1.8 +/- 1.1 and 9.6 +/- 1.4 rad mm(-1), respectively. This study presents consistent theoretical and experimental results important for understanding the adaptive behavior of sperm cells to the external time-periodic force encountered during sperm-egg interaction.

JTD Keywords: Bovine sperm cells, Cell-to-cell interaction, Cilia, Filaments, Flagellar propulsion, Hydrodynamic models, Mechanism, Micro-video, Model, Motility, Thermotaxis, Transformations, Transition

Raptopoulos, M, Fischer, NG, Aparicio, C, (2023). Implant surface physicochemistry affects keratinocyte hemidesmosome formation Journal Of Biomedical Materials Research Part a 111, 1021-1030

Renau-Mínguez C, Herrero-Abadía P, Ruiz-Rodriguez P, Sentandreu V, Torrents E, Chiner-Oms Á, Torres-Puente M, Comas I, Julián E, Coscolla M, (2023). Genomic analysis of Mycobacterium brumae sustains its nonpathogenic and immunogenic phenotype Frontiers In Microbiology 13, 982679

Mycobacterium brumae is a rapid-growing, non-pathogenic Mycobacterium species, originally isolated from environmental and human samples in Barcelona, Spain. Mycobacterium brumae is not pathogenic and it's in vitro phenotype and immunogenic properties have been well characterized. However, the knowledge of its underlying genetic composition is still incomplete. In this study, we first describe the 4 Mb genome of the M. brumae type strain ATCC 51384T assembling PacBio reads, and second, we assess the low intraspecies variability by comparing the type strain with Illumina reads from three additional strains. Mycobacterium brumae genome is composed of a circular chromosome with a high GC content of 69.2% and containing 3,791 CDSs, 97 pseudogenes, one prophage and no CRISPR loci. Mycobacterium brumae has shown no pathogenic potential in in vivo experiments, and our genomic analysis confirms its phylogenetic position with other non-pathogenic and rapid growing mycobacteria. Accordingly, we determined the absence of virulence-related genes, such as ESX-1 locus and most PE/PPE genes, among others. Although the immunogenic potential of M. brumae was proved to be as high as Mycobacterium bovis BCG, the only mycobacteria licensed to treat cancer, the genomic content of M. tuberculosis T cell and B cell antigens in M. brumae genome is considerably lower than those antigens present in M. bovis BCG genome. Overall, this work provides relevant genomic data on one of the species of the mycobacterial genus with high therapeutic potential.Copyright © 2023 Renau-Mínguez, Herrero-Abadía, Ruiz-Rodriguez, Sentandreu, Torrents, Chiner-Oms, Torres-Puente, Comas, Julián and Coscolla.

JTD Keywords: antimicrobial susceptibility, bcg, identification, immunogenic, non-pathogenic, nontuberculous mycobacteria, resistance mechanisms, strain, therapeutic, Diversity, Immunogenic, Non-pathogenic, Nontuberculous mycobacteria, Therapeutic

Acosta-Gutiérrez S, Buckley J, Battaglia G, (2023). The Role of Host Cell Glycans on Virus Infectivity: The SARS-CoV-2 Case Advanced Science 10, 2201853

Glycans are ubiquitously expressed sugars, coating the cell and protein surfaces. They are found on many proteins as either short and branched chains or long chains sticking out from special membrane proteins, known as proteoglycans. This sugar cushion, the glycocalyx, modulates specific interactions and protects the cell. Here it is shown that both the expression of proteoglycans and the glycans expressed on the surface of both the host and virus proteins have a critical role in modulating viral attachment to the cell. A mathematical model using SARS-Cov-2 as an archetypical virus to study the glycan role during infection is proposed. It is shown that this occurs via a tug-of-war of forces. On one side, the multivalent molecular recognition that viral proteins have toward specific host glycans and receptors. On the other side, the glycan steric repulsion that a virus must overcome to approach such specific receptors. By balancing both interactions, viral tropism can be predicted. In other words, the authors can map out the cells susceptible to virus infection in terms of receptors and proteoglycans compositions.© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.

JTD Keywords: binding, entry, glycocalyx, mechanisms, multiplexing, multivalency, nanoparticles, recognition, super-selectivity, viral infectivity, Functional receptor, Glycans, Glycocalyx, Multiplexing, Multivalency, Nanoparticles, Super-selectivity, Viral infectivity

Casanellas I, Jiang H, David CM, Vida Y, Pérez-Inestrosa E, Samitier J, Lagunas A, (2022). Substrate adhesion determines migration during mesenchymal cell condensation in chondrogenesis Journal Of Cell Science 135, 260241

Mesenchymal condensation is a prevalent morphogenetic transition that is essential in chondrogenesis. However, the current understanding of condensation mechanisms is limited. In vivo, progenitor cells directionally migrate from the surrounding loose mesenchyme towards regions of increasing matrix adherence (the condensation centers), which is accompanied by the upregulation of fibronectin. Here, we focused on the mechanisms of cell migration during mesenchymal cell condensation and the effects of matrix adherence. Dendrimer-based nanopatterns of the cell-adhesive peptide arginine-glycine-aspartic acid (RGD), which is present in fibronectin, were used to regulate substrate adhesion. We recorded collective and single-cell migration of mesenchymal stem cells, under chondrogenic induction, using live-cell imaging. Our results show that the cell migration mode of single cells depends on substrate adhesiveness, and that cell directionality controls cell condensation and the fusion of condensates. Inhibition experiments revealed that cell-cell interactions mediated by N-cadherin (also known as CDH2) are also pivotal for directional migration of cell condensates by maintaining cell-cell cohesion, thus suggesting a fine interplay between cell-matrix and cell-cell adhesions. Our results shed light on the role of cell interactions with a fibronectin-depositing matrix during chondrogenesis in vitro, with possible applications in regenerative medicine. This article has an associated First Person interview with the first author of the paper.© 2022. Published by The Company of Biologists Ltd.

JTD Keywords: alpha-v-beta-3, arginine-glycine-aspartic acid, chondrogenesis, dynamics, expression, fibronectin, gastrulation, involvement, mechanisms, mesenchymal condensation, model, nanopatterned substrates, rgd, Arginine-glycine-aspartic acid, Cell migration, Chondrogenesis, Mesenchymal condensation, N-cadherin, Nanopatterned substrates, Rgd

Bouzon-Arnaiz, I, Avalos-Padilla, Y, Biosca, A, Cano-Prades, O, Roman-Alamo, L, Valle, J, Andreu, D, Moita, D, Prudencio, M, Arce, EM, Munoz-Torrero, D, Fernandez-Busquets, X, (2022). The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures Bmc Biology 20, 197

Background By 2016, signs of emergence of Plasmodium falciparum resistance to artemisinin and partner drugs were detected in the Greater Mekong Subregion. Recently, the independent evolution of artemisinin resistance has also been reported in Africa and South America. This alarming scenario calls for the urgent development of new antimalarials with novel modes of action. We investigated the interference with protein aggregation, which is potentially toxic for the cell and occurs abundantly in all Plasmodium stages, as a hitherto unexplored drug target in the pathogen. Results Attempts to exacerbate the P. falciparum proteome's propensity to aggregation by delivering endogenous aggregative peptides to in vitro cultures of this parasite did not significantly affect their growth. In contrast, protein aggregation inhibitors clearly reduced the pathogen's viability. One such compound, the bis(styrylpyridinium) salt YAT2150, exhibited potent antiplasmodial activity with an in vitro IC50 of 90 nM for chloroquine- and artemisinin-resistant lines, arresting asexual blood parasites at the trophozoite stage, as well as interfering with the development of both sexual and hepatic forms of Plasmodium. At its IC50, this compound is a powerful inhibitor of the aggregation of the model amyloid beta peptide fragment 1-40, and it reduces the amount of aggregated proteins in P. falciparum cultures, suggesting that the underlying antimalarial mechanism consists in a generalized impairment of proteostasis in the pathogen. YAT2150 has an easy, rapid, and inexpensive synthesis, and because it fluoresces when it accumulates in its main localization in the Plasmodium cytosol, it is a theranostic agent. Conclusions Inhibiting protein aggregation in Plasmodium significantly reduces the parasite's viability in vitro. Since YAT2150 belongs to a novel structural class of antiplasmodials with a mode of action that potentially targets multiple gene products, rapid evolution of resistance to this drug is unlikely to occur, making it a promising compound for the post-artemisinin era.

JTD Keywords: Amyloid formation, Amyloid pan-inhibitors, Antimalarial drugs, Colocalization, Cytosolic delivery, Derivatives, Disease, Drug, In-vitro, Malaria, Mechanism, Plasmodium falciparum, Polyglutamine, Protein aggregation, Yat2150

Barbacena P, Dominguez-Cejudo M, Fonseca CG, Gómez-González M, Faure LM, Zarkada G, Pena A, Pezzarossa A, Ramalho D, Giarratano Y, Ouarné M, Barata D, Fortunato IC, Misikova LH, Mauldin I, Carvalho Y, Trepat X, Roca-Cusachs P, Eichmann A, Bernabeu MO, Franco CA, (2022). Competition for endothelial cell polarity drives vascular morphogenesis in the mouse retina Developmental Cell 57, 2321-2333

Blood-vessel formation generates unique vascular patterns in each individual. The principles governing the apparent stochasticity of this process remain to be elucidated. Using mathematical methods, we find that the transition between two fundamental vascular morphogenetic programs-sprouting angiogenesis and vascular remodeling-is established by a shift of collective front-to-rear polarity of endothelial cells in the mouse retina. We demonstrate that the competition between biochemical (VEGFA) and mechanical (blood-flow-induced shear stress) cues controls this collective polarity shift. Shear stress increases tension at focal adhesions overriding VEGFA-driven collective polarization, which relies on tension at adherens junctions. We propose that vascular morphogenetic cues compete to regulate individual cell polarity and migration through tension shifts that translates into tissue-level emergent behaviors, ultimately leading to uniquely organized vascular patterns.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

JTD Keywords: activation, angiogenesis, dynamics, flow, forces, image, mechanisms, vinculin, Angiogenesis, Cell polarity, Fluid shear, Mechanobiology, Morphogenesis, Shear stress

Deborde, Sylvie, Gusain, Laxmi, Powers, Ann, Marcadis, Andrea, Yu, Yasong, Chen, Chun-Hao, Frants, Anna, Kao, Elizabeth, Tang, Laura H., Vakiani, Efsevia, Amisaki, Masataka, Balachandran, Vinod P., Calo, Annalisa, Omelchenko, Tatiana, Jessen, Kristjan R., Reva, Boris, Wong, Richard J., (2022). Reprogrammed Schwann cells organize into dynamic tracks that promote pancreatic cancer invasion Cancer Discovery 12, 2454-2473

Abstract Nerves are a component of the tumor microenvironment contributing to cancer progression, but the role of cells from nerves in facilitating cancer invasion remains poorly understood. Here we show that Schwann cells (SCs) activated by cancer cells collectively function as Tumor Activated Schwann cell Tracks (TASTs) that promote cancer cell migration and invasion. Non-myelinating SCs form TASTs and have cell gene expression signatures that correlate with diminished survival in patients with pancreatic ductal adenocarcinoma. In TASTs, dynamic SCs form tracks that serve as cancer pathways and apply forces on cancer cells to enhance cancer motility. These SCs are activated by c-Jun, analogous to their reprogramming during nerve repair. This study reveals a mechanism of cancer cell invasion that co-opts a wound repair process and exploits the ability of SCs to collectively organize into tracks. These findings establish a novel paradigm of how cancer cells spread and reveal therapeutic opportunities.

JTD Keywords: dissemination, escape, mechanisms, progression, Perineural invasion

F Amil A, Rubio Ballester B, Maier M, FMJ Verschure P, (2022). Chronic use of cannabis might impair sensory error processing in the cerebellum through endocannabinoid dysregulation Addictive Behaviors 131, 107297

Chronic use of cannabis leads to both motor deficits and the downregulation of CB1 receptors (CB1R) in the cerebellum. In turn, cerebellar damage is often related to impairments in motor learning and control. Further, a recent motor learning task that measures cerebellar-dependent adaptation has been shown to distinguish well between healthy subjects and chronic cannabis users. Thus, the deteriorating effects of chronic cannabis use in motor performance point to cerebellar adaptation as a key process to explain such deficits. We review the literature relating chronic cannabis use, the endocannabinoid system in the cerebellum, and different forms of cerebellar-dependent motor learning, to suggest that CB1R downregulation leads to a generalized underestimation and misprocessing of the sensory errors driving synaptic updates in the cerebellar cortex. Further, we test our hypothesis with a computational model performing a motor adaptation task and reproduce the behavioral effect of decreased implicit adaptation that appears to be a sign of chronic cannabis use. Finally, we discuss the potential of our hypothesis to explain similar phenomena related to motor impairments following chronic alcohol dependency. © 2022

JTD Keywords: adaptation, addiction, alcohol-abuse, cerebellum, cognition, deficits, endocannabinoid system, error processing, explicit, modulation, motor learning, release, synaptic plasticity, Adaptation, Adaptation, physiological, Alcoholism, Article, Behavioral science, Cannabinoid 1 receptor, Cannabis, Cannabis addiction, Cerebellum, Cerebellum cortex, Cerebellum disease, Chronic cannabis use, Computer model, Down regulation, Endocannabinoid, Endocannabinoid system, Endocannabinoids, Error processing, Hallucinogens, Human, Humans, Motor dysfunction, Motor learning, Nerve cell plasticity, Nonhuman, Physiology, Psychedelic agent, Purkinje-cells, Regulatory mechanism, Sensation, Sensory dysfunction, Sensory error processing impairment, Synaptic transmission, Task performance

Bernabeu, M, Aznar, S, Prieto, A, Huttener, M, Juarez, A, (2022). Differential Expression of Two Copies of the irmA Gene in the Enteroaggregative E. coli Strain 042 Microbiology Spectrum 17, 00454-22

Gene duplications occur in prokaryotic genomes at a detectable frequency. In many instances, the biological function of the duplicates is unknown, and hence, the significance of the presence of multiple copies of these genes remains unclear.; Gene duplications significantly impact the gene repertoires of both eukaryotic and prokaryotic microorganisms. The genomes of pathogenic Escherichia coli strains share a group of duplicated genes whose function is mostly unknown. The irmA gene is one of the duplicates encoded in several pathogenic E. coli strains. The function of its gene product was investigated in the uropathogenic E. coli strain CFT073, which contains a single functional copy. The IrmA protein structure mimics that of human interleukin receptors and likely plays a role during infection. The enteroaggregative E. coli strain 042 contains two functional copies of the irmA gene. In the present work, we investigated their biological roles. The irmA_4509 allele is expressed under several growth conditions. Its expression is modulated by the global regulators OxyR and Hha, with optimal expression at 37 degrees C and under nutritional stress conditions. Expression of the irmA_2244 allele can only be detected when the irmA_4509 allele is knocked out. Differences in the promoter regions of both alleles account for their differential expression. Our results show that under several environmental conditions, the expression of the IrmA protein in strain 042 is dictated by the irmA_4509 allele. The irmA_2244 allele appears to play a backup role to ensure IrmA expression when the irmA_4509 allele loses its function. IMPORTANCE Gene duplications occur in prokaryotic genomes at a detectable frequency. In many instances, the biological function of the duplicates is unknown, and hence, the significance of the presence of multiple copies of these genes remains unclear. In pathogenic E. coli isolates, the irmA gene can be present either as a single copy or in two or more copies. We focused our work on studying why a different pathogenic E. coli strain encodes two functional copies of the irmA gene. We show that under several environmental conditions, one of the alleles dictates IrmA expression, and the second remains silent. The latter allele is only expressed when the former is silenced. The presence of more than one functional copy of the irmA gene in some pathogenic E. coli strains can result in sufficient expression of this virulence factor during the infection process.

JTD Keywords: 042, Adaptation, Aec69, Aggregative adherence, Chromosomal genes, Coli, Duplication, Enteroaggregative e, Escherichia-coli, Evolution, Gene duplications, Hha/ymoa, Irma, Mechanism, Outer-membrane, Protein

Garrido-Charles, A, Huet, A, Matera, C, Thirumalai, A, Hernando, J, Llebaria, A, Moser, T, Gorostiza, P, (2022). Fast Photoswitchable Molecular Prosthetics Control Neuronal Activity in the Cochlea Journal Of The American Chemical Society 144, 9229-9239

Artificial control of neuronal activity enables the study of neural circuits and restoration of neural functions. Direct, rapid, and sustained photocontrol of intact neurons could overcome the limitations of established electrical stimulation such as poor selectivity. We have developed fast photoswitchable ligands of glutamate receptors (GluRs) to enable neuronal control in the auditory system. The new photoswitchable ligands induced photocurrents in untransfected neurons upon covalently tethering to endogenous GluRs and activating them reversibly with visible light pulses of a few milliseconds. As a proof of concept of these molecular prostheses, we applied them to the ultrafast synapses of auditory neurons of the cochlea that encode sound and provide auditory input to the brain. This drug-based method afforded the optical stimulation of auditory neurons of adult gerbils at hundreds of hertz without genetic manipulation that would be required for their optogenetic control. This indicates that the new photoswitchable ligands are also applicable to the spatiotemporal control of fast spiking interneurons in the brain.

JTD Keywords: Acid, Azobenzene, Glutamate-receptor, Ion channels, Mechanisms, Nerve, Optical switches, Release, Stimulation

Mir, M, Palma-Florez, S, Lagunas, A, Lopez-Martinez, MJ, Samitier, J, (2022). Biosensors Integration in Blood-Brain Barrier-on-a-Chip: Emerging Platform for Monitoring Neurodegenerative Diseases Acs Sensors 7, 1237-1247

Over the most recent decades, the development of new biological platforms to study disease progression and drug efficacy has been of great interest due to the high increase in the rate of neurodegenerative diseases (NDDs). Therefore, blood-brain barrier (BBB) as an organ-on-a-chip (OoC) platform to mimic brain-barrier performance could offer a deeper understanding of NDDs as well as a very valuable tool for drug permeability testing for new treatments. A very attractive improvement of BBB-oC technology is the integration of detection systems to provide continuous monitoring of biomarkers in real time and a fully automated analysis of drug permeably, rendering more efficient platforms for commercialization. In this Perspective, an overview of the main BBB-oC configurations is introduced and a critical vision of the BBB-oC platforms integrating electronic read out systems is detailed, indicating the strengths and weaknesses of current devices, proposing the great potential for biosensors integration in BBB-oC. In this direction, we name potential biomarkers to monitor the evolution of NDDs related to the BBB and/or drug cytotoxicity using biosensor technology in BBB-oC.

JTD Keywords: Bbb, Biosensors, Blood-brain barrier (bbb), Electrical-resistance, Electrochemical biosensors, Endothelial-cells, In-vitro model, Matrix metalloproteinases, Mechanisms, Neurodegenerative diseases (ndds), Organ-on-a-chip (ooc), Permeability, Stress, Transendothelial electrical resistance (teer), Transepithelial, Transport

Noguchi, Hiroshi, Tozzi, Caterina, Arroyo, Marino, (2022). Binding of anisotropic curvature-inducing proteins onto membrane tubes Soft Matter 18, 3384-3394

We studied how anisotropic proteins are orientationally ordered and change the radius of membrane tubes using mean-field theory with an orientation-dependent excluded volume interaction.

JTD Keywords: bar, density, driven, generation, inclusions, invagination, mechanisms, monte-carlo, tubulation, Mediated aggregation

Cascione M, Rizzello L, Manno D, Serra A, De Matteis V, (2022). Green Silver Nanoparticles Promote Inflammation Shutdown in Human Leukemic Monocytes Materials (Basel) 15, 775

The use of silver nanoparticles (Ag NPs) in the biomedical field deserves a mindful analysis of the possible inflammatory response which could limit their use in the clinic. Despite the anti-cancer properties of Ag NPs having been widely demonstrated, there are still few studies concerning their involvement in the activation of specific inflammatory pathways. The inflammatory outcome depends on the synthetic route used in the NPs production, in which toxic reagents are employed. In this work, we compared two types of Ag NPs, obtained by two different chemical routes: conventional synthesis using sodium citrate and a green protocol based on leaf extracts as a source of reduction and capping agents. A careful physicochemical characterization was carried out showing spherical and stable Ag NPs with an average size between 20 nm and 35 nm for conventional and green Ag NPs respectively. Then, we evaluated their ability to induce the activation of inflammation in Human Leukemic Monocytes (THP-1) differentiated into M0 macrophages using 1 µM and 2 µM NPs concentrations (corresponded to 0.1 µg/mL and 0.2 µg/mL respectively) and two-time points (24 h and 48 h). Our results showed a clear difference in Nuclear Factor ?B (NF-?b) activation, Interleukins 6–8 (IL-6, IL-8) secretion, Tumor Necrosis Factor-? (TNF-?) and Cyclooxygenase-2 (COX-2) expression exerted by the two kinds of Ag NPs. Green Ag NPs were definitely tolerated by macrophages compared to conventional Ag NPs which induced the activation of all the factors mentioned above. Subsequently, the exposure of breast cancer cell line (MCF-7) to the green Ag NPs showed that they exhibited antitumor activity like the conventional ones, but surprisingly, using the MCF-10A line (not tumoral breast cells) the green Ag NPs did not cause a significant decrease in cell viability. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

JTD Keywords: activation, biosynthesis, gold nanoparticles, green route, inflammation response, mechanism, metal, nanotechnology, physico-chemical properties, raman-spectroscopy, resonance, silver nanoparticles, surface, Biomedical fields, Cell culture, Cell death, Chemical activation, Chemical routes, Conventional synthesis, Diseases, Green route, Inflammation response, Inflammatory response, Macrophages, Metal nanoparticles, Nf-kappa-b, Pathology, Physico-chemical properties, Physicochemical property, Property, Silver nanoparticles, Sodium compounds, Synthetic routes, Toxic reagents

Kadkhodaie-Elyaderani A, de Lama-Odría MC, Rivas M, Martínez-Rovira I, Yousef I, Puiggalí J, Del Valle LJ, (2022). Medicated Scaffolds Prepared with Hydroxyapatite/Streptomycin Nanoparticles Encapsulated into Polylactide Microfibers International Journal Of Molecular Sciences 23, 1282

The preparation, characterization, and controlled release of hydroxyapatite (HAp) nanopar-ticles loaded with streptomycin (STR) was studied. These nanoparticles are highly appropriate for the treatment of bacterial infections and are also promising for the treatment of cancer cells. The analyses involved scanning electron microscopy, dynamic light scattering (DLS) and Z-potential measurements, as well as infrared spectroscopy and X-ray diffraction. Both amorphous (ACP) and crystalline (cHAp) hydroxyapatite nanoparticles were considered since they differ in their release behavior (faster and slower for amorphous and crystalline particles, respectively). The encapsulated nanoparticles were finally incorporated into biodegradable and biocompatible polylactide (PLA) scaf-folds. The STR load was carried out following different pathways during the synthesis/precipitation of the nanoparticles (i.e., nucleation steps) and also by simple adsorption once the nanoparticles were formed. The loaded nanoparticles were biocompatible according to the study of the cytotoxicity of extracts using different cell lines. FTIR microspectroscopy was also employed to evaluate the cytotoxic effect on cancer cell lines of nanoparticles internalized by endocytosis. The results were promising when amorphous nanoparticles were employed. The nanoparticles loaded with STR increased their size and changed their superficial negative charge to positive. The nanoparticles’ crystallinity decreased, with the consequence that their crystal sizes reduced, when STR was incorporated into their structure. STR maintained its antibacterial activity, although it was reduced during the adsorption into the nanoparticles formed. The STR release was faster from the amorphous ACP nanoparticles and slower from the crystalline cHAp nanoparticles. However, in both cases, the STR release was slower when incorporated in calcium and phosphate during the synthesis. The biocompatibility of these nanoparticles was assayed by two approximations. When extracts from the nanoparticles were evaluated in cultures of cell lines, no cytotoxic damage was observed at concen-trations of less than 10 mg/mL. This demonstrated their biocompatibility. Another experiment using FTIR microspectroscopy evaluated the cytotoxic effect of nanoparticles internalized by endocytosis in cancer cells. The results demonstrated slight damage to the biomacromolecules when the cells were treated with ACP nanoparticles. Both ACP and cHAp nanoparticles were efficiently encapsulated in PLA electrospun matrices, providing functionality and bioactive properties. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

JTD Keywords: antibiotics, antimicrobial activity, behavior, cytotoxicity, delivery, drug, drug delivery, hydroxyapatite nanoparticles, in-vitro, mechanisms, mitochondria, polylactide, release, streptomycin, Antimicrobial activity, Cancer stem-cells, Cytotoxicity, Drug delivery, Hydroxyapatite nanoparticles, Polylactide, Streptomycin

Martí, Didac, Alemán, Carlos, Ainsley, Jon, Ahumada, Oscar, Torras, Juan, (2022). IgG1-b12–HIV-gp120 Interface in Solution: A Computational Study Journal Of Chemical Information And Modeling 62, 359-371

The use of broadly neutralizing antibodies against human immunodeficiency virus type 1 (HIV-1) has been shown to be a promising therapeutic modality in the prevention of HIV infection. Understanding the b12-gp120 binding mechanism under physiological conditions may assist the development of more broadly effective antibodies. In this work, the main conformations and interactions between the receptor-binding domain (RBD) of spike glycoprotein gp120 of HIV-1 and the IgG1-b12 mAb are studied. Accelerated molecular dynamics (aMD) and ab initio hybrid molecular dynamics have been combined to determine the most persistent interactions between the most populated conformations of the antibody-antigen complex under physiological conditions. The results show the most persistent receptor-binding mapping in the conformations of the antibody-antigen interface in solution. The binding-free-energy decomposition reveals a small enhancement in the contribution played by the CDR-H3 region to the b12-gp120 interface compared to the crystal structure.

JTD Keywords: antibody, complex, functionals, gp120 envelope glycoprotein, hiv, immunodeficiency-virus, noncovalent interactions, simulations, software integration, Ab initio, Accelerated molecular dynamics, Accelerated molecular-dynamics, Antibodies, Antigens, Binding energy, Binding mechanisms, Computational studies, Crystal structure, Diseases, Free energy, Hiv infection, Human immunodeficiency virus, Molecular dynamics, Neutralizing antibodies, Physiological condition, Physiology, Receptor-binding domains, Therapeutic modality, Viruses

Pérez-Rafael S, Ivanova K, Stefanov I, Puiggalí J, del Valle LJ, Todorova K, Dimitrov P, Hinojosa-Caballero D, Tzanov T, (2021). Nanoparticle-driven self-assembling injectable hydrogels provide a multi-factorial approach for chronic wound treatment Acta Biomaterialia 134, 131-143

Chronic wounds represent a major health burden and drain on medical system. Efficient wound repair is only possible if the dressing materials target simultaneously multiple factors involved in wound chronicity, such as deleterious proteolytic and oxidative enzymes and high bacterial load. Here we develop multifunctional hydrogels for chronic wound management through self-assembling of thiolated hyaluronic acid (HA-SH) and bioactive silver-lignin nanoparticles (Ag@Lig NPs). Dynamic and reversible interactions between the polymer and Ag@Lig NPs yield hybrid nanocomposite hydrogels with shear-thinning and self-healing properties, coupled to zero-order kinetics release of antimicrobial silver in response to infection-related hyalurodinase. The hydrogels inhibit the major enzymes myeloperoxidase and matrix metalloproteinases responsible for wound chronicity in a patient's wound exudate. Furthermore, the lignin-capped AgNPs provide the hydrogel with antioxidant properties and strong antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. The nanocomposite hydrogels are not toxic to human keratinocytes after 7 days of direct contact. Complete tissue remodeling and restoration of skin integrity is demonstrated in vivo in a diabetic mouse model. Hematological analysis reveals lack of wound inflammation due to bacterial infection or toxicity, confirming the potential of HA-SH/Ag@Lig NPs hydrogels for chronic wound management. Statement of significance: Multifunctional hydrogels are promising materials to promote healing of complex wounds. Herein, we report simple and versatile route to prepare biocompatible and multifunctional self-assembled hydrogels for efficient chronic wound treatment utilizing polymer-nanoparticle interactions. Hybrid silver-lignin nanoparticles (Ag@Lig NPs) played both: i) structural role, acting as crosslinking nodes in the hydrogel and endowing it with shear-thinning (ability to flow under applied shear stress) and self-healing properties, and ii) functional role, imparting strong antibacterial and antioxidant activity. Remarkably, the in situ self-assembling of thiolated hyaluronic acid and Ag@Lig NPs yields nanocomposite hydrogels able to simultaneously inhibits the major factors involved in wound chronicity, namely the overexpressed deleterious proteolytic and oxidative enzymes, and high bacterial load.

JTD Keywords: catechol, chronic wounds, dressing materials, inhibition, mechanism, nano-enabled hydrogels, polyphenols, promogran, self-assembling, silver-lignin nanoparticles, systems, tannins, Chronic wounds, Degradation, Dressing materials, Nano-enabled hydrogels, Self-assembling, Silver-lignin nanoparticles, Thiolated hyaluronic acid

Hamouda I, Labay C, Cvelbar U, Ginebra MP, Canal C, (2021). Selectivity of direct plasma treatment and plasma-conditioned media in bone cancer cell lines Scientific Reports 11,

Atmospheric pressure plasma jets have been shown to impact several cancer cell lines, both in vitro and in vivo. These effects are based on the biochemistry of the reactive oxygen and nitrogen species generated by plasmas in physiological liquids, referred to as plasma-conditioned liquids. Plasma-conditioned media are efficient in the generation of reactive species, inducing selective cancer cell death. However, the concentration of reactive species generated by plasma in the cell culture media of different cell types can be highly variable, complicating the ability to draw precise conclusions due to the differential sensitivity of different cells to reactive species. Here, we compared the effects of direct and indirect plasma treatment on non-malignant bone cells (hOBs and hMSCs) and bone cancer cells (SaOs-2s and MG63s) by treating the cells directly or exposing them to previously treated cell culture medium. Biological effects were correlated with the concentrations of reactive species generated in the liquid. A linear increase in reactive species in the cell culture medium was observed with increased plasma treatment time independent of the volume treated. Values up to 700 µM for H2O2 and 140 µM of NO2− were attained in 2 mL after 15 min of plasma treatment in AdvDMEM cell culture media. Selectivity towards bone cancer cells was observed after both direct and indirect plasma treatments, leading to a decrease in bone cancer cell viability at 72 h to 30% for the longest plasma treatment times while maintaining the survival of non-malignant cells. Therefore, plasma-conditioned media may represent the basis for a potentially novel non-invasive technique for bone cancer therapy.

JTD Keywords: expression, in-vitro, jet, mechanisms, nitrate, nitrite, osteosarcoma cells, reactive oxygen, Cold atmospheric plasma

Casellas NM, Albertazzi L, Pujals S, Torres T, García-Iglesias M, (2021). Unveiling Polymerization Mechanism in pH-regulated Supramolecular Fibers in Aqueous Media Chemistry-A European Journal 27, 11056-11060

An amine functionalized C3-symmetric benzotrithiophene (BTT) monomer has been designed and synthetized in order to form pH responsive one-dimensional supramolecular polymers in aqueous media. While most of the reported studies looked at the effect of pH on the size of the aggregates, herein, a detailed mechanistic study is reported, carried out upon modifying the pH to trigger the formation of positively charged ammonium groups. A dramatic and reversible change in the polymerization mechanism and size of the supramolecular fibers is observed and ascribed to the combination of Coulombic repulsive forces and higher monomer solubility. Furthermore, the induced frustrated growth of the fibers is further employed to finely control the one-dimensional supramolecular polymerisation and copolymerization processes.

JTD Keywords: dynamics, ph responsivity, polymerization mechanism, self-assembly, supramolecular chemistry, supramolecular polymers, Ph responsivity, Polymerization mechanism, Polymers, Self-assembly, Supramolecular chemistry, Supramolecular polymers

De Matteis V, Cascione M, Rizzello L, Manno DE, Di Guglielmo C, Rinaldi R, (2021). Synergistic effect induced by gold nanoparticles with polyphenols shell during thermal therapy: Macrophage inflammatory response and cancer cell death assessment Cancers 13,

Background: In recent decades, gold nanoparticle (Au NP)-based cancer therapy has been heavily debated. The physico-chemical properties of AuNPs can be exploited in photothermal therapy, making them a powerful tool for selectively killing cancer cells. However, the synthetic side products and capping agents often induce a strong activation of the inflammatory pathways of macrophages, thus limiting their further applications in vivo. Methods: Here, we described a green method to obtain stable polyphenol-capped AuNPs (Au NPs@polyphenols), as polyphenols are known for their anti-inflammatory and anticancer properties. These NPs were used in human macrophages to test key inflammation-related markers, such as NF-κB, TNF-α, and interleukins-6 and 8. The results were compared with similar NPs obtained by a traditional chemical route (without the polyphenol coating), proving the potential of Au NPs@polyphenols to strongly promote the shutdown of inflammation. This was useful in developing them for use as heat-synergized tools in the thermal treatment of two types of cancer cells, namely, breast cancer (MCF-7) and neuroblastoma (SH-SY5Y) cells. The cell viability, calcium release, oxidative stress, HSP-70 expression, mitochondrial, and DNA damage, as well as cytoskeleton alteration, were evaluated. Results: Our results clearly demonstrate that the combined strategy markedly exerts anticancer effects against the tested cancer cell, while neither of the single treatments (only heat or only NPs) induced significant changes. Conclusions: Au NP@polyphenols may be powerful agents in cancer treatment.

JTD Keywords: antioxidant, aunps, biocompatibility, biology, calcium, cancer, green synthesis, inflammation response, inhibition, interleukin-6, mechanisms, natural polyphenols, physico-chemical properties, polyphenols, size, thermal treatment, Aunps, Cancer, Green synthesis, Inflammation response, Nobilis l. leaves, Physico-chemical properties, Polyphenols, Thermal treatment

Blanco-Fernandez, B, Castano, O, Mateos-Timoneda, MA, Engel, E, Perez-Amodio, S, (2021). Nanotechnology Approaches in Chronic Wound Healing Advances In Wound Care 10, 234-256

Significance: The incidence of chronic wounds is increasing due to our aging population and the augment of people afflicted with diabetes. With the extended knowledge on the biological mechanisms underlying these diseases, there is a novel influx of medical technologies into the conventional wound care market. Recent Advances: Several nanotechnologies have been developed demonstrating unique characteristics that address specific problems related to wound repair mechanisms. In this review, we focus on the most recently developed nanotechnology-based therapeutic agents and evaluate the efficacy of each treatment in in vivo diabetic models of chronic wound healing. Critical Issues: Despite the development of potential biomaterials and nanotechnology-based applications for wound healing, this scientific knowledge is not translated into an increase of commercially available wound healing products containing nanomaterials. Future Directions: Further studies are critical to provide insights into how scientific evidences from nanotechnology-based therapies can be applied in the clinical setting.

JTD Keywords: chronic, diabetes, liposomes, nanofibers, nanoparticles, Chronic, Chronic wound, Diabetes, Diabetic wound, Diabetic-rats, Dressings, Drug mechanism, Extracellular-matrix, Growth-factor, Human, In-vitro, Liposome, Liposomes, Mesenchymal stem-cells, Metal nanoparticle, Nanofiber, Nanofibers, Nanofibrous scaffolds, Nanoparticles, Nanotechnology, Nonhuman, Polyester, Polymer, Polysaccharide, Priority journal, Protein, Review, Self assembled protein nanoparticle, Silk fibroin, Skin wounds, Wound healing, Wound healing promoting agent

Enshaei H, Puiggalí-Jou A, del Valle LJ, Turon P, Saperas N, Alemán C, (2021). Nanotheranostic Interface Based on Antibiotic-Loaded Conducting Polymer Nanoparticles for Real-Time Monitoring of Bacterial Growth Inhibition Advanced Healthcare Materials 10,

© 2020 Wiley-VCH GmbH Conducting polymers have been increasingly used as biologically interfacing electrodes for biomedical applications due to their excellent and fast electrochemical response, reversible doping–dedoping characteristics, high stability, easy processability, and biocompatibility. These advantageous properties can be used for the rapid detection and eradication of infections associated to bacterial growth since these are a tremendous burden for individual patients as well as the global healthcare system. Herein, a smart nanotheranostic electroresponsive platform, which consists of chloramphenicol (CAM)-loaded in poly(3,4-ethylendioxythiophene) nanoparticles (PEDOT/CAM NPs) for concurrent release of the antibiotic and real-time monitoring of bacterial growth is presented. PEDOT/CAM NPs, with an antibiotic loading content of 11.9 ± 1.3% w/w, are proved to inhibit the growth of Escherichia coli and Streptococcus sanguinis due to the antibiotic release by cyclic voltammetry. Furthermore, in situ monitoring of bacterial activity is achieved through the electrochemical detection of β-nicotinamide adenine dinucleotide, a redox active specie produced by the microbial metabolism that diffuse to the extracellular medium. According to these results, the proposed nanotheranostic platform has great potential for real-time monitoring of the response of bacteria to the released antibiotic, contributing to the evolution of the personalized medicine.

JTD Keywords: bacterial detection, chloramphenicol, conducting polymers, drug, drug release, electrochemical sensors, electrochemistry, electrostimulated release, mechanism, peptide, polythiophene, sensor, sulfonate, Bacterial detection, Chloramphenicol, Conducting polymers, Controlled-release, Drug release, Electrochemical sensors, Electrostimulated release, Polythiophene

Consegal M, Valls-Lacalle L, Rodríguez-Sinovas A, (2021). Angiotensin II-induced cardiomyocyte hypertrophy: A complex response dependent on intertwined pathways Revista Portuguesa De Cardiologia 40, 201-203

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.

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

Bolognesi, Benedetta, Faure, Andre J., Seuma, Mireia, Schmiedel, Jörrn M., Tartaglia, Gian Gaetano, Lehner, Ben, (2019). The mutational landscape of a prion-like domain Nature Communications 10, (1), 4162

Insoluble protein aggregates are the hallmarks of many neurodegenerative diseases. For example, aggregates of TDP-43 occur in nearly all cases of amyotrophic lateral sclerosis (ALS). However, whether aggregates cause cellular toxicity is still not clear, even in simpler cellular systems. We reasoned that deep mutagenesis might be a powerful approach to disentangle the relationship between aggregation and toxicity. We generated >50,000 mutations in the prion-like domain (PRD) of TDP-43 and quantified their toxicity in yeast cells. Surprisingly, mutations that increase hydrophobicity and aggregation strongly decrease toxicity. In contrast, toxic variants promote the formation of dynamic liquid-like condensates. Mutations have their strongest effects in a hotspot that genetic interactions reveal to be structured in vivo, illustrating how mutagenesis can probe the in vivo structures of unstructured proteins. Our results show that aggregation of TDP-43 is not harmful but protects cells, most likely by titrating the protein away from a toxic liquid-like phase.

JTD Keywords: Computational biology and bioinformatics, Genomics, Mechanisms of disease, Neurodegeneration, Systems biology

Klein, S., Kleine, C. E., Pieper, A., Granzow, M., Gautsch, S., Himmit, M., Kahrmann, K., Schierwagen, R., Uschner, F. E., Magdaleno, F., Naoum, M. E., Kristiansen, G., Walther, T., Bader, M., Sauerbruch, T., Trebicka, J., (2019). TGR(mREN2)27 rats develop non-alcoholic fatty liver disease-associated portal hypertension responsive to modulations of Janus-kinase 2 and Mas receptor Scientific Reports 9, (1), 11598

Prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Resulting fibrosis and portal hypertension, as a possible secondary event, may necessitate treatment. Overexpression of mouse renin in the transgenic rat model, TGR(mREN2)27, leads to spontaneous development of NAFLD. Therefore, we used TGR(mREN2)27 rats as a model of NAFLD where we hypothesized increased susceptibility and investigated fibrosis and portal hypertension and associated pathways. 12-week old TGR(mREN2)27 rats received either cholestatic (BDL) or toxic injury (CCl4 inhalation). Portal and systemic hemodynamic assessments were performed using microsphere technique with and without injection of the Janus-Kinase 2 (JAK2) inhibitor AG490 or the non-peptidic Ang(1-7) agonist, AVE0991. The extent of liver fibrosis was assessed in TGR(mREN2)27 and wild-type rats using standard techniques. Protein and mRNA levels of profibrotic, renin-angiotensin system components were assessed in liver and primary hepatic stellate cells (HSC) and hepatocytes. TGR(mREN2)27 rats developed spontaneous, but mild fibrosis and portal hypertension due to the activation of the JAK2/Arhgef1/ROCK pathway. AG490 decreased migration of HSC and portal pressure in isolated liver perfusions and in vivo. Fibrosis or portal hypertension after cholestatic (BDL) or toxic injury (CCl4) was not aggravated in TGR(mREN2)27 rats, probably due to decreased mouse renin expression in hepatocytes. Interestingly, portal hypertension was even blunted in TGR(mREN2)27 rats (with or without additional injury) by AVE0991. TGR(mREN2)27 rats are a suitable model of spontaneous liver fibrosis and portal hypertension but not with increased susceptibility to liver damage. After additional injury, the animals can be used to evaluate novel therapeutic strategies targeting Mas.

JTD Keywords: Mechanisms of disease, Molecular medicine

Giraldo, B. F., Tellez, J. P., Herrera, S., Benito, S., (2013). Analysis of heart rate variability in elderly patients with chronic heart failure during periodic breathing CinC 2013 Computing in Cardiology Conference (CinC) , IEEE (Zaragoza, Spain) , 991-994

Assessment of the dynamic interactions between cardiovascular signals can provide valuable information that improves the understanding of cardiovascular control. Heart rate variability (HRV) analysis is known to provide information about the autonomic heart rate modulation mechanism. Using the HRV signal, we aimed to obtain parameters for classifying patients with and without chronic heart failure (CHF), and with periodic breathing (PB), non-periodic breathing (nPB), and Cheyne-Stokes respiration (CSR) patterns. An electrocardiogram (ECG) and a respiratory flow signal were recorded in 36 elderly patients: 18 patients with CHF and 18 patients without CHF. According to the clinical criteria, the patients were classified into the follow groups: 19 patients with nPB pattern, 7 with PB pattern, 4 with Cheyne-Stokes respiration (CSR), and 6 non-classified patients (problems with respiratory signal). From the HRV signal, parameters in the time and frequency domain were calculated. Frequency domain parameters were the most discriminant in comparisons of patients with and without CHF: PTot (p = 0.02), PLF (p = 0.022) and fpHF (p = 0.021). For the comparison of the nPB vs. CSR patients groups, the best parameters were RMSSD (p = 0.028) and SDSD (p = 0.028). Therefore, the parameters appear to be suitable for enhanced diagnosis of decompensated CHF patients and the possibility of developed periodic breathing and a CSR pattern.

JTD Keywords: cardiovascular system, diseases, electrocardiography, frequency-domain analysis, geriatrics, medical signal processing, patient diagnosis, pneumodynamics, signal classification, Cheyne-Stokes respiration patterns, ECG, autonomic heart rate modulation mechanism, cardiovascular control, cardiovascular signals, chronic heart failure, decompensated CHF patients, dynamic interaction assessment, elderly patients, electrocardiogram, enhanced diagnosis, frequency domain parameters, heart rate variability analysis, patient classification, periodic breathing, respiratory flow signal recording, Electrocardiography, Frequency modulation, Frequency-domain analysis, Heart rate variability, Senior citizens, Standards

Jané, R., Lazaro, J., Ruiz, P., Gil, E., Navajas, D., Farre, R., Laguna, P., (2013). Obstructive Sleep Apnea in a rat model: Effects of anesthesia on autonomic evaluation from heart rate variability measures CinC 2013 Computing in Cardiology Conference (CinC) , IEEE (Zaragoza, Spain) , 1011-1014

Rat model of Obstructive Sleep Apnea (OSA) is a realistic approach for studying physiological mechanisms involved in sleep. Rats are usually anesthetized and autonomic nervous system (ANS) could be blocked. This study aimed to assess the effect of anesthesia on ANS activity during OSA episodes. Seven male Sprague-Dawley rats were anesthetized intraperitoneally with urethane (1g/kg). The experiments were conducted applying airway obstructions, simulating 15s-apnea episodes for 15 minutes. Five signals were acquired: respiratory pressure and flow, SaO2, ECG and photoplethysmography (PPG). In total, 210 apnea episodes were studied. Normalized power spectrum of Pulse Rate Variability (PRV) was analyzed in the Low Frequency (LF) and High Frequency (HF) bands, for each episode in consecutive 15s intervals (before, during and after the apnea). All episodes showed changes in respiratory flow and SaO2 signal. Conversely, decreases in the amplitude fluctuations of PPG (DAP) were not observed. Normalized LF presented extremely low values during breathing (median=7,67%), suggesting inhibition of sympathetic system due to anesthetic effect. Subtle increases of LF were observed during apnea. HRV and PPG analysis during apnea could be an indirect tool to assess the effect and deep of anesthesia.

JTD Keywords: electrocardiography, fluctuations, medical disorders, medical signal detection, medical signal processing, neurophysiology, photoplethysmography, pneumodynamics, sleep, ECG, SaO2 flow, SaO2 signal, airway obstructions, amplitude fluctuations, anesthesia effects, anesthetized nervous system, autonomic evaluation, autonomic nervous system, breathing, heart rate variability, high-frequency bands, low-frequency bands, male Sprague-Dawley rats, normalized power spectrum, obstructive sleep apnea, photoplethysmography, physiological mechanisms, pulse rate variability, rat model, respiratory flow, respiratory pressure, signal acquisition, sympathetic system inhibition, time 15 min, time 15 s, Abstracts, Atmospheric modeling, Computational modeling, Electrocardiography, Rats, Resonant frequency

Comelles, J., Hortigüela, V., Samitier, J., Martinez, E., (2012). Versatile gradients of covalently bound proteins on microstructured substrates Langmuir 28, (38), 13688-13697

In this work, we propose an easy method to produce highly tunable gradients of covalently bound proteins on topographically modified poly(methyl methacrylate). We used a rnicrofluidic approach to obtain linear gradients with high slope (0.5, relevant at the single-cell level. These protein gradients were characterized using fluorescence microscopy and surface plasmon resonance. Both experimental results and theoretical modeling on the protein gradients generated have proved them to be highly reproducible, stable up to 7 days, and easily tunable. This method enables formation of versatile cell culture platforms combining both complex biochemical and physical cues in an attempt to approach in vitro cell culture methods to in vivo cellular microenvironments.

JTD Keywords: Cell-migration, Microfluidic channel, Surface, Streptavidin, Molecules, Topography, Mechanisms, Generation, Responses, Guidance

Garde, A., Giraldo, B.F., Jané, R., Latshang, T.D., Turk, A.J., Hess, T., Bosch, M-.M., Barthelmes, D., Hefti, J.P., Maggiorini, M., Hefti, U., Merz, T.M., Schoch, O.D., Bloch, K.E., (2012). Periodic breathing during ascent to extreme altitude quantified by spectral analysis of the respiratory volume signal Engineering in Medicine and Biology Society (EMBC) 34th Annual International Conference of the IEEE , IEEE (San Diego, USA) , 707-710

High altitude periodic breathing (PB) shares some common pathophysiologic aspects with sleep apnea, Cheyne-Stokes respiration and PB in heart failure patients. Methods that allow quantifying instabilities of respiratory control provide valuable insights in physiologic mechanisms and help to identify therapeutic targets. Under the hypothesis that high altitude PB appears even during physical activity and can be identified in comparison to visual analysis in conditions of low SNR, this study aims to identify PB by characterizing the respiratory pattern through the respiratory volume signal. A number of spectral parameters are extracted from the power spectral density (PSD) of the volume signal, derived from respiratory inductive plethysmography and evaluated through a linear discriminant analysis. A dataset of 34 healthy mountaineers ascending to Mt. Muztagh Ata, China (7,546 m) visually labeled as PB and non periodic breathing (nPB) is analyzed. All climbing periods within all the ascents are considered (total climbing periods: 371 nPB and 40 PB). The best crossvalidated result classifying PB and nPB is obtained with Pm (power of the modulation frequency band) and R (ratio between modulation and respiration power) with an accuracy of 80.3% and area under the receiver operating characteristic curve of 84.5%. Comparing the subjects from 1st and 2nd ascents (at the same altitudes but the latter more acclimatized) the effect of acclimatization is evaluated. SaO2 and periodic breathing cycles significantly increased with acclimatization (p-value <; 0.05). Higher Pm and higher respiratory frequencies are observed at lower SaO2, through a significant negative correlation (p-value <; 0.01). Higher Pm is observed at climbing periods visually labeled as PB with >; 5 periodic breathing cycles through a significant positive correlation (p-value <; 0.01). Our data demonstrate that quantification of the respiratory volum- signal using spectral analysis is suitable to identify effects of hypobaric hypoxia on control of breathing.

JTD Keywords: Frequency domain analysis, Frequency modulation, Heart, Sleep apnea, Ventilation, Visualization, Cardiology, Medical disorders, Medical signal processing, Plethysmography, Pneumodynamics, Sensitivity analysis, Sleep, Spectral analysis, Cheyne-Stokes respiration, Climbing periods, Dataset, Heart failure patients, High altitude PB, High altitude periodic breathing, Hypobaric hypoxia, Linear discriminant analysis, Pathophysiologic aspects, Physical activity, Physiologic mechanisms, Power spectral density, Receiver operating characteristic curve, Respiratory control, Respiratory frequency, Respiratory inductive plethysmography, Respiratory pattern, Respiratory volume signal, Sleep apnea, Spectral analysis, Spectral parameters

Mesquita, J., Poree, F., Carrault, G., Fiz, J. A., Abad, J., Jané, R., (2012). Respiratory and spontaneous arousals in patients with Sleep Apnea Hypopnea Syndrome Engineering in Medicine and Biology Society (EMBC) 34th Annual International Conference of the IEEE , IEEE (San Diego, USA) , 6337-6340

Sleep in patients with Sleep Apnea-Hypopnea Syndrome (SAHS) is frequently interrupted with arousals. Increased amounts of arousals result in shortening total sleep time and repeated sleep-arousal change can result in sleep fragmentation. According to the American Sleep Disorders Association (ASDA) an arousal is a marker of sleep disruption representing a detrimental and harmful feature for sleep. The nature of arousals and its role on the regulation of the sleep process raises controversy and has sparked the debate in the last years. In this work, we analyzed and compared the EEG spectral content of respiratory and spontaneous arousals on a database of 45 SAHS subjects. A total of 3980 arousals (1996 respiratory and 1984 spontaneous) were analyzed. The results showed no differences between the spectral content of the two kinds of arousals. Our findings raise doubt as to whether these two kinds of arousals are truly triggered by different organic mechanisms. Furthermore, they may also challenge the current beliefs regarding the underestimation of the importance of spontaneous arousals and their contribution to sleep fragmentation in patients suffering from SAHS.

JTD Keywords: Adaptive filters, Correlation, Databases, Electroencephalography, Hospitals, Sleep apnea, Electroencephalography, Medical signal processing, Pneumodynamics, Sleep, EEG spectral content, Organic mechanism, Respiratory, Sleep apnea hypopnea syndrome, Sleep fragmentation, Spectral content, Spontaneous arousal

Diez-Perez, Ismael, Hihath, Joshua, Hines, Thomas, Wang, Zhong-Sheng, Zhou, Gang, Mullen, Klaus, Tao, Nongjian, (2011). Controlling single-molecule conductance through lateral coupling of [pi] orbitals Nature Nanotechnology , 6, (4), 226-231

In recent years, various single-molecule electronic components have been demonstrated(1). However, it remains difficult to predict accurately the conductance of a single molecule and to control the lateral coupling between the pi orbitals of the molecule and the orbitals of the electrodes attached to it. This lateral coupling is well known to cause broadening and shifting of the energy levels of the molecule; this, in turn, is expected to greatly modify the conductance of an electrodemolecule- electrode junction(2-6). Here, we demonstrate a new method, based on lateral coupling, to mechanically and reversibly control the conductance of a single-molecule junction by mechanically modulating the angle between a single pentaphenylene molecule bridged between two metal electrodes. Changing the angle of the molecule from a highly tilted state to an orientation nearly perpendicular to the electrodes changes the conductance by an order of magnitude, which is in qualitative agreement with theoretical models of molecular pi-orbital coupling to a metal electrode. The lateral coupling is also directly measured by applying a fast mechanical perturbation in the horizontal plane, thus ruling out changes in the contact geometry or molecular conformation as the source for the conductance change.

JTD Keywords: Junction conductance, Electron-transport, Interface, Dependence, Mechanism, Length

Pomareda, Victor, Marco, Santiago, (2011). Chemical plume source localization with multiple mobile sensors using bayesian inference under background signals Olfaction and Electronic Nose: Proceedings of the 14th International Symposium on Olfaction and Electronic Nose AIP Conference Proceedings (ed. Perena Gouma, SUNY Stony Brook), AIP (New York City, USA) 1362, (1), 149-150

This work presents the estimation of a likelihood map for the location of a source of chemical plume using multiple mobile sensors and Bayesian Inference. Previously described methods use a single sensor and just binary detections (concentrations above or below a certain threshold). The main contribution of this work is to extend previous proposals to use concentration information while at the same time being robust against the presence of background signals. The algorithm has two parts. The first part, concerning Adaptive Background Estimation, uses robust statistics measurements to estimate the background level despite the intermittent presence of high concentrations due to plume statistics. The second part of the algorithm estimates likelihood functions for background and for condition plus plume. Then, the algorithm sequentially builds a likelihood probability map for the location of the source. The algorithm allows the use of multiple mobile sensors. The simulation results demonstrate that our algorithm estimates better the source location and is much more robust in the presence of false alarms.

JTD Keywords: Sensors, Inference mechanisms, Probability, Simulation

Caballero-Briones, F., Palacios-Padros, A., Calzadilla, O., Sanz, F., (2010). Evidence and analysis of parallel growth mechanisms in Cu2O films prepared by Cu anodization Electrochimica Acta 55, (14), 4353-4358

We have studied the preparation of Cu2O films by copper anodization in a 0.1 M NaOH electrolyte. We identified the potential range at which Cu dissolution takes place then we prepared films with different times of exposure to this potential. The morphology, crystalline structure, band gap. Urbach energy and thickness of the films were studied. Films prepared with the electrode unexposed to the dissolution potential have a pyramidal growth typical of potential driven processes, while samples prepared at increasing exposure times to dissolution potential present continuous nucleation, growth and grain coalescence. We observed a discrepancy in the respective film thicknesses calculated by coulometry, atomic force microscopy and optical reflectance. We propose that anodic Cu2O film formation involves three parallel mechanisms (i) Cu2O nucleation at the surface, (ii) Cu+ dissolution followed by heterogeneous nucleation and (iii) Cu+ and OH- diffusion through the forming oxide and subsequent reaction in the solid state.

JTD Keywords: Cuprous oxide, Anodic films, Reflectance, Thickness, Band gap, Urbach tail parameter, Dissolution, Growth mechanism

Carreras, A., Rojas, M., Tsapikouni, T., Montserrat, J. M., Navajas, D., Farre, R., (2010). Obstructive apneas induce early activation of mesenchymal stem cells and enhancement of endothelial wound healing Respiratory Research , 11, (91), 1-7

Background: The aim was to test the hypothesis that the blood serum of rats subjected to recurrent airway obstructions mimicking obstructive sleep apnea (OSA) induces early activation of bone marrow-derived mesenchymal stem cells (MSC) and enhancement of endothelial wound healing. Methods: We studied 30 control rats and 30 rats subjected to recurrent obstructive apneas (60 per hour, lasting 15 s each, for 5 h). The migration induced in MSC by apneic serum was measured by transwell assays. MSC-endothelial adhesion induced by apneic serum was assessed by incubating fluorescent-labelled MSC on monolayers of cultured endothelial cells from rat aorta. A wound healing assay was used to investigate the effect of apneic serum on endothelial repair. Results: Apneic serum showed significant increase in chemotaxis in MSC when compared with control serum: the normalized chemotaxis indices were 2.20 +/- 0.58 (m +/- SE) and 1.00 +/- 0.26, respectively (p < 0.05). MSC adhesion to endothelial cells was greater (1.75 +/- 0.14 -fold; p < 0.01) in apneic serum than in control serum. When compared with control serum, apneic serum significantly increased endothelial wound healing (2.01 +/- 0.24 -fold; p < 0.05). Conclusions: The early increases induced by recurrent obstructive apneas in MSC migration, adhesion and endothelial repair suggest that these mechanisms play a role in the physiological response to the challenges associated to OSA.

JTD Keywords: Induced acute lung, Sleep-apnea, Intermitent hypoxia, Cardiovascular-disease, Progenito Cells, Rat model, Inflammation, Mechanisms, Repair, Blood

Mesquita, J., Fiz, J. A., Solà, J., Morera, J., Jané, R., (2010). Regular and non regular snore features as markers of SAHS Engineering in Medicine and Biology Society (EMBC) 32nd Annual International Conference of the IEEE , IEEE (Buenos Aires, Argentina) , 6138-6141

Sleep Apnea-Hypopnea Syndrome (SAHS) diagnosis is still done with an overnight multi-channel polysomnography. Several efforts are being made to study profoundly the snore mechanism and discover how it can provide an opportunity to diagnose the disease. This work introduces the concept of regular snores, defined as the ones produced in consecutive respiratory cycles, since they are produced in a regular way, without interruptions. We applied 2 thresholds (TH/sub adaptive/ and TH/sub median/) to the time interval between successive snores of 34 subjects in order to select regular snores from the whole all-night snore sequence. Afterwards, we studied the effectiveness that parameters, such as time interval between successive snores and the mean intensity of snores, have on distinguishing between different levels of SAHS severity (AHI (Apnea-Hypopnea Index)<5h/sup -1/, AHI<10 h/sup -1/, AHI<15h/sup -1/, AHI<30h/sup -1/). Results showed that TH/sub adaptive/ outperformed TH/sub median/ on selecting regular snores. Moreover, the outcome achieved with non-regular snores intensity features suggests that these carry key information on SAHS severity.

JTD Keywords: Practical, Experimental/ acoustic signal processing, Bioacoustics, Biomedical measurement, Diseases, Feature extraction, Medical signal processing, Patient diagnosis, Pneumodynamics, Sleep/ nonregular snore features, SAHS markers, Sleep apnea hypopnea syndrome, Overnight multichannel polysomnography, Snore mechanism