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by Keyword: Disease

Ferrer I, Andrés-Benito P, Carmona M, Del Rio JA, (2022). Common and Specific Marks of Different Tau Strains Following Intra-Hippocampal Injection of AD, PiD, and GGT Inoculum in hTau Transgenic Mice International Journal Of Molecular Sciences 23, 15940

Blanco-Almazan, Dolores, Groenendaal, Willemijn, Lijnen, Lien, Onder, Rana, Smeets, Christophe, Ruttens, David, Catthoor, Francky, Jane, Raimon, (2022). Breathing Pattern Estimation Using Wearable Bioimpedance for Assessing COPD Severity Ieee Journal Of Biomedical And Health Informatics 26, 5983-5991

Seuma M, Lehner B, Bolognesi B, (2022). An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation Nature Communications 13, 7084

Multiplexed assays of variant effects (MAVEs) guide clinical variant interpretation and reveal disease mechanisms. To date, MAVEs have focussed on a single mutation type-amino acid (AA) substitutions-despite the diversity of coding variants that cause disease. Here we use Deep Indel Mutagenesis (DIM) to generate a comprehensive atlas of diverse variant effects for a disease protein, the amyloid beta (Aβ) peptide that aggregates in Alzheimer's disease (AD) and is mutated in familial AD (fAD). The atlas identifies known fAD mutations and reveals that many variants beyond substitutions accelerate Aβ aggregation and are likely to be pathogenic. Truncations, substitutions, insertions, single- and internal multi-AA deletions differ in their propensity to enhance or impair aggregation, but likely pathogenic variants from all classes are highly enriched in the polar N-terminal region of Aβ. This comparative atlas highlights the importance of including diverse mutation types in MAVEs and provides important mechanistic insights into amyloid nucleation.© 2022. The Author(s).

JTD Keywords: amyloid-beta(1-42), determinants, disease, mutants, protein, secondary nucleation, Atomic-resolution structure


Mughal, S, Lopez-Munoz, GA, Fernandez-Costa, JM, Cortes-Resendiz, A, De Chiara, F, Ramon-Azcon, J, (2022). Organs-on-Chips: Trends and Challenges in Advanced Systems Integration Advanced Materials Interfaces 9, 2201618

Organ-on-chip platforms combined with high-throughput sensing technology allow bridging gaps in information presented by 2D cultures modeled on static microphysiological systems. While these platforms do not aim to replicate whole organ systems with all physiological nuances, they try to mimic relevant structural, physiological, and functional features of organoids and tissues to best model disease and/or healthy states. The advent of this platform has not only challenged animal testing but has also presented the opportunity to acquire real-time, high-throughput data about the pathophysiology of disease progression by employing biosensors. Biosensors allow monitoring of the release of relevant biomarkers and metabolites as a result of physicochemical stress. It, therefore, helps conduct quick lead validation to achieve personalized medicine objectives. The organ-on-chip industry is currently embarking on an exponential growth trajectory. Multiple pharmaceutical and biotechnology companies are adopting this technology to enable quick patient-specific data acquisition at substantially low costs.

JTD Keywords: A-chip, Biosensor, Biosensors, Cancer, Cells, Culture, Disease models, Epithelial electrical-resistance, Hydrogel, Microfabrication, Microphysiological systems, Models, Niches, Organ-on-a-chips, Platform


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


Hutson TH, Hervera A, (2022). Editorial: Biochemical and genetic tools to investigate the underlying mechanisms and treatment of sensorimotor pathologies Frontiers In Molecular Neuroscience 15, 1041458

Sala-Jarque, J, Zimkowska, K, Avila, J, Ferrer, I, del Rio, JA, (2022). Towards a Mechanistic Model of Tau-Mediated Pathology in Tauopathies: What Can We Learn from Cell-Based In Vitro Assays? International Journal Of Molecular Sciences 23, 11527

Tauopathies are a group of neurodegenerative diseases characterized by the hyperphosphorylation and deposition of tau proteins in the brain. In Alzheimer's disease, and other related tauopathies, the pattern of tau deposition follows a stereotypical progression between anatomically connected brain regions. Increasing evidence suggests that tau behaves in a "prion-like" manner, and that seeding and spreading of pathological tau drive progressive neurodegeneration. Although several advances have been made in recent years, the exact cellular and molecular mechanisms involved remain largely unknown. Since there are no effective therapies for any tauopathy, there is a growing need for reliable experimental models that would provide us with better knowledge and understanding of their etiology and identify novel molecular targets. In this review, we will summarize the development of cellular models for modeling tau pathology. We will discuss their different applications and contributions to our current understanding of the "prion-like" nature of pathological tau.

JTD Keywords: Culture model, Efficient generation, Extracellular tau, Familial alzheimers-disease, Microtubule-associated protein, Mouse model, Neurodegeneration, Neurofibrillary tangles, Paired helical filaments, Pathogenic tau, Pluripotent stem-cells, Seeding, Spreading, Tauopathies


Hodásová, Ľudmila, Morena, AGala, Tzanov, Tzanko, Fargas, Gemma, Llanes, Luis, Alemán, Carlos, Armelin, Elaine, (2022). 3D-Printed Polymer-Infiltrated Ceramic Network with Antibacterial Biobased Silver Nanoparticles Acs Applied Bio Materials 5, 4803-4813

Molina-Fernandez, R, Picon-Pages, P, Barranco-Almohalla, A, Crepin, G, Herrera-Fernandez, V, Garcia-Elias, A, Fanlo-Ucar, H, Fernandez-Busquets, X, Garcia-Ojalvo, J, Oliva, B, Munoz, FJ, (2022). Differential regulation of insulin signalling by monomeric and oligomeric amyloid beta-peptide Brain Commun 4, fcac243

Alzheimer's disease and Type 2 diabetes are pathological processes associated to ageing. Moreover, there are evidences supporting a mechanistic link between Alzheimer's disease and insulin resistance (one of the first hallmarks of Type 2 diabetes). Regarding Alzheimer's disease, amyloid beta-peptide aggregation into beta-sheets is the main hallmark of Alzheimer's disease. At monomeric state, amyloid beta-peptide is not toxic but its function in brain, if any, is unknown. Here we show, by in silico study, that monomeric amyloid beta-peptide 1-40 shares the tertiary structure with insulin and is thereby able to bind and activate insulin receptor. We validated this prediction experimentally by treating human neuroblastoma cells with increasing concentrations of monomeric amyloid. beta-peptide 1-40. Our results confirm that monomeric amyloid beta-peptide 1-40 activates insulin receptor autophosphorylation, triggering downstream enzyme phosphorylarions and the glucose Transporter 4 translocation to the membrane. On the other hand, neuronal insulin resistance is known to be associated to Alzheimer's disease since early stages. We thus modelled the docking of oligomeric amyloid peptide 1-40 to insulin receptor. We found that oligomeric amyloid. beta-peptide 1-40 blocks insulin receptor, impairing its activation. It was confirmed in vitro by observing the lack of insulin receptor autophosphorylation, and also the impairment of insulin-induced intracellular enzyme activations and the glucose Transporter 4 translocation to the membrane. By biological system analysis, we have carried out a mathematical model recapitulating the process that turns amyloid beta-peptide binding to insulin receptor from the physiological to the pathophysiological regime. Our results suggest that monomeric amyloid beta-peptide 1-40 contributes to mimic insulin effects in the brain, which could be good when neurons have an extra requirement of energy beside the well-known protective effects on insulin intracellular signalling, while its accumulation and subsequent oligomerization blocks the insulin receptor producing insulin resistance and compromising neuronal metabolism and protective pathways.

JTD Keywords: A-beta, Aggregation, Akt, Alzheimer's disease, Alzheimers-disease, Amyloid beta-peptide, Brain, Design, Insulin, Insulin resistance, Precursor protein, Protein-protein docking, Receptor, Resistance, Site


Martínez-Ara G, Taberner N, Takayama M, Sandaltzopoulou E, Villava CE, Bosch-Padrós M, Takata N, Trepat X, Eiraku M, Ebisuya M, (2022). Optogenetic control of apical constriction induces synthetic morphogenesis in mammalian tissues Nature Communications 13, 5400

The emerging field of synthetic developmental biology proposes bottom-up approaches to examine the contribution of each cellular process to complex morphogenesis. However, the shortage of tools to manipulate three-dimensional (3D) shapes of mammalian tissues hinders the progress of the field. Here we report the development of OptoShroom3, an optogenetic tool that achieves fast spatiotemporal control of apical constriction in mammalian epithelia. Activation of OptoShroom3 through illumination in an epithelial Madin-Darby Canine Kidney (MDCK) cell sheet reduces the apical surface of the stimulated cells and causes displacements in the adjacent regions. Light-induced apical constriction provokes the folding of epithelial cell colonies on soft gels. Its application to murine and human neural organoids leads to thickening of neuroepithelia, apical lumen reduction in optic vesicles, and flattening in neuroectodermal tissues. These results show that spatiotemporal control of apical constriction can trigger several types of 3D deformation depending on the initial tissue context.© 2022. The Author(s).

JTD Keywords: build, developmental biology, disease, light, localization, multicellular structures, organization, plate, shroom, Epithelial-cell shape


Azagra, Marc, Pose, Elisa, Chiara, Francesco, Perez, Martina, Avitabile, Emma, Servitja, Joan‐Marc, Brugnara, Laura, Ramon‐Azcón, Javier, Marco‐Rius, Irene, (2022). Ammonium quantification (AQua) in human plasma by 1 H‐NMR for staging of liver fibrosis in alcohol‐related liver disease and non‐alcoholic fatty liver disease Nmr In Biomedicine 35, e4745

Solomon M, Loeck M, Silva-Abreu M, Moscoso R, Bautista R, Vigo M, Muro S, (2022). Altered blood-brain barrier transport of nanotherapeutics in lysosomal storage diseases Journal Of Controlled Release 349, 1031-1044

Treatment of neurological lysosomal storage disorders (LSDs) are limited because of impermeability of the blood-brain barrier (BBB) to macromolecules. Nanoformulations targeting BBB transcytosis are being explored, but the status of these routes in LSDs is unknown. We studied nanocarriers (NCs) targeted to the transferrin receptor (TfR), ganglioside GM1 or ICAM1, associated to the clathrin, caveolar or cell adhesion molecule (CAM) routes, respectively. We used brain endothelial cells and mouse models of acid sphingomyelinase-deficient Niemann Pick disease (NPD), and postmortem LSD patients' brains, all compared to respective controls. NC transcytosis across brain endothelial cells and brain distribution in mice were affected, yet through different mechanisms. Reduced TfR and clathrin expression were found, along with decreased transcytosis in cells and mouse brain distribution. Caveolin-1 expression and GM1 transcytosis were also reduced, yet increased GM1 levels seemed to compensate, providing similar NC brain distribution in NPD vs. control mice. A tendency to lower NHE-1 levels was seen, but highly increased ICAM1 expression in cells and human brains correlated with increased transcytosis and brain distribution in mice. Thus, transcytosis-related alterations in NPD and likely other LSDs may impact therapeutic access to the brain, illustrating the need for these mechanistic studies.Copyright © 2022 Elsevier B.V. All rights reserved.

JTD Keywords: acid sphingomyelinase, antibody-affinity, blood -brain barrier, drug-delivery, icam-1-targeted nanocarriers, in-vivo, mediated endocytosis, model, neurological diseases, niemann-pick, targeted nanocarriers, trafficking, transcytosis pathways, Blood-brain barrier, Central-nervous-system, Lysosomal storage disorders, Neurological diseases, Targeted nanocarriers, Transcytosis pathways


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


Rizzello, L, De Matteis, V, (2022). Identification of SARS-CoV-2 by Gold Nanoparticles Biocell 46, 2369-2380

The SARS-CoV-2 outbreaks highlighted the need for effective, reliable, fast, easy-to-do and cheap diagnostics procedures. We pragmatically experienced that an early positive-case detection, inevitably coupled with a mass vaccination campaign, is a milestone to control the COVID-19 pandemic. Gold nanoparticles (AuNPs) can indeed play a crucial role in this context, as their physicochemical, optics and electronics properties are being extensively used in photothermal therapy (PTT), radiation therapy (RT), drug delivery and diagnostic. AuNPs can be synthesized by several approaches to obtain different sizes and shapes that can be easily functionalized with many kinds of molecules such as antibodies, proteins, probes, and lipids. In addition, AuNPs showed high biocompatibility making them useful tool in medicine field. We thus reviewed here the most relevant evidence on AuNPs as effective way to detect the presence of SARS-CoV-2 antigens. We trust future diagnostic efforts must take this 'old-fashioned' nanotechnology tool into consideration for the development and commercialization of reliable and feasible detection kits.

JTD Keywords: Aggregation, Antibodies, Assay, Covid-19, Diagnosis, Enhanced raman-scattering, Gold nanoparticles, Immunoassay, Pandemic disease, Physicochemical properties, Rapid detection, Sars-cov-2, Sensors, Surface-plasmon resonance, Therapy


Varea, Olga, Guinovart, Joan J, Duran, Jordi, (2022). Malin restoration as proof of concept for gene therapy for Lafora disease Brain Commun 4, fcac168

Abstract Lafora disease is a fatal neurodegenerative childhood dementia caused by loss-of-function mutations in either the laforin or malin gene. The hallmark of the disease is the accumulation of abnormal glycogen aggregates known as Lafora bodies (LBs) in the brain and other tissues. These aggregates are responsible for the pathological features of the disease. As a monogenic disorder, Lafora disease is a good candidate for gene therapy-based approaches. However, most patients are diagnosed after the appearance of the first symptoms and thus when LBs are already present in the brain. In this context, it was not clear whether the restoration of a normal copy of the defective gene (either laforin or malin) would prove effective. Here we evaluated the effect of restoring malin in a malin-deficient mouse model of Lafora disease as a proof of concept for gene replacement therapy. To this end, we generated a malin-deficient mouse in which malin expression can be induced at a certain time. Our results reveal that malin restoration at an advanced stage of the disease arrests the accumulation of LBs in brain and muscle, induces the degradation of laforin and glycogen synthase bound to the aggregates, and ameliorates neuroinflammation. These results identify malin restoration as the first therapeutic strategy to show effectiveness when applied at advanced stages of Lafora disease.

JTD Keywords: accumulation, gene therapy, glycogen, lafora disease, neurodegeneration, neuroinflammation, neurons, targets, Carbohydrate-binding domain, Glycogen


Lozano-Garcia M, Estrada-Petrocelli L, Blanco-Almazan D, Tas B, Cho PS, Moxham J, Rafferty GF, Torres A, Jane R, Jolley CJ, (2022). Noninvasive Assessment of Neuromechanical and Neuroventilatory Coupling in COPD Ieee Journal Of Biomedical And Health Informatics 26, 3385-3396

This study explored the use of parasternal second intercostal space and lower intercostal space surface electromyogram (sEMG) and surface mechanomyogram (sMMG) recordings (sEMGpara and sMMGpara, and sEMGlic and sMMGlic, respectively) to assess neural respiratory drive (NRD), neuromechanical (NMC) and neuroventilatory (NVC) coupling, and mechanical efficiency (MEff) noninvasively in healthy subjects and chronic obstructive pulmonary disease (COPD) patients. sEMGpara, sMMGpara, sEMGlic, sMMGlic, mouth pressure (Pmo), and volume (Vi) were measured at rest, and during an inspiratory loading protocol, in 16 COPD patients (8 moderate and 8 severe) and 9 healthy subjects. Myographic signals were analyzed using fixed sample entropy and normalized to their largest values (fSEsEMGpara%max, fSEsMMGpara%max, fSEsEMGlic%max, and fSEsMMGlic%max). fSEsMMGpara%max, fSEsEMGpara%max, and fSEsEMGlic%max were significantly higher in COPD than in healthy participants at rest. Parasternal intercostal muscle NMC was significantly higher in healthy than in COPD participants at rest, but not during threshold loading. Pmo-derived NMC and MEff ratios were lower in severe patients than in mild patients or healthy subjects during threshold loading, but differences were not consistently significant. During resting breathing and threshold loading, Vi-derived NVC and MEff ratios were significantly lower in severe patients than in mild patients or healthy subjects. sMMG is a potential noninvasive alternative to sEMG for assessing NRD in COPD. The ratios of Pmo and Vi to sMMG and sEMG measurements provide wholly noninvasive NMC, NVC, and MEff indices that are sensitive to impaired respiratory mechanics in COPD and are therefore of potential value to assess disease severity in clinical practice. Author

JTD Keywords: biomedical measurement, chronic obstructive pulmonary disease, couplings, diaphragm, disease severity, efficiency, electromyography, exacerbations, healthy volunteers, inspiratory muscles, loading, mechanomyography, obstructive pulmonary-disease, pressure measurement, protocols, respiratory mechanics, respiratory muscles, responsiveness, spirometry, stimulation, volume measurement, At rests, Biomedical measurement, Biomedical measurements, Chronic obstructive pulmonary disease, Couplings, Disease severity, Efficiency ratio, Electromyography, Healthy subjects, Healthy volunteers, Loading, Mechanical efficiency, Mechanomyogram, Muscle, Muscles, Neural respiratory drive, Noninvasive medical procedures, Pressure measurement, Protocols, Pulmonary diseases, Surface electromyogram, Volume measurement


Rubies, C, Batlle, M, Sanz-de la Garza, M, Dantas, AP, Jorba, I, Fernandez, G, Sanguesa, G, Abuli, M, Brugada, J, Sitges, M, Navajas, D, Mont, L, Guasch, E, (2022). Long-Term Strenuous Exercise Promotes Vascular Injury by Selectively Damaging the Tunica Media Experimental Evidence Jacc Basic Transl Sci 7, 681-693

Moderate exercise has well-founded benefits in cardiovascular health. However, increasing, yet controversial, evidence suggests that extremely trained athletes may not be protected from cardiovascular events as much as moderately trained individuals. In our rodent model, intensive but not moderate training promoted aorta and carotid stiffening and elastic lamina ruptures, tunica media thickening of intramyocardial arteries, and an imbalance between vasoconstrictor and relaxation agents. An up-regulation of angiotensin-converter enzyme, miR-212, miR-132, and miR-146b might account for this deleterious remodeling. Most changes remained after a 4-week detraining. In conclusion, our results suggest that intensive training blunts the benefits of moderate exercise. (C) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

JTD Keywords: Age, Atherosclerosis, Cacs, coronary artery calcium score, Cad, coronary artery disease, Coronary artery disease, Coronary atherosclerosis, Cv, cardiovascular, Disease, Endurance exercise, Extreme sport, Metalloproteinases, Micrornas, Mmp9, matrix metalloproteinase 9, No, nitric oxide, Phe, phenylephrine, Physical-activity, Prevalence, Rats, Relevance, Risk, Vascular stiffening, Vsmc, vascular smooth muscle cell


Ferrer, I, Andres-Benito, P, Ausin, K, Cartas-Cejudo, P, Lachen-Montes, M, del Rio, JA, Fernandez-Irigoyen, J, Santamaria, E, (2022). Dysregulated Brain Protein Phosphorylation Linked to Increased Human Tau Expression in the hTau Transgenic Mouse Model International Journal Of Molecular Sciences 23, 6427

Altered protein phosphorylation is a major pathologic modification in tauopathies and Alzheimer's disease (AD) linked to abnormal tau fibrillar deposits in neurofibrillary tangles (NFTs) and pre-tangles and beta-amyloid deposits in AD. hTau transgenic mice, which express 3R and less 4R human tau with no mutations in a murine knock-out background, show increased tau deposition in neurons but not NFTs and pre-tangles at the age of nine months. Label-free (phospho)proteomics and SWATH-MS identified 2065 proteins in hTau and wild-type (WT) mice. Only six proteins showed increased levels in hTau; no proteins were down-regulated. Increased tau phosphorylation in hTau was detected at Ser199, Ser202, Ser214, Ser396, Ser400, Thr403, Ser404, Ser413, Ser416, Ser422, Ser491, and Ser494, in addition to Thr181, Thr231, Ser396/Ser404, but not at Ser202/Thr205. In addition, 4578 phosphopeptides (corresponding to 1622 phosphoproteins) were identified in hTau and WT mice; 64 proteins were differentially phosphorylated in hTau. Sixty proteins were grouped into components of membranes, membrane signaling, synapses, vesicles, cytoskeleton, DNA/RNA/protein metabolism, ubiquitin/proteasome system, cholesterol and lipid metabolism, and cell signaling. These results showed that over-expression of human tau without pre-tangle and NFT formation preferentially triggers an imbalance in the phosphorylation profile of specific proteins involved in the cytoskeletal-membrane-signaling axis.

JTD Keywords: Aggregation, Alzheimers-disease, Animal-models, Cytoskeleton, Htau, Membrane, Mice, Networks, Pathology, Phosphoproteome analysis, Phosphorylation, Synapsis, Tau, Tauopathies, Tauopathy


Garreta E, Prado P, Stanifer ML, Monteil V, Marco A, Ullate-Agote A, Moya-Rull D, Vilas-Zornoza A, Tarantino C, Romero JP, Jonsson G, Oria R, Leopoldi A, Hagelkruys A, Gallo M, González F, Domingo-Pedrol P, Gavaldà A, Del Pozo CH, Hasan Ali O, Ventura-Aguiar P, Campistol JM, Prosper F, Mirazimi A, Boulant S, Penninger JM, Montserrat N, (2022). A diabetic milieu increases ACE2 expression and cellular susceptibility to SARS-CoV-2 infections in human kidney organoids and patient cells Cell Metabolism 34, 857-873

It is not well understood why diabetic individuals are more prone to develop severe COVID-19. To this, we here established a human kidney organoid model promoting early hallmarks of diabetic kidney disease development. Upon SARS-CoV-2 infection, diabetic-like kidney organoids exhibited higher viral loads compared with their control counterparts. Genetic deletion of the angiotensin-converting enzyme 2 (ACE2) in kidney organoids under control or diabetic-like conditions prevented viral detection. Moreover, cells isolated from kidney biopsies from diabetic patients exhibited altered mitochondrial respiration and enhanced glycolysis, resulting in higher SARS-CoV-2 infections compared with non-diabetic cells. Conversely, the exposure of patient cells to dichloroacetate (DCA), an inhibitor of aerobic glycolysis, resulted in reduced SARS-CoV-2 infections. Our results provide insights into the identification of diabetic-induced metabolic programming in the kidney as a critical event increasing SARS-CoV-2 infection susceptibility, opening the door to the identification of new interventions in COVID-19 pathogenesis targeting energy metabolism.Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

JTD Keywords: complications, coronavirus, cultured-cells, disease, distal tubule, mouse, protein, reveals, spike, Ace2, Angiotensin-converting enzyme 2, Angiotensin-converting enzyme-2, Covid-19, Diabetes 2, Human kidney organoids, Sars-cov-2


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


De Chiara, Francesco, Ferret-Miñana, Ainhoa, Fernández-Costa, Juan M., Senni, Alice, Jalan, Rajiv, Ramón-Azcón, Javier, (2022). Fatty Hepatocytes Induce Skeletal Muscle Atrophy In Vitro: A New 3D Platform to Study the Protective Effect of Albumin in Non-Alcoholic Fatty Liver Biomedicines 10, 958

The liver neutralizes endogenous and exogenous toxins and metabolites, being metabolically interconnected with many organs. Numerous clinical and experimental studies show a strong association between Non-alcoholic fatty liver disease (NAFLD) and loss of skeletal muscle mass known as sarcopenia. Liver transplantation solves the hepatic-related insufficiencies, but it is unable to revert sarcopenia. Knowing the mechanism(s) by which different organs communicate with each other is crucial to improve the drug development that still relies on the two-dimensional models. However, those models fail to mimic the pathological features of the disease. Here, both liver and skeletal muscle cells were encapsulated in gelatin methacryloyl and carboxymethylcellulose to recreate the disease’s phenotype in vitro. The 3D hepatocytes were challenged with non-esterified fatty acids (NEFAs) inducing features of Non-alcoholic fatty liver (NAFL) such as lipid accumulation, metabolic activity impairment and apoptosis. The 3D skeletal muscle tissues incubated with supernatant from fatty hepatocytes displayed loss of maturation and atrophy. This study demonstrates the connection between the liver and the skeletal muscle in NAFL, narrowing down the players for potential treatments. The tool herein presented was employed as a customizable 3D in vitro platform to assess the protective effect of albumin on both hepatocytes and myotubes.

JTD Keywords: 3r, ammonia, cirrhosis, disease, expression, myostatin, nefas, sarcopenia, tissue engineering, Crosstalk, Nuclear factor 4-alpha


Ferrer I, Andrés-Benito P, Garcia-Esparcia P, López-Gonzalez I, Valiente D, Jordán-Pirla M, Carmona M, Sala-Jarque J, Gil V, Del Rio JA, (2022). Differences in Tau Seeding in Newborn and Adult Wild-Type Mice International Journal Of Molecular Sciences 23, 4789

Alzheimer’s disease (AD) and other tauopathies are common neurodegenerative diseases in older adults; in contrast, abnormal tau deposition in neurons and glial cells occurs only exceptionally in children. Sarkosyl-insoluble fractions from sporadic AD (sAD) containing paired helical filaments (PHFs) were inoculated unilaterally into the thalamus in newborn and three-month-old wild-type C57BL/6 mice, which were killed at different intervals from 24 h to six months after inoculation. Tau-positive cells were scanty and practically disappeared at three months in mice inoculated at the age of a newborn. In contrast, large numbers of tau-positive cells, including neurons and oligodendrocytes, were found in the thalamus of mice inoculated at three months and killed at the ages of six months and nine months. Mice inoculated at the age of newborn and re-inoculated at the age of three months showed similar numbers and distribution of positive cells in the thalamus at six months and nine months. This study shows that (a) differences in tau seeding between newborn and young adults may be related to the ratios between 3Rtau and 4Rtau, and the shift to 4Rtau predominance in adults, together with the immaturity of connections in newborn mice, and (b) intracerebral inoculation of sAD PHFs in newborn mice does not protect from tau seeding following intracerebral inoculation of sAD PHFs in young/adult mice.

JTD Keywords: alzheimer's disease, alzheimer-disease, expression, mouse tau, neurofibrillary tangles, newborn, pathological tau, propagation, protein-tau, spread, thalamus, transgenic mice, Paired helical filaments, Tau seeding and spreading


Tas B, Kalk NJ, Lozano- García M, Rafferty GF, Cho PSP, Kelleher M, Moxham J, Strang J, Jolley CJ, (2022). Undetected Respiratory Depression in People with Opioid Use Disorder Drug And Alcohol Dependence 234, 109401

Background: Opioid-related deaths are increasing globally. Respiratory complications of opioid use and underlying respiratory disease in people with Opioid Use Disorder (OUD) are potential contributory factors. Individual variation in susceptibility to overdose is, however, incompletely understood. This study investigated the prevalence of respiratory depression (RD) in OUD treatment and compared this to patients with chronic obstructive pulmonary disease (COPD) of equivalent severity. We also explored the contribution of opioid agonist treatment (OAT) dosage, and type, to the prevalence of RD. Methods: There were four groups of participants: 1) OUD plus COPD (‘OUD-COPD’, n = 13); 2) OUD without COPD (‘OUD’, n = 7); 3) opioid-naïve COPD patients (‘COPD'n = 13); 4) healthy controls (‘HC'n = 7). Physiological indices, including pulse oximetry (SpO2%), end-tidal CO2 (ETCO2), transcutaneous CO2 (TcCO2), respiratory airflow and second intercostal space parasternal muscle electromyography (EMGpara), were recorded continuously over 40 min whilst awake at rest. Significant RD was defined as: SpO2%< 90% for > 10 s, ETCO2 per breath > 6.6 kPa, TcCO2 overall mean > 6 kPa, respiratory pauses > 10 s Results: At least one indicator was observed in every participant with OUD (n = 20). This compared to RD episode occurrence in only 2/7 HC and 2/13 COPD participants (p < 0.05,Fisher's exact test). The occurrence of RD was similar in OUD participants prescribed methadone (n = 6) compared to those prescribed buprenorphine (n = 12). Conclusions: Undetected RD is common in OUD cohorts receiving OAT and is significantly more severe than in opioid-naïve controls. RD can be assessed using simple objective measures. Further studies are required to determine the association between RD and overdose risk. © 2022 Elsevier B.V.

JTD Keywords: Comorbidity, Lung disease, Opioid substitution treatment, Opioids, Overdose, Respiratory depression


Marte L, Boronat S, Barrios R, Barcons-Simon A, Bolognesi B, Cabrera M, Ayté J, Hidalgo E, (2022). Expression of Huntingtin and TDP-43 Derivatives in Fission Yeast Can Cause Both Beneficial and Toxic Effects International Journal Of Molecular Sciences 23, 3950

Many neurodegenerative disorders display protein aggregation as a hallmark, Huntingtin and TDP-43 aggregates being characteristic of Huntington disease and amyotrophic lateral sclerosis, respectively. However, whether these aggregates cause the diseases, are secondary by-products, or even have protective effects, is a matter of debate. Mutations in both human proteins can modulate the structure, number and type of aggregates, as well as their toxicity. To study the role of protein aggregates in cellular fitness, we have expressed in a highly tractable unicellular model different variants of Huntingtin and TDP-43. They each display specific patterns of aggregation and toxicity, even though in both cases proteins have to be very highly expressed to affect cell fitness. The aggregation properties of Huntingtin, but not of TDP-43, are affected by chaperones such as Hsp104 and the Hsp40 couple Mas5, suggesting that the TDP-43, but not Huntingtin, derivatives have intrinsic aggregation propensity. Importantly, expression of the aggregating form of Huntingtin causes a significant extension of fission yeast lifespan, probably as a consequence of kidnapping chaperones required for maintaining stress responses off. Our study demonstrates that in general these prion-like proteins do not cause toxicity under normal conditions, and in fact they can protect cells through indirect mechanisms which up-regulate cellular defense pathways. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

JTD Keywords: aggregation, antioxidant, degradation, features, fission yeast, gene, neurodegenerative diseases, pap1, polyglutamine toxicity, protein aggregation, proteins, stress, tdp-43, Amyotrophic-lateral-sclerosis, Chaperone, Chemistry, Dna binding protein, Dna-binding proteins, Fission yeast, Genetics, Human, Humans, Huntingtin, Metabolism, Molecular chaperones, Neurodegenerative diseases, Prion, Prions, Protein aggregate, Protein aggregates, Protein aggregation, Schizosaccharomyces, Tdp-43


Tantai, Xinxing, Liu, Yi, Yeo, Yee Hui, Praktiknjo, Michael, Mauro, Ezequiel, Hamaguchi, Yuhei, Engelmann, Cornelius, Zhang, Peng, Jeong, Jae Yoon, van Vugt, Jeroen Laurens Ad, Xiao, Huijuan, Deng, Huan, Gao, Xu, Ye, Qing, Zhang, Jiayuan, Yang, Longbao, Cai, Yaqin, Liu, Yixin, Liu, Na, Li, Zongfang, Han, Tao, Kaido, Toshimi, Sohn, Joo Hyun, Strassburg, Christian, Berg, Thomas, Trebicka, Jonel, Hsu, Yao-Chun, IJzermans, Jan Nicolaas Maria, Wang, Jinhai, Su, Grace L., Ji, Fanpu, Nguyen, Mindie H., (2022). Effect of sarcopenia on survival of patients with cirrhosis: A meta-analysis Journal Of Hepatology 76, 588-599

The association between sarcopenia and prognosis in patients with cirrhosis remains to be determined. In this study, we aimed to quantify the association between sarcopenia and the risk of mortality in patients with cirrhosis, by sex, underlying liver disease etiology, and severity of hepatic dysfunction.PubMed, Web of Science, EMBASE, and major scientific conference sessions were searched without language restriction through 13 January 2021 with additional manual search of bibliographies of relevant articles. Cohort studies of ?100 patients with cirrhosis and ?12 months of follow-up that evaluated the association between sarcopenia, muscle mass and the risk of mortality were included.22 studies with 6965 patients with cirrhosis were included. The pooled prevalence of sarcopenia in patients with cirrhosis was 37.5% overall (95% CI 32.4%-42.8%), higher in male patients, patients with alcohol associated liver disease (ALD), patients with CTP grade C, and when sarcopenia was defined in patients by lumbar 3- skeletal muscle index (L3-SMI). Sarcopenia was associated with the increased risk of mortality in patients with cirrhosis (adjusted-hazard ratio [aHR] 2.30, 95% CI 2.01-2.63), with similar findings in sensitivity analysis of cirrhosis patients without HCC (aHR 2.35, 95% CI 1.95-2.83) and in subgroup analysis by sex, liver disease etiology, and severity of hepatic dysfunction. The association between quantitative muscle mass index and mortality further supports the poor prognosis for patients with sarcopenia (aHR 0.95, 95% CI 0.93-0.98). There was no significant heterogeneity in all analyses.Sarcopenia was highly and independently associated with higher risk of mortality in patients with cirrhosis.The prevalence of sarcopenia and its association with death in patients with cirrhosis remain unclear. This meta-analysis indicated that sarcopenia affected about one-third of patients with cirrhosis and up to 50% in patients with ALD or Child's class C cirrhosis. Sarcopenia was independently associated with about 2-fold higher risk of mortality in patients with cirrhosis. The mortality rate increased with greater severity or longer period of having sarcopenia. Increasing awareness about the importance of sarcopenia in patients with cirrhosis among stakeholders must be prioritized.Copyright © 2021. Published by Elsevier B.V.

JTD Keywords: alcohol associated liver disease, alcohol-associated liver disease, cirrhosis, failure, frailty, impact, list, mass, model, mortality, prognosis, prognostic value, sarcopenia, severe muscle depletion, skeletal muscle index, Alcohol-associated liver disease, Cirrhosis, Liver-transplant candidates, Prognosis, Sarcopenia, Skeletal muscle index


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


Pellegrini P, Hervera A, Varea O, Brewer MK, López-Soldado I, Guitart A, Aguilera M, Prats N, del Río JA, Guinovart JJ, Duran J, (2022). Lack of p62 Impairs Glycogen Aggregation and Exacerbates Pathology in a Mouse Model of Myoclonic Epilepsy of Lafora Molecular Neurobiology 59, 1214-1229

Lafora disease (LD) is a fatal childhood-onset dementia characterized by the extensive accumulation of glycogen aggregates—the so-called Lafora Bodies (LBs)—in several organs. The accumulation of LBs in the brain underlies the neurological phenotype of the disease. LBs are composed of abnormal glycogen and various associated proteins, including p62, an autophagy adaptor that participates in the aggregation and clearance of misfolded proteins. To study the role of p62 in the formation of LBs and its participation in the pathology of LD, we generated a mouse model of the disease (malinKO) lacking p62. Deletion of p62 prevented LB accumulation in skeletal muscle and cardiac tissue. In the brain, the absence of p62 altered LB morphology and increased susceptibility to epilepsy. These results demonstrate that p62 participates in the formation of LBs and suggest that the sequestration of abnormal glycogen into LBs is a protective mechanism through which it reduces the deleterious consequences of its accumulation in the brain. © 2021, The Author(s).

JTD Keywords: accumulation, astrocytes, autophagy receptors, contributes, deficient mice, epilepsy, glycogen, lafora bodies, lafora disease, malin, metabolism, neurodegeneration, neuroinflammation, p62, polyglucosan bodies, temporal-lobe epilepsy, Epilepsy, Glycogen, Inclusion-body formation, Lafora bodies, Lafora disease, Malin, Neuroinflammation, P62


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


Boloix, A, Feiner-Gracia, N, Kober, M, Repetto, J, Pascarella, R, Soriano, A, Masanas, M, Segovia, N, Vargas-Nadal, G, Merlo-Mas, J, Danino, D, Abutbul-Ionita, I, Foradada, L, Roma, J, Cordoba, A, Sala, S, Toledo, JS, Gallego, S, Veciana, J, Albertazzi, L, Segura, MF, Ventosa, N, (2022). Engineering pH-Sensitive Stable Nanovesicles for Delivery of MicroRNA Therapeutics Small 18, 2101959

MicroRNAs (miRNAs) are small non-coding endogenous RNAs, which are attracting a growing interest as therapeutic molecules due to their central role in major diseases. However, the transformation of these biomolecules into drugs is limited due to their unstability in the bloodstream, caused by nucleases abundantly present in the blood, and poor capacity to enter cells. The conjugation of miRNAs to nanoparticles (NPs) could be an effective strategy for their clinical delivery. Herein, the engineering of non-liposomal lipid nanovesicles, named quatsomes (QS), for the delivery of miRNAs and other small RNAs into the cytosol of tumor cells, triggering a tumor-suppressive response is reported. The engineered pH-sensitive nanovesicles have controlled structure (unilamellar), size (<150 nm) and composition. These nanovesicles are colloidal stable (>24 weeks), and are prepared by a green, GMP compliant, and scalable one-step procedure, which are all unavoidable requirements for the arrival to the clinical practice of NP based miRNA therapeutics. Furthermore, QS protect miRNAs from RNAses and when injected intravenously, deliver them into liver, lung, and neuroblastoma xenografts tumors. These stable nanovesicles with tunable pH sensitiveness constitute an attractive platform for the efficient delivery of miRNAs and other small RNAs with therapeutic activity and their exploitation in the clinics.

JTD Keywords: cancer therapy, mirnas delivery, nanocarriers, nanovesicles, neuroblastoma, pediatric cancer, quatsomes, Biodistribution, Cancer therapy, Cell engineering, Cells, Cholesterol, Controlled drug delivery, Diseases, Dna, Dysregulated ph, Lipoplex, Microrna delivery, Mirnas delivery, Nanocarriers, Nanoparticles, Nanovesicle, Nanovesicles, Neuroblastoma, Neuroblastomas, Pediatric cancer, Ph sensitive, Ph sensors, Quatsome, Quatsomes, Rna, Sirna, Sirna delivery, Sirnas delivery, Small interfering rna, Small rna, Targeted drug delivery, Tumors, Vesicles


Gawish R, Starkl P, Pimenov L, Hladik A, Lakovits K, Oberndorfer F, Cronin SJF, Ohradanova-Repic A, Wirnsberger G, Agerer B, Endler L, Capraz T, Perthold JW, Cikes D, Koglgruber R, Hagelkruys A, Montserrat N, Mirazimi A, Boon L, Stockinger H, Bergthaler A, Oostenbrink C, Penninger JM, Knapp S, (2022). ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF-and IFNy-driven immunopathology Elife 11, e74623

Despite tremendous progress in the understanding of COVID-19, mechanistic insight into immunological, disease-driving factors remains limited. We generated maVie16, a mouse-adapted SARS-CoV-2, by serial passaging of a human isolate. In silico modeling revealed how only three Spike mutations of maVie16 enhanced interaction with murine ACE2. maVie16 induced profound pathology in BALB/c and C57BL/6 mice, and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia, and specific adaptive immunity. Inhibition of the proinflammatory cyto-kines IFN? and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo. © Gawish et al.

JTD Keywords: covid-19 mouse model, covid-19 therapy, cytokine storm, mavie16, mouse, program, recombinant soluble ace2, tmprss2, Adaptive immunity, Angiotensin converting enzyme 2, Angiotensin-converting enzyme 2, Animal, Animal cell, Animal experiment, Animal model, Animal tissue, Animals, Apoptosis, Article, Bagg albino mouse, Breathing rate, Bronchoalveolar lavage fluid, C57bl mouse, Cell composition, Cell infiltration, Controlled study, Coronavirus disease 2019, Coronavirus spike glycoprotein, Covid-19, Cytokeratin 18, Cytokine production, Dipeptidyl carboxypeptidase, Disease model, Disease models, animal, Disease severity, Drosophila-melanogaster, Enzyme linked immunosorbent assay, Expression vector, Flow cytometry, Gamma interferon, Gene editing, Gene expression, Gene mutation, Genetic engineering, Genetics, Glycosylation, High mobility group b1 protein, Histology, Histopathology, Immune response, Immunocompetent cell, Immunology, Immunopathology, Interferon-gamma, Interleukin 2, Metabolism, Mice, inbred balb c, Mice, inbred c57bl, Mouse-adapted sars-cov-2, Myeloperoxidase, Neuropilin 1, Nonhuman, Nucleocapsid protein, Pathogenicity, Peptidyl-dipeptidase a, Pyroptosis, Renin angiotensin aldosterone system, Rna extraction, Rna isolation, Sars-cov-2, Severe acute respiratory syndrome coronavirus 2, Spike glycoprotein, coronavirus, T lymphocyte activation, Trabecular meshwork, Tumor necrosis factor, Virology, Virus load, Virus replication, Virus transmission, Virus virulence


Andrés-Benito, Pol, Carmona, Margarita, Jordán, Mónica, Fernández-Irigoyen, Joaquín, Santamaría, Enrique, del Rio, José Antoni, Ferrer, Isidro, (2022). Host Tau Genotype Specifically Designs and Regulates Tau Seeding and Spreading and Host Tau Transformation Following Intrahippocampal Injection of Identical Tau AD Inoculum International Journal Of Molecular Sciences 23, 718

Several studies have demonstrated the different characteristics of tau seeding and spreading following intracerebral inoculation in murine models of tau-enriched fractions of brain homogenates from AD and other tauopathies. The present study is centered on the importance of host tau in tau seeding and the molecular changes associated with the transformation of host tau into abnormal tau. The brains of three adult murine genotypes expressing different forms of tau—WT (murine 4Rtau), hTau (homozygous transgenic mice knock-out for murine tau protein and heterozygous expressing human forms of 3Rtau and 4Rtau proteins), and mtWT (homozygous transgenic mice knock-out for murine tau protein)—were analyzed following unilateral hippocampal inoculation of sarkosyl-insoluble tau fractions from the same AD and control cases. The present study reveals that (a) host tau is mandatory for tau seeding and spreading following tau inoculation from sarkosyl-insoluble fractions obtained from AD brains; (b) tau seeding does not occur following intracerebral inoculation of sarkosyl-insoluble fractions from controls; (c) tau seeding and spreading are characterized by variable genotype-dependent tau phosphorylation and tau nitration, MAP2 phosphorylation, and variable activation of kinases that co-localize with abnormal tau deposits; (d) transformation of host tau into abnormal tau is an active process associated with the activation of specific kinases; (e) tau seeding is accompanied by modifications in tau splicing, resulting in the expression of new 3Rtau and 4Rtau isoforms, thus indicating that inoculated tau seeds have the capacity to model exon 10 splicing of the host mapt or MAPT with a genotype-dependent pattern; (e) selective regional and cellular vulnerabilities, and different molecular compositions of the deposits, are dependent on the host tau of mice injected with identical AD tau inocula.

JTD Keywords: 3rtau and 4rtau, alzheimer's disease, alzheimer’s disease, brains, granulovacuolar degeneration, host tau, htau, intranuclear distribution, messenger-rna, pathological tau, propagation, protein-kinases, seeding and spreading, tauopathies, transmission, 3rtau and 4rtau, Alzheimers-disease, Alzheimer’s disease, Host tau, Htau, Seeding and spreading, Tauopathies


Leite, DM, Seifi, M, Ruiz-Perez, L, Nguemo, F, Plomann, M, Swinny, JD, Battaglia, G, (2022). Syndapin-2 mediated transcytosis of amyloid-beta across the blood brain barrier Brain Commun 4, fcac039

A deficient transport of amyloid-beta across the blood-brain barrier, and its diminished clearance from the brain, contribute to neurodegenerative and vascular pathologies, such as Alzheimer's disease and cerebral amyloid angiopathy, respectively. At the blood-brain barrier, amyloid-beta efflux transport is associated with the low-density lipoprotein receptor-related protein 1. However, the precise mechanisms governing amyloid-beta transport across the blood-brain barrier, in health and disease, remain to be fully understood. Recent evidence indicates that the low-density lipoprotein receptor-related protein 1 transcytosis occurs through a tuhulation-mediated mechanism stabilized by syndapin-2. Here, we show that syndapin-2 is associated with amyloid-beta clearance via low-density lipoprotein receptor-related protein 1 across the blood-brain barrier. We further demonstrate that risk factors for Alzheimer's disease, amyloid-beta expression and ageing, are associated with a decline in the native expression of syndapin-2 within the brain endothelium. Our data reveals that syndapin-2-mediated pathway, and its balance with the endosomal sorting, are important for amyloid-beta clearance proposing a measure to evaluate Alzheimer's disease and ageing, as well as a target for counteracting amyloid-beta build-up. Moreover, we provide evidence for the impact of the avidity of amyloid-beta assemblies in their trafficking across the brain endothelium and in low-density lipoprotein receptor-related protein 1 expression levels, which may affect the overall clearance of amyloid-beta across the blood-brain barrier.

JTD Keywords: Alzheimer's disease, Alzheimers-disease, Amyloid-beta, Apolipoprotein-j, Blood-brain barrier, Clearance, Expression, Membrane invagination, Peptide, Protein, Rab gtpases, Receptor, Syndapin-2, Transport, Tubular transcytosis


Andrés-Benito P, Carmona M, Pirla MJ, Torrejón-Escribano B, del Rio JA, Ferrer I, (2022). Dysregulated Protein Phosphorylation as Main Contributor of Granulovacuolar Degeneration at the First Stages of Neurofibrillary Tangles Pathology Neuroscience ,

The hippocampus of cases with neurofibrillary tangles (NFT) pathology classified as stages I–II, III–IV, and V–VI without comorbidities, and middle-aged (MA) individuals with no NFT pathology, were examined to learn about the composition of granulovacuolar degeneration (GVD). Our results confirm the presence of CK1-?, p38-P Thr180/Tyr182, SAPK/JNK-P Thr183/Thr185, GSK-3?/?-P Tyr279/Tyr216, and GSK-3? Ser9 in the cytoplasmic granules in a subset of neurons of the CA1 and CA2 subfields of the hippocampus. Also, we identify the presence of PKA ?/?-P Thr197, SRC-P Tyr416, PAK1-P Ser199/Ser204, CAMK2A-P Tyr197, and PKCG-P Thr655 in cytoplasmic granules in cases with NFT pathology, but not in MA cases. Our results also confirm the presence of ?-catenin-P Ser45/Thr41, IRE?-P Ser274, eIF2?-P Ser51, TDP-43-P Ser403-404 (but absent TDP-43), and ubiquitin in cytoplasmic granules. Other components of the cytoplasmic granules are MAP2-P Thr1620/1623, MAP1B-P Thr1265, ADD1-P Ser726, and ADD1/ADD1-P Ser726/Ser713, in addition to several tau species including 3Rtau, 4Rtau, and tau-P Ser262. The analysis of GVD at progressive stages of NFT pathology reveals the early appearance of phosphorylated kinases and proteins in cytoplasmic granules at stages I–II, before the appearance of pre-tangles and NFTs. Most of these granules are not surrounded by LAMP1-positive membranes. Markers of impaired ubiquitin-protesome system, abnormal reticulum stress response, and altered endocytic and autophagic pathways occur in a subpopulation of neurons containing cytoplasmic granules, and they appear later. These observations suggest early phosphorylation of kinases leading to their activation, and resulting in the abnormal phosphorylation of various substrates, including tau, as a main alteration at the first stages of GVD. © 2021 The Author(s)

JTD Keywords: alzheimer’s disease, brain aging, granulovacuolar degeneration, kinases, protein phosphorylation, Alzheimer's disease, Brain aging, Granulovacuolar degeneration, Kinases, Protein phosphorylation, Tau


Ballester, BR, Antenucci, F, Maier, M, Coolen, ACC, Verschure, PFMJ, (2021). Estimating upper-extremity function from kinematics in stroke patients following goal-oriented computer-based training Journal Of Neuroengineering And Rehabilitation 18,

Introduction: After a stroke, a wide range of deficits can occur with varying onset latencies. As a result, assessing impairment and recovery are enormous challenges in neurorehabilitation. Although several clinical scales are generally accepted, they are time-consuming, show high inter-rater variability, have low ecological validity, and are vulnerable to biases introduced by compensatory movements and action modifications. Alternative methods need to be developed for efficient and objective assessment. In this study, we explore the potential of computer-based body tracking systems and classification tools to estimate the motor impairment of the more affected arm in stroke patients. Methods: We present a method for estimating clinical scores from movement parameters that are extracted from kinematic data recorded during unsupervised computer-based rehabilitation sessions. We identify a number of kinematic descriptors that characterise the patients' hemiparesis (e.g., movement smoothness, work area), we implement a double-noise model and perform a multivariate regression using clinical data from 98 stroke patients who completed a total of 191 sessions with RGS. Results: Our results reveal a new digital biomarker of arm function, the Total Goal-Directed Movement (TGDM), which relates to the patients work area during the execution of goal-oriented reaching movements. The model's performance to estimate FM-UE scores reaches an accuracy of R-2: 0.38 with an error (sigma: 12.8). Next, we evaluate its reliability (r = 0.89 for test-retest), longitudinal external validity (95% true positive rate), sensitivity, and generalisation to other tasks that involve planar reaching movements (R-2: 0.39). The model achieves comparable accuracy also for the Chedoke Arm and Hand Activity Inventory (R-2: 0.40) and Barthel Index (R-2: 0.35). Conclusions: Our results highlight the clinical value of kinematic data collected during unsupervised goal-oriented motor training with the RGS combined with data science techniques, and provide new insight into factors underlying recovery and its biomarkers.

JTD Keywords: interactive feedback, motion classification, motion sensing, multivariate regression, posture monitoring, rehabilitation, stroke, Adult, Aged, Analytic method, Arm movement, Article, Barthel index, Brain hemorrhage, Cerebrovascular accident, Chedoke arm and hand activity inventory, Clinical protocol, Cognitive defect, Computer analysis, Controlled study, Convergent validity, Correlation coefficient, Disease severity, External validity, Female, Fugl meyer assessment for the upper extremity, Functional assessment, Functional status assessment, General health status assessment, Hemiparesis, Human, Interactive feedback, Ischemic stroke, Kinematics, Major clinical study, Male, Mini mental state examination, Motion classification, Motion sensing, Motor analog scale, Movement, Multivariate regression, Muscle function, Posture monitoring, Probability, Recovery, Rehabilitation, Reliability, Retrospective study, Stroke, Stroke patient, Test retest reliability, Therapy, Total goal directed movement, Upper extremities, Upper limb, Upper-limb, Wolf motor function test


Dulay, S, Rivas, L, Pla, L, Berdun, S, Eixarch, E, Gratacos, E, Illa, M, Mir, M, Samitier, J, (2021). Fetal ischemia monitoring with in vivo implanted electrochemical multiparametric microsensors Journal Of Biological Engineering 15,

Under intrauterine growth restriction (IUGR), abnormal attainment of the nutrients and oxygen by the fetus restricts the normal evolution of the prenatal causing in many cases high morbidity being one of the top-ten causes of neonatal death. The current gold standards in hospitals to detect this relevant problem is the clinical observation by echography, cardiotocography and Doppler. These qualitative techniques are not conclusive and requires risky invasive fetal scalp blood testing and/or amniocentesis. We developed micro-implantable multiparametric electrochemical sensors for measuring ischemia in real time in fetal tissue and vascular. This implantable technology is designed to continuous monitoring for an early detection of ischemia to avoid potential fetal injury. Two miniaturized electrochemical sensors were developed based on oxygen and pH detection. The sensors were optimized in vitro under controlled concentration, to assess the selectivity and sensitivity required. The sensors were then validated in vivo in the ewe fetus model, by means of their insertion in the muscle leg and inside the iliac artery of the fetus. Ischemia was achieved by gradually obstructing the umbilical cord to regulate the amount of blood reaching the fetus. An important challenge in fetal monitoring is the detection of low levels of oxygen and pH changes under ischemic conditions, requiring high sensitivity sensors. Significant differences were observed in both; pH and pO(2) sensors under changes from normoxia to hypoxia states in the fetus tissue and vascular with both sensors. Herein, we demonstrate the feasibility of the developed sensors for future fetal monitoring in medical applications.

JTD Keywords: electrochemical biosensor, implantable sensor, in vivo validation, ischemia detection, tissue and vascular monitoring, Animal experiment, Animal model, Animal tissue, Article, Blood-gases, Brain, Classification, Controlled study, Diagnosis, Doppler, Early diagnosis, Electrochemical analysis, Electrochemical biosensor, Ewe, Feasibility study, Female, Fetus, Fetus disease, Fetus monitoring, Gestational age, Hypoxemia, Iliac artery, Implantable sensor, In vivo validation, Intrauterine growth restriction, Intrauterine growth retardation, Ischemia detection, Leg muscle, Management, Nonhuman, Oxygen consumption, Ph, Ph and oxygen detection, Ph measurement, Process optimization, Sheep, Tissue and vascular monitoring, Umbilical-cord occlusion


Chausse, Victor, Schieber, Romain, Raymond, Yago, Ségry, Brian, Sabaté, Ramon, Kolandaivelu, Kumaran, Ginebra, Maria-Pau, Pegueroles, Marta, (2021). Solvent-cast direct-writing as a fabrication strategy for radiopaque stents Additive Manufacturing 48,

Garreta, E, Nauryzgaliyeva, Z, Montserrat, N, (2021). Human induced pluripotent stem cell-derived kidney organoids toward clinical implementations Curr Opin Biomed Eng 20,

The generation of kidney organoids from human pluripotent stem cells (hPSCs) has represented a relevant scientific achievement in the organoid field. Importantly, hPSC-derived kidney organoids contain multiple nephron-like structures that exhibit some renal functional characteristics and have the capacity to respond to nephrotoxic agents. In this review, we first discuss how bioengineering approaches can help overcome current kidney organoid challenges. Next, we focus on recent works exploiting kidney organoids for drug screening and disease modeling applications. Finally, we provide a state of the art on current research toward the potential application of kidney organoids and renal cells derived from hPSCs for future renal replacement therapies.

JTD Keywords: Bioengineering, Converting enzyme-ii, Crispr/cas9 gene editing, Disease, Disease modeling, Extracellular-matrix, Generation, Human pluripotent stem cells, Kidney organoids, Kidney regeneration, Model, Mouse, Reveals, Scaffold, Transplantation


Ferrer I, Andrés-Benito P, Ausín K, Pamplona R, del Rio JA, Fernández-Irigoyen J, Santamaría E, (2021). Dysregulated protein phosphorylation: A determining condition in the continuum of brain aging and Alzheimer's disease Brain Pathology 31,

Tau hyperphosphorylation is the first step of neurofibrillary tangle (NFT) formation. In the present study, samples of the entorhinal cortex (EC) and frontal cortex area 8 (FC) of cases with NFT pathology classified as stages I–II, III–IV, and V–VI without comorbidities, and of middle-aged (MA) individuals with no NFT pathology, were analyzed by conventional label-free and SWATH-MS (sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) to assess the (phospho)proteomes. The total number of identified dysregulated phosphoproteins was 214 in the EC, 65 of which were dysregulated at the first stages (I–II) of NFT pathology; 167 phosphoproteins were dysregulated in the FC, 81 of them at stages I–II of NFT pathology. A large percentage of dysregulated phosphoproteins were identified in the two regions and at different stages of NFT progression. The main group of dysregulated phosphoproteins was made up of components of the membranes, cytoskeleton, synapses, proteins linked to membrane transport and ion channels, and kinases. The present results show abnormal phosphorylation of proteins at the first stages of NFT pathology in the elderly (in individuals clinically considered representative of normal aging) and sporadic Alzheimer's disease (sAD). Dysregulated protein phosphorylation in the FC precedes the formation of NFTs and SPs. The most active period of dysregulated phosphorylation is at stages III–IV when a subpopulation of individuals might be clinically categorized as suffering from mild cognitive impairment which is a preceding determinant stage in the progression to dementia. Altered phosphorylation of selected proteins, carried out by activation of several kinases, may alter membrane and cytoskeletal functions, among them synaptic transmission and membrane/cytoskeleton signaling. Besides their implications in sAD, the present observations suggest a molecular substrate for “benign” cognitive deterioration in “normal” brain aging.

JTD Keywords: (phospho)proteomics, alzheimer's disease, amyloid-beta, association guidelines, brain aging, cytoskeleton, frontal-cortex, kinases, lipid rafts, membranes, national institute, neuropathologic assessment, pathological process, protein phosphorylation, synapse pathology, synapses, tau, tau pathology, (phospho)proteomics, Age-related tauopathy, Alzheimer's disease, Brain aging, Cytoskeleton, Kinases, Membranes, Protein phosphorylation, Synapses, Tau


Duran, J, Hervera, A, Markussen, KH, Varea, O, Lopez-Soldado, I, Sun, RC, del Rio, JA, Gentry, MS, Guinovart, JJ, (2021). Astrocytic glycogen accumulation drives the pathophysiology of neurodegeneration in Lafora disease Brain 144, 2349-2360

The hallmark of Lafora disease, a fatal neurodegenerative disorder, is the accumulation of intracellular glycogen aggregates called Lafora bodies. Until recently, it was widely believed that brain Lafora bodies were present exclusively in neurons and thus that Lafora disease pathology derived from their accumulation in this cell population. However, recent evidence indicates that Lafora bodies are also present in astrocytes. To define the role of astrocytic Lafora bodies in Lafora disease pathology, we deleted glycogen synthase specifically from astrocytes in a mouse model of the disease (malin(KO)). Strikingly, blocking glycogen synthesis in astrocytes-thus impeding Lafora bodies accumulation in this cell type-prevented the increase in neurodegeneration markers, autophagy impairment, and metabolic changes characteristic of the malin(KO) model. Conversely, mice that over-accumulate glycogen in astrocytes showed an increase in these markers. These results unveil the deleterious consequences of the deregulation of glycogen metabolism in astrocytes and change the perspective that Lafora disease is caused solely by alterations in neurons.

JTD Keywords: Bodies, Deficient mice, Epilepsy, Glycogen, Impairment, Lafora disease, Malin, Modulation, Mouse model, Neurodegeneration, Neuroinflammation, Neurons, Progressive myoclonus epilepsy, Seizure susceptibility, Synthase


Rizzuto V, Mencattini A, Álvarez-González B, Di Giuseppe D, Martinelli E, Beneitez-Pastor D, Mañú-Pereira MDM, Lopez-Martinez MJ, Samitier J, (2021). Combining microfluidics with machine learning algorithms for RBC classification in rare hereditary hemolytic anemia Scientific Reports 11,

Combining microfluidics technology with machine learning represents an innovative approach to conduct massive quantitative cell behavior study and implement smart decision-making systems in support of clinical diagnostics. The spleen plays a key-role in rare hereditary hemolytic anemia (RHHA), being the organ responsible for the premature removal of defective red blood cells (RBCs). The goal is to adapt the physiological spleen filtering strategy for in vitro study and monitoring of blood diseases through RBCs shape analysis. Then, a microfluidic device mimicking the slits of the spleen red pulp area and video data analysis are combined for the characterization of RBCs in RHHA. This microfluidic unit is designed to evaluate RBC deformability by maintaining them fixed in planar orientation, allowing the visual inspection of RBC's capacity to restore their original shape after crossing microconstrictions. Then, two cooperative learning approaches are used for the analysis: the majority voting scheme, in which the most voted label for all the cell images is the class assigned to the entire video; and the maximum sum of scores to decide the maximally scored class to assign. The proposed platform shows the capability to discriminate healthy controls and patients with an average efficiency of 91%, but also to distinguish between RHHA subtypes, with an efficiency of 82%.

JTD Keywords: chip, disease, Red-blood-cell


Cereta, AD, Oliveira, VR, Costa, IP, Guimaraes, LL, Afonso, JPR, Fonseca, AL, de Sousa, ART, Silva, GAM, Mello, DACPG, de Oliveira, LVF, da Palma, RK, (2021). Early Life Microbial Exposure and Immunity Training Effects on Asthma Development and Progression Frontiers Of Medicine 8, 662262

Asthma is the most common inflammatory disease affecting the lungs, which can be caused by intrauterine or postnatal insults depending on the exposure to environmental factors. During early life, the exposure to different risk factors can influence the microbiome leading to undesired changes to the immune system. The modulations of the immunity, caused by dysbiosis during development, can increase the susceptibility to allergic diseases. On the other hand, immune training approaches during pregnancy can prevent allergic inflammatory diseases of the airways. In this review, we focus on evidence of risk factors in early life that can alter the development of lung immunity associated with dysbiosis, that leads to asthma and affect childhood and adult life. Furthermore, we discuss new ideas for potential prevention strategies that can be applied during pregnancy and postnatal period.

JTD Keywords: asthma, dysbiosis, early life immunity, lung microbiome, Adulthood, Antibiotic exposure, Asthma, Childhood, Disease, Disease exacerbation, Dysbiosis, Early life immunity, Gut microbiome, Human, Immunity, Intestine flora, Lung development, Lung microbiome, Lung microbiota, Nonhuman, Perinatal period, Pregnancy, Prevention, Prevention strategies, Review, Risk, Risk factor, Sensitization, Supplementation, Vitamin-d, Wheeze


Diaz-Lucena D, Kruse N, Thüne K, Schmitz M, Villar-Piqué A, da Cunha JEG, Hermann P, López-Pérez Ó, Andrés-Benito P, Ladogana A, Calero M, Vidal E, Riggert J, Pineau H, Sim V, Zetterberg H, Blennow K, del Río JA, Marín-Moreno A, Espinosa JC, Torres JM, Sánchez-Valle R, Mollenhauer B, Ferrer I, Zerr I, Llorens F, (2021). TREM2 expression in the brain and biological fluids in prion diseases Acta Neuropathologica 141, 841-859

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune cell surface receptor that regulates microglial function and is involved in the pathophysiology of several neurodegenerative diseases. Its soluble form (sTREM2) results from shedding of the TREM2 ectodomain. The role of TREM2 in prion diseases, a group of rapidly progressive dementias remains to be elucidated. In the present study, we analysed the expression of TREM2 and its main sheddase ADAM10 in the brain of sporadic Creutzfeldt-Jakob disease (sCJD) patients and evaluated the role of CSF and plasma sTREM2 as a potential diagnostic marker of prion disease. Our data indicate that, compared to controls, TREM2 is increased in sCJD patient brains at the mRNA and protein levels in a regional and subtype dependent fashion, and expressed in a subpopulation of microglia. In contrast, ADAM10 is increased at the protein, but not the mRNA level, with a restricted neuronal expression. Elevated CSF sTREM2 is found in sCJD, genetic CJD with mutations E200K and V210I in the prion protein gene (PRNP), and iatrogenic CJD, as compared to healthy controls (HC) (AUC = 0.78–0.90) and neurological controls (AUC = 0.73–0.85), while CSF sTREM2 is unchanged in fatal familial insomnia. sTREM2 in the CSF of cases with Alzheimer’s disease, and multiple sclerosis was not significantly altered in our series. CSF sTREM2 concentrations in sCJD are PRNP codon 129 and subtype-related, correlate with CSF 14-3-3 positivity, total-tau and YKL-40, and increase with disease progression. In plasma, sTREM2 is increased in sCJD compared with HC (AUC = 0.80), displaying positive correlations with plasma total-tau, neurofilament light, and YKL-40. We conclude that comparative study of TREM2 in brain and biological fluids of prion diseases reveals TREM2 to be altered in human prion diseases with a potential value in target engagement, patient stratification, and disease monitoring.

JTD Keywords: cerebrospinal fluid, creutzfeldt-jakob disease, microglia, plasma, prion diseases, Cerebrospinal fluid, Creutzfeldt-jakob disease, Microglia, Plasma, Prion diseases, Trem2


Torp N, Israelsen M, Madsen B, Lutz P, Jansen C, Strassburg C, Mortensen C, Knudsen AW, Sorensen GL, Holmskov U, Schlosser A, Thiele M, Trebicka J, Krag A, (2021). Level of MFAP4 in ascites independently predicts 1-year transplant-free survival in patients with cirrhosis Jhep Rep 3,

Background & Aims: Prognostic models of cirrhosis underestimate disease severity for patients with cirrhosis and ascites. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein linked to hepatic neoangiogenesis and fibrogenesis. We investigated ascites MFAP4 as a predictor of transplant-free survival in patients with cirrhosis and ascites. Methods: A dual-centre observational study of patients with cirrhosis and ascites recruited consecutively in relation to a paracentesis was carried out. Patients were followed up for 1 year, until death or liver transplantation (LTx). Ascites MFAP4 was tested with the model for end-stage liver disease (MELD-Na), CLIF Consortium Acute Decompensation (CLIF-C AD), and Child-Pugh score in Cox regression models. Results: Ninety-three patients requiring paracentesis were included. Median ascites MFAP4 was 29.7 U/L [22.3–41.3], and MELD-Na was 19 [16–23]. A low MELD-Na score (<20) was observed in 49 patients (53%). During follow-up, 20 patients died (22%), and 6 received LTx (6%). High ascites MFAP4 (>29.7 U/L) was associated with 1-year transplant-free survival (p = 0.002). In Cox regression, ascites MFAP4 and MELD-Na independently predicted 1-year transplant-free survival (hazard ratio [HR] = 0.97, p = 0.03, and HR = 1.08, p = 0.01, respectively). Ascites MFAP4 and CLIF-C AD also predicted survival independently (HR = 0.96, p = 0.02, and HR = 1.05, p = 0.03, respectively), whereas only ascites MFAP4 did, controlling for the Child-Pugh score (HR = 0.97, p = 0.03, and HR = 1.18, p = 0.16, respectively). For patients with MELD-Na <20, ascites MFAP4 but not ascites protein predicted 1-year transplant-free survival (HR 0.91, p = 0.02, and HR = 0.94, p = 0.17, respectively). Conclusions: Ascites MFAP4 predicts 1-year transplant-free survival in patients with cirrhosis and ascites. In patients with low MELD-Na scores, ascites MFAP4, but not total ascites protein, significantly predicted 1-year transplant-free survival. Lay summary: Patients with cirrhosis who have fluid in the abdomen, ascites, are at an increased risk of death and in need for liver transplantation. Our study identified patients with ascites and a poor prognosis by measuring microfibrillar associated protein 4 (MFAP4), a protein present in the abdominal fluid. Patients with low levels of the MFAP4 protein are at particularly increased risk of death or liver transplantation, suggesting that clinical care should be intensified in this group of patients. © 2021 The Authors

JTD Keywords: biomarker, clif-c ad, clif consortium acute decompensation, cps, child-pugh score, crp, c-reactive protein, ct, computed tomography, decompensated, ecm, extracellular matrix, fibrosis, fluid protein, gfr, glomerular filtration rate, hr, hazard ratio, inr, internationalised normal ratio, liver disease, liver-cirrhosis, ltx, liver transplantation, markers, meld-na, model for end-stage liver disease, mfap4, microfibrillar associated protein 4, mortality, nash, non-alcoholic steatohepatitis, natural-history, prognosis, risk-factors, sbp, spontaneous bacterial peritonitis, scores, stage, Biomarker, Decompensated, Egfr, estimated gfr, Fibrosis, Liver disease, Mortality, Prognosis, Spontaneous bacterial peritonitis


Lidón L, Llaó-Hierro L, Nuvolone M, Aguzzi A, Ávila J, Ferrer I, Del Río JA, Gavín R, (2021). Tau exon 10 inclusion by prpc through downregulating gsk3? activity International Journal Of Molecular Sciences 22,

Tau protein is largely responsible for tauopathies, including Alzheimer’s disease (AD), where it accumulates in the brain as insoluble aggregates. Tau mRNA is regulated by alternative splicing, and inclusion or exclusion of exon 10 gives rise to the 3R and 4R isoforms respectively, whose balance is physiologically regulated. In this sense, one of the several factors that regulate alternative splicing of tau is GSK3?, whose activity is inhibited by the cellular prion protein (PrPC), which has different physiological functions in neuroprotection and neuronal differentiation. Moreover, a relationship between PrPC and tau expression levels has been reported during AD evolution. For this reason, in this study we aimed to analyze the role of PrPC and the implication of GSK3? in the regulation of tau exon 10 alternative splicing. We used AD human samples and mouse models of PrPC ablation and tau overexpression. In addition, we used primary neuronal cultures to develop functional studies. Our results revealed a paralleled association between PrPC expression and tau 4R isoforms in all models analyzed. In this sense, reduction or ablation of PrPC levels induces an increase in tau 3R/4R balance. More relevantly, our data points to GSK3? activity downstream from PrPC in this phenomenon. Our results indicate that PrPC plays a role in tau exon 10 inclusion through the inhibitory capacity of GSK3?. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

JTD Keywords: alternative splicing, alzheimer's disease, alzheimers-disease, alzheimer’s disease, amyloid-beta, cellular prion protein, frontotemporal dementia, glycogen-synthase kinase-3, gsk3 beta, gsk3?, messenger-rna, microtubule-associated protein tau, neurofibrillary tangles, progressive supranuclear palsy, promotes neuronal differentiation, stem-cells, tauopathies, Alternative splicing, Alzheimer’s disease, Cellular prion protein, Gsk3?, Microtubule-associated protein tau, Tauopathies


Cereta AD, Oliveira VR, Costa IP, Afonso JPR, Fonseca AL, de Souza ART, Silva GAM, Mello DACPG, Oliveira LVFd, da Palma RK, (2021). Emerging Cell-Based Therapies in Chronic Lung Diseases: What About Asthma? Frontiers In Pharmacology 12, 648506

Asthma is a widespread disease characterized by chronic airway inflammation. It causes substantial disability, impaired quality of life, and avoidable deaths around the world. The main treatment for asthmatic patients is the administration of corticosteroids, which improves the quality of life; however, prolonged use of corticosteroids interferes with extracellular matrix elements. Therefore, cell-based therapies are emerging as a novel therapeutic contribution to tissue regeneration for lung diseases. This study aimed to summarize the advancements in cell therapy involving mesenchymal stromal cells, extracellular vesicles, and immune cells such as T-cells in asthma. Our findings provide evidence that the use of mesenchymal stem cells, their derivatives, and immune cells such as T-cells are an initial milestone to understand how emergent cell-based therapies are effective to face the challenges in the development, progression, and management of asthma, thus improving the quality of life.

JTD Keywords: asthma treatments, cell-based therapies, chronic lung diseases, extracellular vesicles, immune cells, mesenchymal stromal cells, Asthma treatments, Cell-based therapies, Chronic lung diseases, Extracellular vesicles, Immune cells, Mesenchymal stromal cells


Blaya, D, Pose, E, Coll, M, Lozano, JJ, Graupera, I, Schierwagen, R, Jansen, C, Castro, P, Fernandez, S, Sidorova, J, Vasa-Nicotera, M, Sola, E, Caballeria, J, Trebicka, J, Gines, P, Sancho-Bru, P, (2021). Profiling circulating microRNAs in patients with cirrhosis and acute-on-chronic liver failure Jhep Rep 3,

Background & Aims: MicroRNAs (miRNAs) circulate in several body fluids and can be useful biomarkers. The aim of this study was to identify blood-circulating miRNAs associated with cirrhosis progression and acute-on-chronic liver failure (ACLF). Methods: Using high-throughput screening of 754 miRNAs, serum samples from 45 patients with compensated cirrhosis, decompensated cirrhosis, or ACLF were compared with those from healthy individuals (n = 15). miRNA levels were correlated with clinical parameters, organ failure, and disease progression and outcome. Dysregulated miRNAs were evaluated in portal and hepatic vein samples (n = 33), liver tissues (n = 17), and peripheral blood mononuclear cells (PBMCs) (n = 16). Results: miRNA screening analysis revealed that circulating miRNAs are dysregulated in cirrhosis progression, with 51 miRNAs being differentially expressed among all groups of patients. Unsupervised clustering and principal component analysis indicated that the main differences in miRNA expression occurred at decompensation, showing similar levels in patients with decompensated cirrhosis and those with ACLF. Of 43 selected miRNAs examined for differences among groups, 10 were differentially expressed according to disease progression. Moreover, 20 circulating miRNAs were correlated with model for end-stage liver disease and Child-Pugh scores. Notably, 11 dysregulated miRNAs were associated with kidney or liver failure, encephalopathy, bacterial infection, and poor outcomes. The most severely dysregulated miRNAs (i.e. miR-146a5p, miR-26a-5p, and miR-191-5p) were further evaluated in portal and hepatic vein blood and liver tissue, but showed no differences. However, PBMCs from patients with cirrhosis showed significant downregulation of miR-26 and miR-146a, suggesting a extrahepatic origin of some circulating miRNAs. Conclusions: This study is a repository of circulating miRNA data following cirrhosis progression and ACLF. Circulating miRNAs were profoundly dysregulated during the progression of chronic liver disease, were associated with failure of several organs and could have prognostic utility. Lay summary: Circulating miRNAs are small molecules in the blood that can be used to identify or predict a clinical condition. Our study aimed to identify miRNAs for use as biomarkers in patients with cirrhosis or acute-on-chronic liver failure. Several miRNAs were found to be dysregulated during the progression of disease, and some were also related to organ failure and disease-related outcomes. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).

JTD Keywords: aclf, acute-on-chronic liver failure, alt, alanine aminotransferase, ast, aspartate aminotransferase, biomarkers, chronic liver disease, cxcl10, c-x-c motif chemokine ligand 10, ef clif, european foundation for the study of chronic liver failure, foxo, forkhead box o, inr, international normalised ratio, ldh, lactate dehydrogenase, liver decompensation, mapk, mitogen-activated protein kinase, meld, model for end-stage liver disease, nash, non-alcoholic steatohepatitis, non-coding rnas, pbmcs, peripheral blood mononuclear cells, pca, principal component analysis, tgf, transforming growth factor, tips, transjugular intrahepatic portosystemic shunt, Biomarkers, Chronic liver disease, Expression, Liver decompensation, Markers, Mir-146a, Non-coding rnas, Qpcr, quantitative pcr


Seras-Franzoso J, Díaz-Riascos ZV, Corchero JL, González P, García-Aranda N, Mandaña M, Riera R, Boullosa A, Mancilla S, Grayston A, Moltó-Abad M, Garcia-Fruitós E, Mendoza R, Pintos-Morell G, Albertazzi L, Rosell A, Casas J, Villaverde A, Schwartz S, Abasolo I, (2021). Extracellular vesicles from recombinant cell factories improve the activity and efficacy of enzymes defective in lysosomal storage disorders Journal Of Extracellular Vesicles 10,

In the present study the use of extracellular vesicles (EVs) as vehicles for therapeutic enzymes in lysosomal storage disorders was explored. EVs were isolated from mammalian cells overexpressing alpha-galactosidase A (GLA) or N-sulfoglucosamine sulfohydrolase (SGSH) enzymes, defective in Fabry and Sanfilippo A diseases, respectively. Direct purification of EVs from cell supernatants was found to be a simple and efficient method to obtain highly active GLA and SGSH proteins, even after EV lyophilization. Likewise, EVs carrying GLA (EV-GLA) were rapidly uptaken and reached the lysosomes in cellular models of Fabry disease, restoring lysosomal functionality much more efficiently than the recombinant enzyme in clinical use. In vivo, EVs were well tolerated and distributed among all main organs, including the brain. DiR-labelled EVs were localized in brain parenchyma 1 h after intra-arterial (internal carotid artery) or intravenous (tail vein) administrations. Moreover, a single intravenous administration of EV-GLA was able to reduce globotriaosylceramide (Gb3) substrate levels in clinically relevant tissues, such kidneys and brain. Overall, our results demonstrate that EVs from cells overexpressing lysosomal enzymes act as natural protein delivery systems, improving the activity and the efficacy of the recombinant proteins and facilitating their access to organs neglected by conventional enzyme replacement therapies.

JTD Keywords: alpha?galactosidase a, drug delivery, enzyme replacement therapy, fabry disease, lysosomal storage disorders, n-sulfoglucosamine sulfohydrolase, n?sulfoglucosamine sulfohydrolase, sanfilippo syndrome, Alpha-galactosidase a, Drug delivery, Enzyme replacement therapy, Fabry disease, Lysosomal storage disorders, N-sulfoglucosamine sulfohydrolase, Sanfilippo syndrome


Dhillon P, Park J, Hurtado del Pozo C, Li L, Doke T, Huang S, Zhao J, Kang HM, Shrestra R, Balzer MS, Chatterjee S, Prado P, Han SY, Liu H, Sheng X, Dierickx P, Batmanov K, Romero JP, Prósper F, Li M, Pei L, Kim J, Montserrat N, Susztak K, (2021). The Nuclear Receptor ESRRA Protects from Kidney Disease by Coupling Metabolism and Differentiation Cell Metabolism 33,

© 2020 Elsevier Inc. Using single-cell RNA sequencing, Susztak and colleagues, show major changes in cell diversity in mouse models of kidney fibrosis. Proximal tubule (PT) cells are highly vulnerable to dysfunction in fibrosis and show altered differentiation. Nuclear receptors such as ESRRA maintain both PT cell metabolism and differentiation by directly regulating PT-cell-specific genes.

JTD Keywords: chronic kidney disease, esrra, fatty-acid oxidation, fibrosis, kidney, organoids, ppara, proximal tubule cells, single-cell atac sequencing, Chronic kidney disease, Esrra, Fatty-acid oxidation, Fibrosis, Kidney, Organoids, Ppara, Proximal tubule cells, Single-cell atac sequencing, Single-cell rna sequencing


Marrugo-Ramírez J, Rodríguez-Núñez M, Marco MP, Mir M, Samitier J, (2021). Kynurenic Acid Electrochemical Immunosensor: Blood-Based Diagnosis of Alzheimer's Disease Biosensors 11,

Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by a functional deterioration of the brain. Currently, there are selected biomarkers for its diagnosis in cerebrospinal fluid. However, its extraction has several disadvantages for the patient. Therefore, there is an urgent need for a detection method using sensitive and selective blood-based biomarkers. Kynurenic acid (KYNA) is a potential biomarker candidate for this purpose. The alteration of the KYNA levels in blood has been related with inflammatory processes in the brain, produced as a protective function when neurons are damaged. This paper describes a novel electrochemical immunosensor for KYNA detection, based on successive functionalization multi-electrode array. The resultant sensor was characterized by cyclic voltammetry (CV), chronoamperometry (CA), and electrochemical impedance spectroscopy (EIS). The proposed biosensor detects KYNA within a linear calibration range from 10 pM to 100 nM using CA and EIS, obtaining a limit of detection (LOD) of 16.9 pM and 37.6 pM in buffer, respectively, being the lowest reported LOD for this biomarker. Moreover, to assess our device closer to the real application, the developed immunosensor was also tested under human serum matrix, obtaining an LOD of 391.71 pM for CA and 278.8 pM for EIS with diluted serum.

JTD Keywords: alzheimer’s disease (ad), blood analysis, chronoamperometry (ca), electrochemical biosensor, electrochemical impedance spectroscopy (eis), immunosensor, in vitro diagnosis (ivd), kynurenic acid (kyna), Alzheimer’s disease (ad), Blood analysis, Chronoamperometry (ca), Electrochemical biosensor, Electrochemical impedance spectroscopy (eis), Immunosensor, In vitro diagnosis (ivd), Kynurenic acid (kyna), Point of care diagnosis (poc)


Wiers RW, Verschure P, (2021). Curing the broken brain model of addiction: Neurorehabilitation from a systems perspective Addictive Behaviors 112,

© 2020 The Author(s) The dominant biomedical perspective on addictions has been that they are chronic brain diseases. While we acknowledge that the brains of people with addictions differ from those without, we argue that the “broken brain” model of addiction has important limitations. We propose that a systems-level perspective more effectively captures the integrated architecture of the embodied and situated human mind and brain in relation to the development of addictions. This more dynamic conceptualization places addiction in the broader context of the addicted brain that drives behavior, where the addicted brain is the substrate of the addicted mind, that in turn is situated in a physical and socio-cultural environment. From this perspective, neurorehabilitation should shift from a “broken-brain” to a systems theoretical framework, which includes high-level concepts related to the physical and social environment, motivation, self-image, and the meaning of alternative activities, which in turn will dynamically influence subsequent brain adaptations. We call this integrated approach system-oriented neurorehabilitation. We illustrate our proposal by showing the link between addiction and the architecture of the embodied brain, including a systems-level perspective on classical conditioning, which has been successfully translated into neurorehabilitation. Central to this example is the notion that the human brain makes predictions on future states as well as expected (or counterfactual) errors, in the context of its goals. We advocate system-oriented neurorehabilitation of addiction where the patients' goals are central in targeted, personalized assessment and intervention.

JTD Keywords: addiction, brain disease model, neurorehabilitation, Addiction, Brain disease model, Neurorehabilitation, Systems approach


Ben Hamouda S, Vargas A, Boivin R, Miglino MA, da Palma RK, Lavoie JP, (2021). Recellularization of Bronchial Extracellular Matrix With Primary Bronchial Smooth Muscle Cells Journal Of Equine Veterinary Science 96,

© 2020 Elsevier Inc. Severe asthma is associated with an increased airway smooth muscle (ASM) mass and altered composition of the extracellular matrix (ECM). Studies have indicated that ECM-ASM cell interactions contribute to this remodeling and its limited reversibility with current therapy. Three-dimensional matrices allow the study of complex cellular responses to different stimuli in an almost natural environment. Our goal was to obtain acellular bronchial matrices and then develop a recellularization protocol with ASM cells. We studied equine bronchi as horses spontaneously develop a human asthma-like disease. The bronchi were decellularized using Triton/Sodium Deoxycholate. The obtained scaffolds retained their anatomical and histological properties. Using immunohistochemistry and a semi-quantitative score to compare native bronchi to scaffolds revealed no significant variation for matrixial proteins. DNA quantification and electrophoresis revealed that most DNA was 29.6 ng/mg of tissue ± 5.6, with remaining fragments of less than 100 bp. Primary ASM cells were seeded on the scaffolds. Histological analysis of the recellularizations showed that ASM cells migrated and proliferated primarily in the decellularized smooth muscle matrix, suggesting a chemotactic effect of the scaffolds. This is the first report of primary ASM cells preferentially repopulating the smooth muscle matrix layer in bronchial matrices. This protocol is now being used to study the molecular interactions occurring between the asthmatic ECMs and ASM to identify effectors of asthmatic bronchial remodeling.

JTD Keywords: 2d, airway smooth muscle cells, asthma, decellularization, disease, elastin, extracellular matrix, lung scaffolds, migration, peptide, recellularization, tissues, Airway smooth muscle cells, Asthma, Culture-systems, Decellularization, Extracellular matrix, Recellularization


Blanco-Almazan D, Groenendaal W, Lozano-Garcia M, Estrada-Petrocelli L, Lijnen L, Smeets C, Ruttens D, Catthoor F, Jane R, (2021). Combining Bioimpedance and Myographic Signals for the Assessment of COPD during Loaded Breathing Ieee Transactions On Biomedical Engineering 68, 298-307

© 1964-2012 IEEE. Chronic Obstructive Pulmonary Disease (COPD) is one of the most common chronic conditions. The current assessment of COPD requires a maximal maneuver during a spirometry test to quantify airflow limitations of patients. Other less invasive measurements such as thoracic bioimpedance and myographic signals have been studied as an alternative to classical methods as they provide information about respiration. Particularly, strong correlations have been shown between thoracic bioimpedance and respiratory volume. The main objective of this study is to investigate bioimpedance and its combination with myographic parameters in COPD patients to assess the applicability in respiratory disease monitoring. We measured bioimpedance, surface electromyography and surface mechanomyography in forty-three COPD patients during an incremental inspiratory threshold loading protocol. We introduced two novel features that can be used to assess COPD condition derived from the variation of bioimpedance and the electrical and mechanical activity during each respiratory cycle. These features demonstrate significant differences between mild and severe patients, indicating a lower inspiratory contribution of the inspiratory muscles to global respiratory ventilation in the severest COPD patients. In conclusion, the combination of bioimpedance and myographic signals provides useful indices to noninvasively assess the breathing of COPD patients.

JTD Keywords: Bioimpedance, Chronic obstructive pulmonary disease, Inspiratory threshold protocol, Myographic signals, Wearables


Marti, D, Martin-Martinez, E, Torras, J, Bertran, O, Turon, P, Aleman, C, (2021). In silico antibody engineering for SARS-CoV-2 detection Computational And Structural Biotechnology Journal 19, 5525-5534

Engineered immunoglobulin-G molecules (IgGs) are of wide interest for the development of detection elements in protein-based biosensors with clinical applications. The strategy usually employed for the de novo design of such engineered IgGs consists on merging fragments of the three-dimensional structure of a native IgG, which is immobilized on the biosensor surface, and of an antibody with an exquisite target specificity and affinity. In this work conventional and accelerated classical molecular dynamics (cMD and aMD, respectively) simulations have been used to propose two IgG-like antibodies for COVID-19 detection. More specifically, the crystal structure of the IgG1 B12 antibody, which inactivates the human immunodeficiency virus-1, has been merged with the structure of the antibody CR3022 Fab tightly bounded to SARS-CoV-2 receptor-binding domain (RBD) and the structure of the 5309 antibody Fab fragment complexed with SARS-CoV-2 RBD. The two constructed antibodies, named IgG1-CR3022 and IgG1-S309, respectively, have been immobilized on a stable gold surface through a linker. Analyses of the influence of both the merging strategy and the substrate on the stability of the two constructs indicate that the IgG1-S309 antibody better preserves the neutralizing structure than the IgG1-CR3022 one. Overall, results indicate that the IgG1-S309 is appropriated for the generation of antibody based sensors for COVID-19 diagnosis. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.

JTD Keywords: cr3022, igg1, molecular engineering, s309, Antibodies, Antibody engineering, Biosensors, Chemical detection, Clinical application, Cov, Cr3022, Crystal structure, Design, Diseases, Gold nanoparticles, Igg1, Igg1 antibody, Immobilization, Immunoglobulin g, Immunosensor, In-silico, Merging, Molecular dynamics, Molecular engineering, Orientation, Protein-based biosensors, Receptor-binding domains, S309, Sars, Sensor, Spike protein, Target, Vaccine, Viruses


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

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

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


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

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

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


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

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

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


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

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

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


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

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

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


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

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

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


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

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

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


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

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

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


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

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

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


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

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

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


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


Picón-Pagès, P., Bonet, J., García-García, J., Garcia-Buendia, J., Gutierrez, D., Valle, J., Gómez-Casuso, C. E. S., Sidelkivska, V., Alvarez, A., Perálvarez-Marín, A., Suades, A., Fernàndez-Busquets, X., Andreu, D., Vicente, R., Oliva, B., Muñoz, F. J., (2019). Human albumin impairs amyloid β-peptide fibrillation through its C-terminus: From docking modeling to protection against neurotoxicity in Alzheimer's disease Computational and Structural Biotechnology Journal 17, 963-971

Alzheimer's disease (AD) is a neurodegenerative process characterized by the accumulation of extracellular deposits of amyloid β-peptide (Aβ), which induces neuronal death. Monomeric Aβ is not toxic but tends to aggregate into β-sheets that are neurotoxic. Therefore to prevent or delay AD onset and progression one of the main therapeutic approaches would be to impair Aβ assembly into oligomers and fibrils and to promote disaggregation of the preformed aggregate. Albumin is the most abundant protein in the cerebrospinal fluid and it was reported to bind Aβ impeding its aggregation. In a previous work we identified a 35-residue sequence of clusterin, a well-known protein that binds Aβ, that is highly similar to the C-terminus (CTerm) of albumin. In this work, the docking experiments show that the average binding free energy of the CTerm-Aβ1–42 simulations was significantly lower than that of the clusterin-Aβ1–42 binding, highlighting the possibility that the CTerm retains albumin's binding properties. To validate this observation, we performed in vitro structural analysis of soluble and aggregated 1 μM Aβ1–42 incubated with 5 μM CTerm, equimolar to the albumin concentration in the CSF. Reversed-phase chromatography and electron microscopy analysis demonstrated a reduction of Aβ1–42 aggregates when the CTerm was present. Furthermore, we treated a human neuroblastoma cell line with soluble and aggregated Aβ1–42 incubated with CTerm obtaining a significant protection against Aβ-induced neurotoxicity. These in silico and in vitro data suggest that the albumin CTerm is able to impair Aβ aggregation and to promote disassemble of Aβ aggregates protecting neurons.

JTD Keywords: Albumin, Alzheimer's disease, Amyloid, Docking, β-Sheet


Rafols-de-Urquia, M., Estrada, L., Estevez-Piorno, J., Sarlabous, L., Jane, R., Torres, A., (2019). Evaluation of a wearable device to determine cardiorespiratory parameters from surface diaphragm electromyography IEEE Journal of Biomedical and Health Informatics 23, (5), 1964-1971

The use of wearable devices in clinical routines could reduce healthcare costs and improve the quality of assessment in patients with chronic respiratory diseases. The purpose of this study is to evaluate the capacity of a Shimmer3 wearable device to extract reliable cardiorespiratory parameters from surface diaphragm electromyography (EMGdi). Twenty healthy volunteers underwent an incremental load respiratory test whilst EMGdi was recorded with a Shimmer3 wearable device (EMGdiW). Simultaneously, a second EMGdi (EMGdiL), inspiratory mouth pressure (Pmouth) and lead-I electrocardiogram (ECG) were recorded via a standard wired laboratory acquisition system. Different cardiorespiratory parameters were extracted from both EMGdiW and EMGdiL signals: heart rate, respiratory rate, respiratory muscle activity and mean frequency of EMGdi signals. Alongside these, similar parameters were also extracted from reference signals (Pmouth and ECG). High correlations were found between the data extracted from the EMGdiW and the reference signal data: heart rate (R = 0.947), respiratory rate (R = 0.940), respiratory muscle activity (R = 0.877), and mean frequency (R = 0.895). Moreover, similar increments in EMGdiW and EMGdiL activity were observed when Pmouth was raised, enabling the study of respiratory muscle activation. In summary, the Shimmer3 device is a promising and cost-effective solution for the ambulatory monitoring of respiratory muscle function in chronic respiratory diseases.

JTD Keywords: Cardiorespiratory monitoring, Chronic respiratory diseases, Fixed sample entropy, Non-invasive respiratory monitoring, Surface diaphragm electromyography, Wearable wireless device


Garcia-Puig, A., Mosquera, J. L., Jiménez-Delgado, S., García-Pastor, C., Jorba, I., Navajas, D., Canals, F., Raya, A., (2019). Proteomics analysis of extracellular matrix remodeling during zebrafish heart regeneration Molecular & cellular proteomics 18, (9), 1745-1755

Adult zebrafish, in contrast to mammals, are able to regenerate their hearts in response to injury or experimental amputation. Our understanding of the cellular and molecular bases that underlie this process, although fragmentary, has increased significantly over the last years. However, the role of the extracellular matrix (ECM) during zebrafish heart regeneration has been comparatively rarely explored. Here, we set out to characterize the ECM protein composition in adult zebrafish hearts, and whether it changed during the regenerative response. For this purpose, we first established a decellularization protocol of adult zebrafish ventricles that significantly enriched the yield of ECM proteins. We then performed proteomic analyses of decellularized control hearts and at different times of regeneration. Our results show a dynamic change in ECM protein composition, most evident at the earliest (7 days post-amputation) time-point analyzed. Regeneration associated with sharp increases in specific ECM proteins, and with an overall decrease in collagens and cytoskeletal proteins. We finally tested by atomic force microscopy that the changes in ECM composition translated to decreased ECM stiffness. Our cumulative results identify changes in the protein composition and mechanical properties of the zebrafish heart ECM during regeneration.

JTD Keywords: Animal models, Atomic force microscopy, Cardiovascular disease, Cardiovascular function or biology, Developmental biology, Extracellular matrix, Heart regeneration, Proteomic analysis


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


Lozano-García, M., Estrada-Petrocelli, L., Moxham, J., Rafferty, G. F., Torres, A., Jolley, C. J., Jané, R. , (2019). Noninvasive assessment of inspiratory muscle neuromechanical coupling during inspiratory threshold loading IEEE Access 7, 183634-183646

Diaphragm neuromechanical coupling (NMC), which reflects the efficiency of conversion of neural activation to transdiaphragmatic pressure (Pdi), is increasingly recognized to be a useful clinical index of diaphragm function and respiratory mechanics in neuromuscular weakness and cardiorespiratory disease. However, the current gold standard assessment of diaphragm NMC requires invasive measurements of Pdi and crural diaphragm electromyography (oesEMGdi), which complicates the measurement of diaphragm NMC in clinical practice. This is the first study to compare invasive measurements of diaphragm NMC (iNMC) using the relationship between Pdi and oesEMGdi, with noninvasive assessment of NMC (nNMC) using surface mechanomyography (sMMGlic) and electromyography (sEMGlic) of lower chest wall inspiratory muscles. Both invasive and noninvasive measurements were recorded in twelve healthy adult subjects during an inspiratory threshold loading protocol. A linear relationship between noninvasive sMMGlic and sEMGlic measurements was found, resulting in little change in nNMC with increasing inspiratory load. By contrast, a curvilinear relationship between invasive Pdi and oesEMGdi measurements was observed, such that there was a progressive increase in iNMC with increasing inspiratory threshold load. Progressive recruitment of lower ribcage muscles, serving to enhance the mechanical advantage of the diaphragm, may explain the more linear relationship between sMMGlic and sEMGlic (both representing lower intercostal plus costal diaphragm activity) than between Pdi and crural oesEMGdi. Noninvasive indices of NMC derived from sEMGlic and sMMGlic may prove to be useful indices of lower chest wall inspiratory muscle NMC, particularly in settings that do not have access to invasive measures of diaphragm function.

JTD Keywords: Cardiovascular system, Diaphragms, Diseases, Electromyography, Medical signal processing, Neurophysiology, Patient monitoring, Pneumodynamics, Inspiratory muscle neuromechanical coupling, Diaphragm neuromechanical coupling, Neural activation, Transdiaphragmatic pressure, Diaphragm function, Respiratory mechanics, Diaphragm NMC, Invasive measurements, Crural diaphragm electromyography, iNMC, Noninvasive assessment, nNMC, Lower chest wall inspiratory muscles, Inspiratory threshold loading protocol, Noninvasive sMMGlic measurements, sEMGlic measurements, oesEMGdi measurements, Inspiratory threshold load, Lower ribcage muscles, Lower intercostal plus costal diaphragm activity, Crural oesEMGdi, Noninvasive indices, sEMGlic sMMGlic, Lower chest wall inspiratory muscle NMC, Surface mechanomyography, Electromyography, Inspiratory threshold loading, Mechanomyography, Neuromechanical coupling, Respiratory muscles


Blanco-Almazan, D., Groenendaal, W., Catthoor, F., Jane, R., (2019). Wearable bioimpedance measurement for respiratory monitoring during inspiratory loading IEEE Access 7, 89487-89496

Bioimpedance is an unobtrusive noninvasive technique to measure respiration and has a linear relation with volume during normal breathing. The objective of this paper was to assess this linear relation during inspiratory loading protocol and determine the best electrode configuration for bioimpedance measurement. The inspiratory load is a way to estimate inspiratory muscle function and has been widely used in studies of respiratory mechanics. Therefore, this protocol permitted us to evaluate bioimpedance performance under breathing pattern changes. We measured four electrode configurations of bioimpedance and airflow simultaneously in ten healthy subjects using a wearable device and a standard wired laboratory acquisition system, respectively. The subjects were asked to perform an incremental inspiratory threshold loading protocol during the measurements. The load values were selected to increase progressively until the 60% of the subject's maximal inspiratory pressure. The linear relation of the signals was assessed by Pearson correlation (r ) and the waveform agreement by the mean absolute percentage error (MAPE), both computed cycle by cycle. The results showed a median greater than 0.965 in r coefficients and lower than 11 % in the MAPE values for the entire population in all loads and configurations. Thus, a strong linear relation was found during all loaded breathing and configurations. However, one out of the four electrode configurations showed robust results in terms of agreement with volume during the highest load. In conclusion, bioimpedance measurement using a wearable device is a noninvasive and a comfortable alternative to classical methods for monitoring respiratory diseases in normal and restrictive breathing.

JTD Keywords: Bioimpedance, Chronic respiratory diseases, Electrode configurations, Inspiratory threshold protocol, Wearable


Enshaei, H., Molina, B. G., del Valle, L. J., Estrany, F., Arnan, C., Puiggalí, J., Saperas, N., Alemán, C., (2019). Scaffolds for sustained release of ambroxol hydrochloride, a pharmacological chaperone that increases the activity of misfolded β-glucocerebrosidase. Macromolecular Bioscience 19, (8), 1900130

Ambroxol is a pharmacological chaperone (PC) for Gaucher disease that increases lysosomal activity of misfolded β-glucocerebrosidase (GCase) while displaying a safe toxicological profile. In this work, different poly(ε-caprolactone) (PCL)-based systems are developed to regulate the sustained release of small polar drugs in physiological environments. For this purpose, ambroxol is selected as test case since the encapsulation and release of PCs using polymeric scaffolds have not been explored yet. More specifically, ambroxol is successfully loaded in electrospun PCL microfibers, which are subsequently coated with additional PCL layers using dip-coating or spin-coating. The time needed to achieve 80% release of loaded ambroxol increases from ≈15 min for uncoated fibrous scaffolds to 3 days and 1 week for dip-coated and spin-coated systems, respectively. Furthermore, it is proven that the released drug maintains its bioactivity, protecting GCase against induced thermal denaturation.

JTD Keywords: Electrospinning, Gaucher's disease, Lysosomal storage disorders, Misfolding diseases, Poly(ε-caprolactone), Polyester, Release regulation


Sarlabous, L., Estrada, L., Cerezo-Hernández, A., Leest, Sietske V. D., Torres, A., Jané, R., Duiverman, M., Garde, Ainara, (2019). Electromyography-based respiratory onset detection in COPD patients on non-invasive mechanical ventilation Entropy 21, (3), 258

To optimize long-term nocturnal non-invasive ventilation in patients with chronic obstructive pulmonary disease, surface diaphragm electromyography (EMGdi) might be helpful to detect patient-ventilator asynchrony. However, visual analysis is labor-intensive and EMGdi is heavily corrupted by electrocardiographic (ECG) activity. Therefore, we developed an automatic method to detect inspiratory onset from EMGdi envelope using fixed sample entropy (fSE) and a dynamic threshold based on kernel density estimation (KDE). Moreover, we combined fSE with adaptive filtering techniques to reduce ECG interference and improve onset detection. The performance of EMGdi envelopes extracted by applying fSE and fSE with adaptive filtering was compared to the root mean square (RMS)-based envelope provided by the EMG acquisition device. Automatic onset detection accuracy, using these three envelopes, was evaluated through the root mean square error (RMSE) between the automatic and mean visual onsets (made by two observers). The fSE-based method provided lower RMSE, which was reduced from 298 ms to 264 ms when combined with adaptive filtering, compared to 301 ms provided by the RMS-based method. The RMSE was negatively correlated with the proposed EMGdi quality indices. Following further validation, fSE with KDE, combined with adaptive filtering when dealing with low quality EMGdi, indicates promise for detecting the neural onset of respiratory drive.

JTD Keywords: Fixed sample entropy, Adaptive filtering, Root mean square, Diaphragm electromyography, Non-invasive mechanical ventilation, Chronic obstructive pulmonary disease


Lozano-García, M., Davidson, C. M., Jané, R., (2019). Analysis of tracheal and pulmonary continuous adventitious respiratory sounds in asthma Engineering in Medicine and Biology Society (EMBC) 41st Annual International Conference of the IEEE , IEEE (Berlín, Germany) , 4930-4933

Continuous adventitious sounds (CAS) are commonly observed in obstructive pulmonary diseases and are of great clinical interest. However, their evaluation is generally subjective. We have previously developed an automatic CAS segmentation and classification algorithm for CAS recorded on the chest surface. The aim of this study is to establish whether these pulmonary CAS can be identified in a similar way using a tracheal microphone. Respiratory sounds were originally recorded from 25 participants using five contact microphones, four on the chest and one on the trachea, during three progressive respiratory maneuvers. In this work CAS component detection was performed on the tracheal channel using our automatic algorithm based on the Hilbert spectrum. The tracheal CAS detected were then compared to the previously analyzed pulmonary CAS. The sensitivity of CAS identification was lower at the tracheal microphone, with CAS that appeared simultaneously in all four pulmonary recordings more likely to be identified in the tracheal recordings. These observations could be due to the CAS being obscured by the lower SNR present in the tracheal recordings or not being transmitted through the airways to the trachea. Further work to optimize the algorithm for the tracheal recordings will be conducted in the future.

JTD Keywords: Microphones, Lung, Diseases, Time-frequency analysis, Spectrogram, Sensitivity


Calvo, M., Cano, I., Hernández, C., Ribas, V., Miralles, F., Roca, J., Jané, R., (2019). Class imbalance impact on the prediction of complications during home hospitalization: A comparative study Engineering in Medicine and Biology Society (EMBC) 41st Annual International Conference of the IEEE , IEEE (Berlín, Germany) , 3446-3449

Home hospitalization (HH) is presented as a healthcare alternative capable of providing high standards of care when patients no longer need hospital facilities. Although HH seems to lower healthcare costs by shortening hospital stays and improving patient's quality of life, the lack of continuous observation at home may lead to complications in some patients. Since blood tests have been proven to provide relevant prognosis information in many diseases, this paper analyzes the impact of different sampling methods on the prediction of HH outcomes. After a first exploratory analysis, some variables extracted from routine blood tests performed at the moment of HH admission, such as hemoglobin, lymphocytes or creatinine, were found to unmask statistically significant differences between patients undergoing successful and unsucessful HH stays. Then, predictive models were built with these data, in order to identify unsuccessful cases eventually needing hospital facilities. However, since these hospital admissions during HH programs are rare, their identification through conventional machine-learning approaches is challenging. Thus, several sampling strategies designed to face class imbalance were herein overviewed and compared. Among the analyzed approaches, over-sampling strategies, such as ROSE (Random Over-Sampling Examples) and conventional random over-sampling, showed the best performances. Nevertheless, further improvements should be proposed in the future so as to better identify those patients not benefiting from HH.

JTD Keywords: Hospitals, Blood, Training, Standards, Diseases, Prognostics and health management


Muro, Silvia, (2018). Alterations in cellular processes involving vesicular trafficking and implications in drug delivery Biomimetics 3, (3), 19

Endocytosis and vesicular trafficking are cellular processes that regulate numerous functions required to sustain life. From a translational perspective, they offer avenues to improve the access of therapeutic drugs across cellular barriers that separate body compartments and into diseased cells. However, the fact that many factors have the potential to alter these routes, impacting our ability to effectively exploit them, is often overlooked. Altered vesicular transport may arise from the molecular defects underlying the pathological syndrome which we aim to treat, the activity of the drugs being used, or side effects derived from the drug carriers employed. In addition, most cellular models currently available do not properly reflect key physiological parameters of the biological environment in the body, hindering translational progress. This article offers a critical overview of these topics, discussing current achievements, limitations and future perspectives on the use of vesicular transport for drug delivery applications.

JTD Keywords: Cellular vesicles, Vesicle fusion, Fission and intracellular trafficking, Drug delivery systems and nanomedicines, Transcytosis and endocytosis of drugs carriers, Disease effects on vesicular trafficking, Drug effects on vesicular trafficking, Role of the biological environment


Garcia-Esparcia, P., Koneti, A., Rodríguez-Oroz, M. C., Gago, B., del Rio, J. A., Ferrer, Isidro, (2018). Mitochondrial activity in the frontal cortex area 8 and angular gyrus in Parkinson's disease and Parkinson's disease with dementia Brain Pathology 28, (1), 43-57

Altered mitochondrial function is characteristic in the substantia nigra in Parkinson's disease (PD). Information about mitochondria in other brain regions such as the cerebral cortex is conflicting mainly because most studies have not contemplated the possibility of variable involvement depending on the region, stage of disease progression and clinical symptoms such as the presence or absence of dementia. RT-qPCR of 18 nuclear mRNAs encoding subunits of mitochondrial complexes and 12 mRNAs encoding energy metabolism-related enzymes; western blotting of mitochondrial proteins; and analysis of enzymatic activities of complexes I, II, II, IV and V of the respiratory chain were assessed in frontal cortex area 8 and the angular gyrus of middle-aged individuals (MA), and those with incidental PD (iPD), long-lasting PD with parkinsonism without dementia (PD) and long-lasting PD with dementia (PDD). Up-regulation of several genes was found in frontal cortex area 8 in PD when compared with MA and in the angular gyrus in iPD when compared with MA. Marked down-regulation of genes encoding mitochondrial subunits and energy metabolism-related enzymes occurs in frontal cortex but only of genes coding for energy metabolism-related enzymes in the angular gyrus in PDD. Significant decrease in the protein expression levels of several mitochondrial subunits encoded by these genes occurs in frontal cortex area 8 and angular gyrus in PDD. Moreover, expression of MT-ND1 which is encoded by mitochondrial DNA is also reduced in PDD. Reduced enzymatic activity of complex III in frontal cortex area 8 and angular gyrus is observed in PD, but dramatic reduction in the activity of complexes I, II, II and IV in both regions characterizes PDD. Dementia in the context of PD is linked to region-specific deregulation of genomic genes encoding subunits of mitochondrial complexes and to marked reduction in the activity of mitochondrial complexes I, II, III and IV.

JTD Keywords: Cerebral cortex, Dementia, Energy metabolism, Incidental PD, Mitochondria, Oxidative phosphorylation, Parkinson disease, PDD, Respiratory chain


Torras, N., García-Díaz, M., Fernández-Majada, V., Martínez, Elena, (2018). Mimicking epithelial tissues in three-dimensional cell culture models Frontiers in Bioengineering and Biotechnology 6, Article 197

Epithelial tissues are composed of layers of tightly connected cells shaped into complex three-dimensional (3D) structures such as cysts, tubules, or invaginations. These complex 3D structures are important for organ-specific functions and often create biochemical gradients that guide cell positioning and compartmentalization within the organ. One of the main functions of epithelia is to act as physical barriers that protect the underlying tissues from external insults. In vitro, epithelial barriers are usually mimicked by oversimplified models based on cell lines grown as monolayers on flat surfaces. While useful to answer certain questions, these models cannot fully capture the in vivo organ physiology and often yield poor predictions. In order to progress further in basic and translational research, disease modeling, drug discovery, and regenerative medicine, it is essential to advance the development of new in vitro predictive models of epithelial tissues that are capable of representing the in vivo-like structures and organ functionality more accurately. Here, we review current strategies for obtaining biomimetic systems in the form of advanced in vitro models that allow for more reliable and safer preclinical tests. The current state of the art and potential applications of self-organized cell-based systems, organ-on-a-chip devices that incorporate sensors and monitoring capabilities, as well as microfabrication techniques including bioprinting and photolithography, are discussed. These techniques could be combined to help provide highly predictive drug tests for patient-specific conditions in the near future.

JTD Keywords: 3D cell culture models, Biofabrication, Disease modeling, Drug screening, Epithelial barriers, Microengineered tissues, Organ-on-a-chip, Organoids


Franco, Rafael, Aguinaga, David, Reyes, Irene, Canela, Enric I., Lillo, Jaume, Tarutani, Airi, Hasegawa, Masato, del Ser-Badia, Anna, del Rio, José A., Kreutz, Michael R., Saura, Carlos A., Navarro, Gemma, (2018). N-methyl-D-aspartate receptor link to the MAP kinase pathway in cortical and hippocampal neurons and microglia Is dependent on calcium sensors and Is blocked by α-Synuclein, Tau, and phospho-Tau in non-transgenic and transgenic APPSw,Ind Mice Frontiers in Molecular Neuroscience 11, (273), Article 273

N-methyl-D-aspartate receptors (NMDARs) respond to glutamate to allow the influx of calcium ions and the signaling to the mitogen-activated protein kinase (MAPK) cascade. Both MAPK- and Ca2+-mediated events are important for both neurotransmission and neural cell function and fate. Using a heterologous expression system, we demonstrate that NMDAR may interact with the EF-hand calcium-binding proteins calmodulin, calneuron-1, and NCS1 but not with caldendrin. NMDARs were present in primary cultures of both neurons and microglia from cortex and hippocampus. Calmodulin in microglia, and calmodulin and NCS1 in neurons, are necessary for NMDA-induced MAP kinase pathway activation. Remarkably, signaling to the MAP kinase pathway was blunted in primary cultures of cortical and hippocampal neurons and microglia from wild-type animals by proteins involved in neurodegenerative diseases: α-synuclein, Tau, and p-Tau. A similar blockade by pathogenic proteins was found using samples from the APPSw,Ind transgenic Alzheimer’s disease model. Interestingly, a very marked increase in NMDAR–NCS1 complexes was identified in neurons and a marked increase of both NMDAR–NCS1 and NMDAR–CaM complexes was identified in microglia from the transgenic mice. The results show that α-synuclein, Tau, and p-Tau disrupt the signaling of NMDAR to the MAPK pathway and that calcium sensors are important for NMDAR function both in neurons and microglia. Finally, it should be noted that the expression of receptor–calcium sensor complexes, specially those involving NCS1, is altered in neural cells from APPSw,Ind mouse embryos/pups.

JTD Keywords: Alzheimer’s disease, Calmodulin, Calneuron-1, Caldendrin, NCS1, Extracellular signal-regulated kinase, Glutamate receptor, Proximity ligation assay


Menal, M. J., Jorba, I., Torres, M., Montserrat, J. M., Gozal, D., Colell, A., Piñol-Ripoll, G., Navajas, D., Almendros, I., Farré, R., (2018). Alzheimer's disease mutant mice exhibit reduced brain tissue stiffness compared to wild-type mice in both normoxia and following intermittent hypoxia mimicking sleep apnea Frontiers in Neurology 9, Article 1

Background: Evidence from patients and animal models suggests that obstructive sleep apnea (OSA) may increase the risk of Alzheimer’s disease (AD) and that AD is associated with reduced brain tissue stiffness. Aim: To investigate whether intermittent hypoxia (IH) alters brain cortex tissue stiffness in AD mutant mice exposed to IH mimicking OSA. Methods: Six-eight month old (B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J) AD mutant mice and wild-type (WT) littermates were subjected to IH (21% O2 40 s to 5% O2 20 s; 6 h/day) or normoxia for 8 weeks. After euthanasia, the stiffness (E) of 200-μm brain cortex slices was measured by atomic force microscopy. Results: Two-way ANOVA indicated significant cortical softening and weight increase in AD mice compared to WT littermates, but no significant effects of IH on cortical stiffness and weight were detected. In addition, reduced myelin was apparent in AD (vs. WT), but no significant differences emerged in the cortex extracellular matrix components laminin and glycosaminoglycans when comparing baseline AD and WT mice. Conclusion: AD mutant mice exhibit reduced brain tissue stiffness following both normoxia and IH mimicking sleep apnea, and such differences are commensurate with increased edema and demyelination in AD.

JTD Keywords: Animal model, Atomic force microscopy, Brain mechanics, Cortex stiffness, Neurodegenerative disease


Garreta, E., González, F., Montserrat, N., (2018). Studying kidney disease using tissue and genome engineering in human pluripotent stem cells Nephron 138, 48-59

Kidney morphogenesis and patterning have been extensively studied in animal models such as the mouse and zebrafish. These seminal studies have been key to define the molecular mechanisms underlying this complex multistep process. Based on this knowledge, the last 3 years have witnessed the development of a cohort of protocols allowing efficient differentiation of human pluripotent stem cells (hPSCs) towards defined kidney progenitor populations using two-dimensional (2D) culture systems or through generating organoids. Kidney organoids are three-dimensional (3D) kidney-like tissues, which are able to partially recapitulate kidney structure and function in vitro. The current possibility to combine state-of-the art tissue engineering with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated systems 9 (Cas9)-mediated genome engineering provides an unprecedented opportunity for studying kidney disease with hPSCs. Recently, hPSCs with genetic mutations introduced through CRISPR/Cas9-mediated genome engineering have shown to produce kidney organoids able to recapitulate phenotypes of polycystic kidney disease and glomerulopathies. This mini review provides an overview of the most recent advances in differentiation of hPSCs into kidney lineages, and the latest implementation of the CRISPR/Cas9 technology in the organoid setting, as promising platforms to study human kidney development and disease.

JTD Keywords: Clustered regularly interspaced short palindromic repeats/CRISPR-associated systems 9, Disease modeling, Gene editing, Human pluripotent stem cells, Kidney genetics, Tissue engineering


Valls-Comamala, V., Guivernau, B., Bonet, J., Puig, M., Perálvarez-Marín, A., Palomer, E., Fernàndez-Busquets, X., Altafaj, X., Tajes, M., Puig-Pijoan, A., Vicente, R., Oliva, B., Muñoz, F. J., (2017). The antigen-binding fragment of human gamma immunoglobulin prevents amyloid β-peptide folding into β-sheet to form oligomers Oncotarget 8, (25), 41154-41165

The amyloid beta-peptide (Aβ) plays a leading role in Alzheimer’s disease (AD) physiopathology. Even though monomeric forms of Aβ are harmless to cells, Aβ can aggregate into β-sheet oligomers and fibrils, which are both neurotoxic. Therefore, one of the main therapeutic approaches to cure or delay AD onset and progression is targeting Aβ aggregation. In the present study, we show that a pool of human gamma immunoglobulins (IgG) protected cortical neurons from the challenge with Aβ oligomers, as assayed by MTT reduction, caspase-3 activation and cytoskeleton integrity. In addition, we report the inhibitory effect of IgG on Aβ aggregation, as shown by Thioflavin T assay, size exclusion chromatography and atomic force microscopy. Similar results were obtained with Palivizumab, a human anti-sincitial virus antibody. In order to dissect the important domains, we cleaved the pool of human IgG with papain to obtain Fab and Fc fragments. Using these cleaved fragments, we functionally identified Fab as the immunoglobulin fragment inhibiting Aβ aggregation, a result that was further confirmed by an in silico structural model. Interestingly, bioinformatic tools show a highly conserved structure able to bind amyloid in the Fab region. Overall, our data strongly support the inhibitory effect of human IgG on Aβ aggregation and its neuroprotective role.

JTD Keywords: Alzheimer’s disease, Amyloid, Immunoglobulin, Fab, Oligomers


Mata, Agata, Urrea, Laura, Vilches, Silvia, Llorens, Franc, Thüne, Katrin, Espinosa, Juan-Carlos, Andréoletti, Olivier, Sevillano, Alejandro M., Torres, Juan María, Requena, Jesús Rodríguez, Zerr, Inga, Ferrer, Isidro, Gavín, Rosalina, del Río, José Antonio, (2017). Reelin expression in Creutzfeldt-Jakob disease and experimental models of transmissible spongiform encephalopathies Molecular Neurobiology 54, (8), 6412-6425

Reelin is an extracellular glycoprotein involved in key cellular processes in developing and adult nervous system, including regulation of neuronal migration, synapse formation, and plasticity. Most of these roles are mediated by the intracellular phosphorylation of disabled-1 (Dab1), an intracellular adaptor molecule, in turn mediated by binding Reelin to its receptors. Altered expression and glycosylation patterns of Reelin in cerebrospinal and cortical extracts have been reported in Alzheimer’s disease. However, putative changes in Reelin are not described in natural prionopathies or experimental models of prion infection or toxicity. With this is mind, in the present study, we determined that Reelin protein and mRNA levels increased in CJD human samples and in mouse models of human prion disease in contrast to murine models of prion infection. However, changes in Reelin expression appeared only at late terminal stages of the disease, which prevent their use as an efficient diagnostic biomarker. In addition, increased Reelin in CJD and in in vitro models does not correlate with Dab1 phosphorylation, indicating failure in its intracellular signaling. Overall, these findings widen our understanding of the putative changes of Reelin in neurodegeneration.

JTD Keywords: Reelin, Creutzfeldt-Jakob disease, Dab-1, Cellular prion protein


Garcia-Esparcia, Paula, López-González, Irene, Grau-Rivera, Oriol, García-Garrido, María Francisca, Konetti, Anusha, Llorens, Franc, Zafar, Saima, Carmona, Margarita, del Rio, José Antonio, Zerr, Inga, Gelpi, Ellen, Ferrer, Isidro, (2017). Dementia with Lewy Bodies: Molecular pathology in the frontal cortex in typical and rapidly progressive forms Frontiers in Neurology 8, Article 89

Objectives: The goal of this study was to assess mitochondrial function, energy, and purine metabolism, protein synthesis machinery from the nucleolus to the ribosome, inflammation, and expression of newly identified ectopic olfactory receptors (ORs) and taste receptors (TASRs) in the frontal cortex of typical cases of dementia with Lewy bodies (DLB) and cases with rapid clinical course (rpDLB: 2 years or less) compared with middle-aged non-affected individuals, in order to learn about the biochemical abnormalities underlying Lewy body pathology. Methods: Real-time quantitative PCR, mitochondrial enzymatic assays, and analysis of β-amyloid, tau, and synuclein species were used. Results: The main alterations in DLB and rpDLB, which are more marked in the rapidly progressive forms, include (i) deregulated expression of several mRNAs and proteins of mitochondrial subunits, and reduced activity of complexes I, II, III, and IV of the mitochondrial respiratory chain; (ii) reduced expression of selected molecules involved in energy metabolism and increased expression of enzymes involved in purine metabolism; (iii) abnormal expression of nucleolar proteins, rRNA18S, genes encoding ribosomal proteins, and initiation factors of the transcription at the ribosome; (iv) discrete inflammation; and (v) marked deregulation of brain ORs and TASRs, respectively. Severe mitochondrial dysfunction involving activity of four complexes, minimal inflammatory responses, and dramatic altered expression of ORs and TASRs discriminate DLB from Alzheimer’s disease. Altered solubility and aggregation of α-synuclein, increased β-amyloid bound to membranes, and absence of soluble tau oligomers are common in DLB and rpDLB. Low levels of soluble β-amyloid are found in DLB. However, increased soluble β-amyloid 1–40 and β-amyloid 1–42, and increased TNFα mRNA and protein expression, distinguish rpDLB. Conclusion: Molecular alterations in frontal cortex in DLB involve key biochemical pathways such as mitochondria and energy metabolism, protein synthesis, purine metabolism, among others and are accompanied by discrete innate inflammatory response.

JTD Keywords: Dementia with Lewy bodies, Alzheimer’s disease, α-synuclein, Mitochondria, Protein synthesis, Inflammation, β-amyloid, Olfactory receptors


Urrea, Laura, Ferrer, Isidro, Gavín, Rosalina, del Río, José Antonio, (2017). The cellular prion protein (PrPC) as neuronal receptor for α-synuclein Prion , 11, (4), 226-233

The term ‘prion-like’ is used to define some misfolded protein species that propagate intercellularly, triggering protein aggregation in recipient cells. For cell binding, both direct plasma membrane interaction and membrane receptors have been described for particular amyloids. In this respect, emerging evidence demonstrates that several β-sheet enriched proteins can bind to the cellular prion protein (PrPC). Among other interactions, the physiological relevance of the binding between β-amyloid and PrPC has been a relevant focus of numerous studies. At the molecular level, published data point to the second charged cluster domain of the PrPC molecule as the relevant binding domain of the β-amyloid/PrPC interaction. In addition to β-amyloid, participation of PrPC in binding α-synuclein, responsible for neurodegenerative synucleopathies, has been reported. Although results indicate relevant participation of PrPC in the spreading of α-synuclein in living mice, the physiological relevance of the interaction remains elusive. In this comment, we focus our attention on summarizing current knowledge of PrPC as a receptor for amyloid proteins and its physiological significance, with particular focus on α-synuclein.

JTD Keywords: α-synuclein, Charged cluster domain, Interneuronal transport, LAG3, Neurodegeneration, PrPC, Parkinson disease


Garreta, Elena, Marco, Andrés, Eguizábal, Cristina, Tarantino, Carolina, Samitier, Mireia, Badiola, Maider, Gutiérrez, Joaquín, Samitier, Josep, Montserrat, Nuria, (2017). Pluripotent stem cells and skeletal muscle differentiation: Challenges and immediate applications The Plasticity of Skeletal Muscle: From Molecular Mechanism to Clinical Applications (ed. Sakuma, Kunihiro), Springer Singapore (Singapore, Singapore) 2018, 1-35

Recent advances in the generation of skeletal muscle derivatives from pluripotent stem cells (PSCs) provide innovative tools for muscle development, disease modeling, and cell replacement therapies. Here, we revise major relevant findings that have contributed to these advances in the field, by the revision of how early findings using mouse embryonic stem cells (ESCs) set the bases for the derivation of skeletal muscle cells from human pluripotent stem cells (hPSCs) and patient-derived human-induced pluripotent stem cells (hiPSCs) to the use of genome editing platforms allowing for disease modeling in the petri dish.

JTD Keywords: Pluripotent stem cells, Differentiation, Genome editing, Disease modeling


Giannotti, M. I., Abasolo, Ibane, Oliva, Mireia, Andrade, Fernanda, García-Aranda, Natalia, Melgarejo, Marta, Pulido, Daniel, Corchero, José Luis, Fernández, Yolanda, Villaverde, Antonio, Royo, Miriam, Garcia-Parajo, Maria F., Sanz, Fausto, Schwartz Jr, Simó, (2016). Highly versatile polyelectrolyte complexes for improving the enzyme replacement therapy of lysosomal storage disorders ACS Applied Materials & Interfaces 8, (39), 25741–25752

Lysosomal storage disorders are currently treated by enzyme replacement therapy (ERT) through the direct administration of the unprotected recombinant protein to the patients. Herein we present an ionically cross-linked polyelectrolyte complex (PEC) composed of trimethyl chitosan (TMC) and α-galactosidase A (GLA), the defective enzyme in Fabry disease, with the capability of directly targeting endothelial cells by incorporating peptide ligands containing the RGD sequence. We assessed the physicochemical properties, cytotoxicity, and hemocompatibility of RGD-targeted and untargeted PECs, the uptake by endothelial cells and the intracellular activity of PECs in cell culture models of Fabry disease. Moreover, we also explored the effect of different freeze-drying procedures in the overall activity of the PECs. Our results indicate that the use of integrin-binding RGD moiety within the PEC increases their uptake and the efficacy of the GLA enzyme, while the freeze-drying allows the activity of the therapeutic protein to remain intact. Overall, these results highlight the potential of TMC-based PECs as a highly versatile and feasible drug delivery system for improving the ERT of lysosomal storage disorders.

JTD Keywords: Enzyme replacement therapy, Fabry disease, Lysosomal delivery, Nanomedicine, Polyelectrolyte complexes, Trimethyl chitosan, α-galactosidase A


Montserrat, N., Garreta, E., Izpisua Belmonte, J. C., (2016). Regenerative strategies for kidney engineering FEBS Journal , 283, (18), 3303-3324

The kidney is the most important organ for water homeostasis and waste excretion. It performs several important physiological functions for homeostasis: it filters the metabolic waste out of circulation, regulates body fluid balances, and acts as an immune regulator and modulator of cardiovascular physiology. The development of in vitro renal disease models with pluripotent stem cells (both human embryonic stem cells and induced pluripotent stem cells) and the generation of robust protocols for in vitro derivation of renal-specific-like cells from patient induced pluripotent stem cells have just emerged. Here we review major findings in the field of kidney regeneration with a major focus on the development of stepwise protocols for kidney cell production from human pluripotent stem cells and the latest advances in kidney bioengineering (i.e. decellularized kidney scaffolds and bioprinting). The possibility of generating renal-like three-dimensional structures to be recellularized with renal-derived induced pluripotent stem cells may offer new avenues to develop functional kidney grafts on-demand.

JTD Keywords: Induced pluripotent stem cells, Kidney disease, Kidney engineering, Pluripotent stem cells, Renal differentiation


Ansoleaga, B., Garcia-Esparcia, Paula, Llorens, Franc, Hernández-Ortega, Karina, Carmona Tech, Margarita, Antonio del Rio, José, Zerr, Inga, Ferrer, Isidro, (2016). Altered mitochondria, protein synthesis machinery, and purine metabolism are molecular contributors to the pathogenesis of Creutzfeldt–Jakob disease Journal of Neuropathology & Experimental Neurology , 75, (8), 755-769

Neuron loss, synaptic decline, and spongiform change are the hallmarks of sporadic Creutzfeldt–Jakob disease (sCJD), and may be related to deficiencies in mitochondria, energy metabolism, and protein synthesis. To investigate these relationships, we determined the expression levels of genes encoding subunits of the 5 protein complexes of the electron transport chain, proteins involved in energy metabolism, nucleolar and ribosomal proteins, and enzymes of purine metabolism in frontal cortex samples from 15 cases of sCJD MM1 and age-matched controls. We also assessed the protein expression levels of subunits of the respiratory chain, initiation and elongation translation factors of protein synthesis, and localization of selected mitochondrial components. We identified marked, generalized alterations of mRNA and protein expression of most subunits of all 5 mitochondrial respiratory chain complexes in sCJD cases. Expression of molecules involved in protein synthesis and purine metabolism were also altered in sCJD. These findings point to altered mRNA and protein expression of components of mitochondria, protein synthesis machinery, and purine metabolism as components of the pathogenesis of CJD.

JTD Keywords: Creutzfeldt–Jakob disease, Electron transport chain, Mitochondria, Oxidative phosphorylation, Protein synthesis, Purine.


Lozano-Garcia, M., Fiz, J. A., Jané, R., (2016). Automatic differentiation of normal and continuous adventitious respiratory sounds using ensemble empirical mode decomposition and instantaneous frequency IEEE Journal of Biomedical and Health Informatics 20, (2), 486-497

Differentiating normal from adventitious respiratory sounds (RS) is a major challenge in the diagnosis of pulmonary diseases. Particularly, continuous adventitious sounds (CAS) are of clinical interest because they reflect the severity of certain diseases. This study presents a new classifier that automatically distinguishes normal sounds from CAS. It is based on the multi-scale analysis of instantaneous frequency (IF) and envelope (IE) calculated after ensemble empirical mode decomposition (EEMD). These techniques have two major advantages over previous techniques: high temporal resolution is achieved by calculating IF-IE and a priori knowledge of signal characteristics is not required for EEMD. The classifier is based on the fact that the IF dispersion of RS signals markedly decreases when CAS appear in respiratory cycles. Therefore, CAS were detected by using a moving window to calculate the dispersion of IF sequences. The study dataset contained 1494 RS segments extracted from 870 inspiratory cycles recorded from 30 patients with asthma. All cycles and their RS segments were previously classified as containing normal sounds or CAS by a highly experienced physician to obtain a gold standard classification. A support vector machine classifier was trained and tested using an iterative procedure in which the dataset was randomly divided into training (65%) and testing (35%) sets inside a loop. The SVM classifier was also tested on 4592 simulated CAS cycles. High total accuracy was obtained with both recorded (94.6% ± 0.3%) and simulated (92.8% ± 3.6%) signals. We conclude that the proposed method is promising for RS analysis and classification.

JTD Keywords: Diseases, Dispersion, Empirical mode decomposition, Feature extraction, Informatics, Support vector machines


Tahirbegi, I.B., Pardo, W.A., Alvira, M., Mir, M., Samitier, J., (2016). Amyloid Aβ 42, a promoter of magnetite nanoparticle formation in Alzheimer's disease Nanotechnology 27, (46), 465102

The accumulation of iron oxides - mainly magnetite - with amyloid peptide is a key process in the development of Alzheimer's disease (AD). However, the mechanism for biogeneration of magnetite inside the brain of someone with AD is still unclear. The iron-storing protein ferritin has been identified as the main magnetite-storing molecule. However, accumulations of magnetite in AD are not correlated with an increase in ferritin, leaving this question unresolved. Here we demonstrate the key role of amyloid peptide Aβ 42, one of the main hallmarks of AD, in the generation of magnetite nanoparticles in the absence of ferritin. The capacity of amyloid peptide to bind and concentrate iron hydroxides, the basis for the formation of magnetite, benefits the spontaneous synthesis of these nanoparticles, even under unfavorable conditions for their formation. Using scanning and transmission electron microscopy, electron energy loss spectroscopy and magnetic force microscopy we characterized the capacity of amyloid peptide Aβ 42 to promote magnetite formation.

JTD Keywords: Alzheimer disease (AD), amyloid peptide Ab42, magnetite nanoparticle, metallobiomolecule, iron oxide, neurodegenerative brain diseases


González, F., (2016). CRISPR/Cas9 genome editing in human pluripotent stem cells: Harnessing human genetics in a dish Developmental Dynamics , 245, (7), 788-806

Abstract: Because of their extraordinary differentiation potential, human pluripotent stem cells (hPSCs) can differentiate into virtually any cell type of the human body, providing a powerful platform not only for generating relevant cell types useful for cell replacement therapies, but also for modeling human development and disease. Expanding this potential, structures resembling human organs, termed organoids, have been recently obtained from hPSCs through tissue engineering. Organoids exhibit multiple cell types self-organizing into structures recapitulating in part the physiology and the cellular interactions observed in the organ in vivo, offering unprecedented opportunities for human disease modeling. To fulfill this promise, tissue engineering in hPSCs needs to be supported by robust and scalable genome editing technologies. With the advent of the CRISPR/Cas9 technology, manipulating the genome of hPSCs has now become an easy task, allowing modifying their genome with superior precision, speed, and throughput. Here we review current and potential applications of the CRISPR/Cas9 technology in hPSCs and how they contribute to establish hPSCs as a model of choice for studying human genetics.

JTD Keywords: CRISPR/Cas9, Disease modeling, Human genetics, Human pluripotent stem cells, Tissue and genome engineering


Paoli, R., Samitier, J., (2016). Mimicking the kidney: A key role in organ-on-chip development Micromachines , 7, (7), 126

Pharmaceutical drug screening and research into diseases call for significant improvement in the effectiveness of current in vitro models. Better models would reduce the likelihood of costly failures at later drug development stages, while limiting or possibly even avoiding the use of animal models. In this regard, promising advances have recently been made by the so-called "organ-on-chip" (OOC) technology. By combining cell culture with microfluidics, biomedical researchers have started to develop microengineered models of the functional units of human organs. With the capacity to mimic physiological microenvironments and vascular perfusion, OOC devices allow the reproduction of tissue- and organ-level functions. When considering drug testing, nephrotoxicity is a major cause of attrition during pre-clinical, clinical, and post-approval stages. Renal toxicity accounts for 19% of total dropouts during phase III drug evaluation-more than half the drugs abandoned because of safety concerns. Mimicking the functional unit of the kidney, namely the nephron, is therefore a crucial objective. Here we provide an extensive review of the studies focused on the development of a nephron-on-chip device.

JTD Keywords: Disease model, Drug discovery, Kidney, Nephron-on-chip, Organ-on-chip


Vergara, C., Ordóñez-Gutiérrez, L., Wandosell, F., Ferrer, Isidro, del Río, J. A., Gavín, R., (2015). Role of PrPC expression in tau protein levels and phosphorylation in alzheimer's disease evolution Molecular Neurobiology 51, (3), 1206-1220

Alzheimer's disease (AD) is characterized by the presence of amyloid plaques mainly consisting of hydrophobic β-amyloid peptide (Aβ) aggregates and neurofibrillary tangles (NFTs) composed principally of hyperphosphorylated tau. Aβ oligomers have been described as the earliest effectors to negatively affect synaptic structure and plasticity in the affected brains, and cellular prion protein (PrPC) has been proposed as receptor for these oligomers. The most widely accepted theory holds that the toxic effects of Aβ are upstream of change in tau, a neuronal microtubule-associated protein that promotes the polymerization and stabilization of microtubules. However, tau is considered decisive for the progression of neurodegeneration, and, indeed, tau pathology correlates well with clinical symptoms such as dementia. Different pathways can lead to abnormal phosphorylation, and, as a consequence, tau aggregates into paired helical filaments (PHF) and later on into NFTs. Reported data suggest a regulatory tendency of PrPC expression in the development of AD, and a putative relationship between PrPC and tau processing is emerging. However, the role of tau/PrPC interaction in AD is poorly understood. In this study, we show increased susceptibility to Aβ-derived diffusible ligands (ADDLs) in neuronal primary cultures from PrPC knockout mice, compared to wild-type, which correlates with increased tau expression. Moreover, we found increased PrPC expression that paralleled with tau at early ages in an AD murine model and in early Braak stages of AD in affected individuals. Taken together, these results suggest a protective role for PrPC in AD by downregulating tau expression, and they point to this protein as being crucial in the molecular events that lead to neurodegeneration in AD.

JTD Keywords: Aβ oligomers, Alzheimer's disease, Cellular prion protein, Microtubule-associated protein tau


Llorens, Franc, Zafar, Saima, Ansoleaga, Belén, Shafiq, Mohsin, Blanco, Rosi, Carmona, Marga, Grau-Rivera, Oriol, Nos, Carlos, Gelpí, Ellen, del Río, José Antonio, Zerr, Inga, Ferrer, Isidre, (2015). Subtype and regional regulation of prion biomarkers in sporadic Creutzfeldt-Jakob disease Neuropathology and Applied Neurobiology , 41, (5), 631-645

Aims Creutzfeldt-Jakob disease (CJD) is a rapid progressive neurological disease leading to dementia and death. Prion biomarkers are altered in the cerebrospinal fluid (CSF) of CJD patients, but the pathogenic mechanisms underlying these alterations are still unknown. The present study examined prion biomarker levels in the brain and CSF of sporadic CJD (sCJD) cases and their correlation with neuropathological lesion profiles. Methods The expression levels of 14-3-3, Tau, phospho-Tau and α-synuclein were measured in the CSF and brain of sCJD cases in a subtype- and region-specific manner. In addition, the activity of prion biomarker kinases, the expression levels of CJD hallmarks and the most frequent neuropathological sCJD findings were analysed. Results Prion biomarkers levels were increased in the CSF of sCJD patients; however, correlations between mRNA, total protein and their phosphorylated forms in brain were different. The observed downregulation of the main Tau kinase, GSK3, in sCJD brain samples may help to explain the differential phospho-Tau/Tau ratios between sCJD and other dementias in the CSF. Importantly, CSF biomarkers levels do not necessarily correlate with sCJD neuropathological findings. Interpretation Present findings indicate that prion biomarkers levels in sCJD tissues and their release into the CSF are differentially regulated following specific modulated responses, and suggest a functional role for these proteins in sCJD pathogenesis.

JTD Keywords: Creutzfeldt-Jakob disease, Prion Protein, Cerebrospinal fluid, Prion Biomarkers, disease subtype, Glycogen synthase kinase 3


de Oñate, L., Garreta, E., Tarantino, C., Martínez, Elena, Capilla, E., Navarro, I., Gutiérrez, J., Samitier, J., Campistol, J.M., Muñoz-Cánovas, P., Montserrat, N., (2015). Research on skeletal muscle diseases using pluripotent stem cells Muscle Cell and Tissue (ed. Sakuma, K.), InTech (Rijeka, Croatia) , 333-357

The generation of induced pluripotent stem cells (iPSCs), especially the generation of patient-derived pluripotent stem cells (PSCs) suitable for disease modelling in vitro, opens the door for the potential translation of stem-cell related studies into the clinic. Successful replacement, or augmentation, of the function of damaged cells by patient-derived differentiated stem cells would provide a novel cell-based therapy for skeletal muscle-related diseases. Since iPSCs resemble human embryonic stem cells (hESCs) in their ability to generate cells of the three germ layers, patient-specific iPSCs offer definitive solutions for the ethical and histo-incompatibility issues related to hESCs. Indeed human iPSC (hiPSC)-based autologous transplantation is heralded as the future of regenerative medicine. Interestingly, during the last years intense research has been published on disease-specific hiPSCs derivation and differentiation into relevant tissues/organs providing a unique scenario for modelling disease progression, to screen patient-specific drugs and enabling immunosupression-free cell replacement therapies. Here, we revise the most relevant findings in skeletal muscle differentiation using mouse and human PSCs. Finally and in an effort to bring iPSC technology to the daily routine of the laboratory, we provide two different protocols for the generation of patient-derived iPSCs.

JTD Keywords: Pluripotent stem cells, Myogenic differentiation, Disease modelling, Patient-specific induced pluripotent stem cells, Muscular dystrophy


Ramos-Fernández, E., Tajes, M., Palomer, E., Ill-Raga, G., Bosch-Morató, M., Guivernau, B., Román-Dégano, I., Eraso-Pichot, A., Alcolea, D., Fortea, J., Nuñez, L., Paez, A., Alameda, F., Fernàndez-Busquets, X., Lleó, A., Elosúa, R., Boada, M., Valverde, M. A., Muñoz, F. J., (2014). Posttranslational nitro-glycative modifications of albumin in Alzheimer's disease: Implications in cytotoxicity and amyloid-β peptide aggregation Journal of Alzheimer's Disease , 40, (3), 643-657

Glycation and nitrotyrosination are pathological posttranslational modifications that make proteins prone to losing their physiological properties. Since both modifications are increased in Alzheimer's disease (AD) due to amyloid-β peptide (Aβ) accumulation, we have studied their effect on albumin, the most abundant protein in cerebrospinal fluid and blood. Brain and plasmatic levels of glycated and nitrated albumin were significantly higher in AD patients than in controls. In vitro turbidometry and electron microscopy analyses demonstrated that glycation and nitrotyrosination promote changes in albumin structure and biochemical properties. Glycated albumin was more resistant to proteolysis and less uptake by hepatoma cells occurred. Glycated albumin also reduced the osmolarity expected for a solution containing native albumin. Both glycation and nitrotyrosination turned albumin cytotoxic in a cell type-dependent manner for cerebral and vascular cells. Finally, of particular relevance to AD, these modified albumins were significantly less effective in avoiding Aβ aggregation than native albumin. In summary, nitrotyrosination and especially glycation alter albumin structural and biochemical properties, and these modifications might contribute for the progression of AD.

JTD Keywords: Albumin, Alzheimer's disease, amyloid, glycation, nitrotyrosination, oxidative stress


Tellez, J. P., Herrera, S., Benito, S., Giraldo, B. F., (2014). Analysis of the breathing pattern in elderly patients using the hurst exponent applied to the respiratory flow signal Engineering in Medicine and Biology Society (EMBC) 36th Annual International Conference of the IEEE , IEEE (Chicago, USA) , 3422-3425

Due to the increasing elderly population and the extensive number of comorbidities that affect them, studies are required to determine future increments in admission to emergency departments. Some of these studies could focus on the relation between chronic diseases and breathing pattern in elderly patients. Variations in the fractal properties of respiratory signals can be associated with several diseases. To determine the relationship between these variations and breathing patterns, and to quantify the fractal properties of respiratory flow signals, we estimated the Hurst exponent (H). Detrended fluctuation analysis (DFA) and discrete wavelet transform-based estimation (DWTE) methods were applied. The estimation methods were analyzed using simulated data series generated by fractional Gaussian noise. 43 elderly patients (19 patients with a non-periodic breathing pattern - nPB, and 24 patients with a periodic breathing pattern - PB) were studied. The results were evaluated according to the length of data and the number of averaged data series used to obtain a good estimation. The DWTE method estimated the respiratory flow signals better than the DFA method, and obtained Hurst values clustered by group. We found significant differences in the H exponent (p = 0.002) between PB and nPB patients, which showed different behavior in the fractal properties.

JTD Keywords: Discrete wavelet transforms, Diseases, Estimation, Fractals, Modulation, Senior citizens, Time series analysis


Estrada, Luis, Torres, Abel, Sarlabous, Leonardo, Fiz, Jose A., Gea, Joaquim, Martinez-Llorens, Juana, Jané, Raimon, (2014). Estimation of bilateral asynchrony between diaphragm mechanomyographic signals in patients with Chronic Obstructive Pulmonary Disease Engineering in Medicine and Biology Society (EMBC) 36th Annual International Conference of the IEEE , IEEE (Chicago, USA) , 3813-3816

The aim of the present study was to measure bilateral asynchrony in patients suffering from Chronic Obstructive Pulmonary Disease (COPD) performing an incremental inspiratory load protocol. Bilateral asynchrony was estimated by the comparison of respiratory movements derived from diaphragm mechanomyographic (MMGdi) signals, acquired by means of capacitive accelerometers placed on left and right sides of the rib cage. Three methods were considered for asynchrony evaluation: Lissajous figure, Hilbert transform and Motto's algorithm. Bilateral asynchrony showed an increase at 20, 40 and 60% (values of normalized inspiratory pressure by their maximum value reached in the last inspiratory load) while the very severe group showed and increase at 20, 40, 80, and 100 % during the protocol. These increments in the phase's shift can be due to an increase of the inspiratory load along the protocol, and also as a consequence of distress and fatigue. In summary, this work evidenced the capability to estimate bilateral asynchrony in COPD patients. These preliminary results also showed that the use of capacitive accelerometers can be a suitable sensor for recording of respiratory movement and evaluation of asynchrony in COPD patients.

JTD Keywords: Accelerometers, Diseases, Estimation, Fatigue, IP networks, Protocols, Transforms


Correa, L.S., Giraldo, B., Correa, R., Arini, P.D., Laciar, E., (2014). Estudio de la pausa espiratoria en pacientes con enfermedades obstructivas en proceso de desconexión de la ventilación mecánica IFMBE Proceedings VI Latin American Congress on Biomedical Engineering (CLAIB 2014) , Springer (Paraná, Argentina) 49, 705-708

In this work, the flow signal Expiratory Pause (EP) temporal analysis is used in 18 patients with obstructive lung diseases going through spontaneous breathing trial at weaning process. The main objective was to identify the patients who were successfully disconnected (success group: 9 patients), and those who were not (failure and reintubated group: 9 patients). A variable selection stage was done by mean group comparison and step wise variable inclusion, leading to a 3 parameters set: EP time median; cycle time mean; and median absolute deviation of the EP maxima local number. Next, this set was used in a classifier based on linear discriminant analysis, which results in 17 patients (94.4%) correctly classified, with 88.9% of specificity (Sp) and 100% of sensitivity (Se). Finally, applying the leave-one-out cross validation method, results were 88.9% of correctly classified patients (Sp=77.8% and Se=100%). In conclusion, the proposed parameters showed a good performance and could be used to help therapists to wean patients with obstructive diseases.

JTD Keywords: Chronic Obstructive Pulmonary Disease (COPD), Weaning, Mechanical ventilation, Expiratory pause


Pérez-Amodio, Soledad, Engel, Elisabeth, (2014). Bone biology and Regeneration Bio-Ceramics with Clinical Applications (ed. Vallet-Regí, M.), John Wiley & Sons, Ltd (Chichester, UK) , 315-342

Each bone of the skeleton constantly undergoes modeling during life to help it to adapt to changing biomechanical forces as well as remodeling to remove old bone and replace it with new, mechanically stronger bone to help preserve bone strength. Bone remodeling involves the removal of mineralized bone by osteoclasts, followed by the formation of bone matrix through the osteoblasts that subsequently become mineralized. All these assets make bone a suitable model for regeneration. Bone tissue can be grossly divided into inorganic mineral material (mostly HA), and organic material from cells and the extracellular matrix. This chapter outlines some of the bone diseases such as osteoporosis and Paget's disease. Bone can be considered as a biphasic composite material, with two phases: one the mineral and the other collagen. This combination confers better mechanical properties on the tissue than each component itself.

JTD Keywords: Bone biology, Bone cells, Bone diseases, Bone extracellular matrix, Bone mechanics, Bone remodeling, Bone tissue regeneration, Skeleton


Sánchez-Danes, A., Benzoni, P., Memo, M., Dell'Era, P., Raya, A., Consiglio, A., (2013). Induced pluripotent stem cell-based studies of Parkinson's disease: Challenges and promises CNS and Neurological Disorders - Drug Targets , 12, (8), 1114-1127

A critical step in the development of effective therapeutics to treat Parkinson's disease (PD) is the identification of molecular pathogenic mechanisms underlying this chronically progressive neurodegenerative disease. However, while animal models have provided valuable information about the molecular basis of PD, the lack of faithful cellular and animal models that recapitulate human pathophysiology is delaying the development of new therapeutics. The reprogramming of somatic cells to induced pluripotent stem cells (iPSC) using delivery of defined combinations of transcription factors is a groundbreaking discovery that opens great opportunities for modeling human diseases, including PD, since iPSC can be generated from patients and differentiated into disease-relevant cell types, which would capture the patients' genetic complexity. Furthermore, human iPSC-derived neuronal models offer unprecedented access to early stages of the disease, allowing the investigation of the events that initiate the pathologic process in PD. Recently, human iPSC-derived neurons from patients with familial and sporadic PD have been generated and importantly they recapitulate some PD-related cell phenotypes, including abnormal α-synuclein accumulation in vitro, and alterations in the autophagy machinery. This review highlights the current PD iPSC-based models and discusses the potential future research directions of this field.

JTD Keywords: Human cellular model, Induced pluripotent stem cells, Neurodegenerative disease, Parkinson's disease


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


Arcentales, A., Voss, A., Caminal, P., Bayes-Genis, A., Domingo, M. T., Giraldo, B. F., (2013). Characterization of patients with different ventricular ejection fractions using blood pressure signal analysis CinC 2013 Computing in Cardiology Conference (CinC) , IEEE (Zaragoza, Spain) , 795-798

Ischemic and dilated cardiomyopathy are associated with disorders of myocardium. Using the blood pressure (BP) signal and the values of the ventricular ejection fraction, we obtained parameters for stratifying cardiomyopathy patients as low- and high-risk. We studied 48 cardiomyopathy patients characterized by NYHA ≥2: 19 patients with dilated cardiomyopathy (DCM) and 29 patients with ischemic cardiomyopathy (ICM). The left ventricular ejection fraction (LVEF) percentage was used to classify patients in low risk (LR: LVEF > 35%, 17 patients) and high risk (HR: LVEF ≤ 35%, 31 patients) groups. From the BP signal, we extracted the upward systolic slope (BPsl), the difference between systolic and diastolic BP (BPA), and systolic time intervals (STI). When we compared the LR and HR groups in the time domain analysis, the best parameters were standard deviation (SD) of 1=STI, kurtosis (K) of BPsl, and K of BPA. In the frequency domain analysis, very low frequency (VLF) and high frequency (HF) bands showed statistically significant differences in comaprisons of LR and HR groups. The area under the curve of power spectral density was the best parameter in all classifications, and particularly in the very-low-and high- frequency bands (p <; 0.001). These parameters could help to improve the risk stratification of cardiomyopathy patients.

JTD Keywords: blood pressure measurement, cardiovascular system, diseases, medical disorders, medical signal processing, statistical analysis, time-domain analysis, BP signal, HR groups, LR groups, blood pressure signal analysis, cardiomyopathy patients, diastolic BP, dilated cardiomyopathy, frequency domain analysis, high-frequency bands, ischemic cardiomyopathy, left ventricular ejection fraction, low-frequency bands, myocardium disorders, patient characterization, power spectral density curve, standard deviation, statistical significant differences, systolic BP, systolic slope, systolic time intervals, time domain analysis, ventricular ejection fraction, Abstracts, Databases, Parameter extraction, Telecommunication standards, Time-frequency analysis


Hernando, D., Alcaine, A., Pueyo, E., Laguna, P., Orini, M., Arcentales, A., Giraldo, B., Voss, A., Bayes-Genis, A., Bailon, R., (2013). Influence of respiration in the very low frequency modulation of QRS slopes and heart rate variability in cardiomyopathy patients CinC 2013 Computing in Cardiology Conference (CinC) , IEEE (Zaragoza, Spain) , 117-120

This work investigates the very low frequency (VLF) modulation of QRS slopes and heart rate variability (HRV). Electrocardiogram (ECG) and respiratory flow signal were acquired from patients with dilated cardiomyopathy and ischemic cardiomyopathy. HRV as well as the upward QRS slope (IUS) and downward QRS slope (IDS) were extracted from the ECG. The relation between HRV and QRS slopes in the VLF band was measured using ordinary coherence in 5-minute segments. Partial coherence was then used to remove the influence that respiration simultaneously exerts on HRV and QRS slopes. A statistical threshold was determined, below which coherence values were considered not to represent a linear relation. 7 out of 276 segments belonging to 5 out of 29 patients for IUS and 10 segments belonging to 5 patients for IDS presented a VLF modulation in QRS slopes, HRV and respiration. In these segments spectral coherence was statistically significant, while partial coherence decreased, indicating that the coupling HRV and QRS slopes was related to respiration. 4 segments had a partial coherence value below the threshold for IUS, 3 segments for IDS. The rest of the segments also presented a notable decrease in partial coherence, but still above the threshold, which means that other non-linearly effects may also affect this modulation.

JTD Keywords: diseases, electrocardiography, feature extraction, medical signal processing, pneumodynamics, statistical analysis, ECG, QRS slopes, cardiomyopathy patients, dilated cardiomyopathy, electrocardiogram, feature extraction, heart rate variability, ischemic cardiomyopathy, ordinary coherence, partial coherence value, respiration, respiratory flow signal acquisition, spectral coherence, statistical threshold, time 5 min, very low frequency modulation, Coherence, Educational institutions, Electrocardiography, Frequency modulation, Heart rate variability


Giraldo, B. F., Tellez, J. P., Herrera, S., Benito, S., (2013). Study of the oscillatory breathing pattern in elderly patients Engineering in Medicine and Biology Society (EMBC) 35th Annual International Conference of the IEEE , IEEE (Osaka, Japan) , 5228-5231

Some of the most common clinical problems in elderly patients are related to diseases of the cardiac and respiratory systems. Elderly patients often have altered breathing patterns, such as periodic breathing (PB) and Cheyne-Stokes respiration (CSR), which may coincide with chronic heart failure. In this study, we used the envelope of the respiratory flow signal to characterize respiratory patterns in elderly patients. To study different breathing patterns in the same patient, the signals were segmented into windows of 5 min. In oscillatory breathing patterns, frequency and time-frequency parameters that characterize the discriminant band were evaluated to identify periodic and non-periodic breathing (PB and nPB). In order to evaluate the accuracy of this characterization, we used a feature selection process, followed by linear discriminant analysis. 22 elderly patients (7 patients with PB and 15 with nPB pattern) were studied. The following classification problems were analyzed: patients with either PB (with and without apnea) or nPB patterns, and patients with CSR versus PB, CSR versus nPB and PB versus nPB patterns. The results showed 81.8% accuracy in the comparisons of nPB and PB patients, using the power of the modulation peak. For the segmented signal, the power of the modulation peak, the frequency variability and the interquartile ranges provided the best results with 84.8% accuracy, for classifying nPB and PB patients.

JTD Keywords: cardiovascular system, diseases, feature extraction, geriatrics, medical signal processing, oscillations, pneumodynamics, signal classification, time-frequency analysis, Cheyne-Stokes respiration, apnea, cardiac systems, chronic heart failure, classification problems, discriminant band, diseases, elderly patients, feature selection process, frequency variability, interquartile ranges, linear discriminant analysis, nonperiodic breathing, oscillatory breathing pattern, periodic breathing, respiratory How signal, respiratory systems, signal segmentation, time 5 min, time-frequency parameters, Accuracy, Aging, Frequency modulation, Heart, Senior citizens, Time-frequency analysis


Sánchez-Danés, A., Richaud-Patin, Y., Carballo-Carbajal, I., Jiménez-Delgado, S., Caig, C., Mora, S., Di Guglielmo, C., Ezquerra, M., Patel, B., Giralt, A., Canals, J. M., Memo, M., Alberch, J., López-Barneo, J., Vila, M., Cuervo, A. M., Tolosa, E., Consiglio, A., Raya, A., (2012). Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease EMBO Molecular Medicine 4, (5), 380-395

Induced pluripotent stem cells (iPSC) offer an unprecedented opportunity to model human disease in relevant cell types, but it is unclear whether they could successfully model age-related diseases such as Parkinson's disease (PD). Here, we generated iPSC lines from seven patients with idiopathic PD (ID-PD), four patients with familial PD associated to the G2019S mutation in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene (LRRK2-PD) and four age- and sex-matched healthy individuals (Ctrl). Over long-time culture, dopaminergic neurons (DAn) differentiated from either ID-PD- or LRRK2-PD-iPSC showed morphological alterations, including reduced numbers of neurites and neurite arborization, as well as accumulation of autophagic vacuoles, which were not evident in DAn differentiated from Ctrl-iPSC. Further induction of autophagy and/or inhibition of lysosomal proteolysis greatly exacerbated the DAn morphological alterations, indicating autophagic compromise in DAn from ID-PD- and LRRK2-PD-iPSC, which we demonstrate occurs at the level of autophagosome clearance. Our study provides an iPSC-based in vitro model that captures the patients' genetic complexity and allows investigation of the pathogenesis of both sporadic and familial PD cases in a disease-relevant cell type.

JTD Keywords: Autophagy, Disease modeling, LRRK2 mutation, Neurodegeneration, Pluripotent stem cells


Mir, Mònica , Tahirbegi, Islam Bogachan , Valle-Delgado, Juan José , Fernàndez-Busquets, X., Samitier, Josep , (2012). In vitro study of magnetite-amyloid β complex formation Nanomedicine: Nanotechnology, Biology, and Medicine 8, (6), 974-980

Biogenic magnetite (Fe3O4) has been identified in human brain tissue. However, abnormal concentration of magnetite nanoparticles in the brain has been observed in different neurodegenerative pathologies. In the case of Alzheimer's disease (AD), these magnetic nanoparticles have been identified attached to the characteristic brain plaques, which are mainly formed by fibrils of amyloid β peptide (Aβ). However, few clues about the formation of the magnetite-Aβ complex have been reported. We have investigated the interaction between these important players in the AD with superconducting quantum interference, scanning electron microscope, surface plasmon resonance, and magnetic force microscopy. The results support the notion that the magnetite-Aβ complex is created before the synthesis of the magnetic nanoparticles, bringing a highly stable interaction of this couple.

JTD Keywords: Alzheimer's disease, Biogenic magnetite, Amyloid β peptide (Aβ), Superconducting quantum interference, Scanning electron microscope, Surface plasmon resonance, Magnetic force microscopy


McLenachan, S., Menchon, C., Raya, A., Consiglio, A., Edel, M. J., (2012). Cyclin A(1) is essential for setting the pluripotent state and reducing tumorigenicity of induced pluripotent stem cells Stem Cells and Development , 21, (15), 2891-2899

The proper differentiation and threat of cancer rising from the application of induced pluripotent stem (iPS) cells are major bottlenecks in the field and are thought to be inherently linked to the pluripotent nature of iPS cells. To address this question, we have compared iPS cells to embryonic stem cells (ESCs), the gold standard of ground state pluripotency, in search for proteins that may improve pluripotency of iPS cells. We have found that when reprogramming somatic cells toward pluripotency, 1%-5% of proteins of 5 important cell functions are not set to the correct expression levels compared to ESCs, including mainly cell cycle proteins. We have shown that resetting cyclin A1 protein expression of early- passage iPS cells closer to the ground state pluripotent state of mouse ESCs improves the pluripotency and reduces the threat of cancer of iPS cells. This work is a proof of principle that reveals that setting expression of certain proteins correctly during reprogramming is essential for achieving ESC- state pluripotency. This finding would be of immediate help to those researchers in different fields of iPS cell work that specializes in cell cycle, apoptosis, cell adhesion, cell signaling, and cytoskeleton.

JTD Keywords: Self-renewal, IPS cells, Ground-state, C-MYC, Generation, Pathway, Disease, Mice, Link, P53


Yue, J. J., Morgenstern, R., Morgenstern, C., Lauryssen, C., (2011). Shape memory hydrogels - A novel material for treating age-related degenerative conditions of the Spine European Musculoskeletal Review , 6, (3), 184-188

Hydrogels are water-insoluble hydrophilic polymers used in a wide range of medical products such as, drug delivery, tissue replacement, heart surgery, gynaecology, ophthalmology, plastic surgery and orthopaedic surgery. These polymers exhibit low toxicity, reduced tissue adherence, and are highly biocompatible. A class of hydrogels, hydrolysed polyacrylonitriles, possess unique shape memory properties, which, when combined with biodurability, mechanical strength and viscoelasticity make them ideal for treating certain degenerative conditions of the spine. Animal and other in vitro studies have shown that the hydrogel is biocompatible and well tolerated by host tissues. This article focuses on two specific indications in spine surgery that demonstrate the potential of hydrogel-based technology to provide significant treatment advantages.

JTD Keywords: Biocompatibility, Degenerative disc disease, Hydrolysed polyacrylonitrile, Minimally invasive surgery, Shape memory hydrogel, Spinal stenosis


Carreras, Alba, Wang, Yang, Gozal, David, Montserrat, Josep M., Navajas, Daniel, Farre, Ramon, (2011). Non-invasive system for applying airway obstructions to model obstructive sleep apnea in mice Respiratory Physiology & Neurobiology , 175, (1), 164-168

Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstructions during sleep. The most common animal model of OSA is based on subjecting rodents to intermittent hypoxic exposures and does not mimic important OSA features, such as recurrent hypercapnia and increased inspiratory efforts. To circumvent some of these issues, a novel murine model involving non-invasive application of recurrent airway obstructions was developed. An electronically controlled airbag system is placed in front of the mouse's snout, whereby inflating the airbag leads to obstructed breathing and spontaneous breathing occurs with the airbag deflated. The device was tested on 29 anesthetized mice by measuring inspiratory effort and arterial oxygen saturation (SaO(2)). Application of recurrent obstructive apneas (6s each, 120/h) for 6h resulted in SaO(2) oscillations to values reaching 84.4 +/- 2.5% nadir, with swings mimicking OSA patients. This novel system, capable of applying controlled recurrent airway obstructions in mice, is an easy-to-use tool for investigating pertinent aspects of OSA.

JTD Keywords: Animal model, Upper airway Obstruction, Mouse model, Non-invasive system, Model sleep apnea, Respiratory disease


Adrados, B., Julian, E., Codony, F., Torrents, E., Luquin, M., Morato, J., (2011). Prevalence and concentration of non-tuberculous Mycobacteria in cooling towers by means of quantitative PCR: A prospective study Current Microbiology , 62, (1), 313-319

There is an increasing level of interest in non-tuberculous mycobacteria (NTM) due to the increasing reported rates of diseases caused by them. Although it is well known that NTM are widely distributed in the environment it is necessary to identify its reservoirs to prevent possible infections. In this study, we aimed to investigate the occurrence and levels of NTM in cooling towers to provide evidences for considering these settings as possible sources of respiratory infections. In the current study, we detected and quantified the presence of NTM by means of a rapid method in water samples taken from 53 cooling towers of an urban area (Barcelona, Spain). A genus-specific quantitative PCR (Q-PCR) assay with a quantification limit (QL) of 500 cells l(-1) was used. 56% (30) of samples were positive with a concentration range from 4.6 x 10(3) to 1.79 x 10(6) cells l(-1). In some cases (9/30), samples were positive but with levels below the QL. The colonization rate confirmed that cooling towers could be considered as a potential reservoir for NTM. This study also evaluated Q-PCR as a useful method to detect and quantify NTM in samples coming from environmental sources.

JTD Keywords: Real-time PCR, Disease, Identification, Tuberculosis, Pathogens, Waters


Juanola-Feliu, E., Colomer-Farrarons, J., Miribel-Catala, P., Samitier, J., Valls-Pasola, J., (2011). Challenges facing academic research in commercializing event-detector implantable devices for an in-vivo biomedical subcutaneous device for biomedical analysis Proceedings of the SPIE - The International Society for Optical Engineering VLSI Circuits and Systems V (ed. -----), SPIE - The International Society for Optical Engineering, USA (Prague, Czech Republic) 8067, 80670P

It is widely recognized that the welfare of the most advanced economies is at risk, and that the only way to tackle this situation is by controlling the knowledge economies and dealing with. To achieve this ambitious goal, we need to improve the performance of each dimension in the "knowledge triangle": education, research and innovation. Indeed, recent findings point to the importance of strategies of adding-value and marketing during R+D processes so as to bridge the gap between the laboratory and the market and so ensure the successful commercialization of new technology-based products. Moreover, in a global economy in which conventional manufacturing is dominated by developing economies, the future of industry in the most advanced economies must rely on its ability to innovate in those high-tech activities that can offer a differential added-value, rather than on improving existing technologies and products. It seems quite clear, therefore, that the combination of health (medicine) and nanotechnology in a new biomedical device is very capable of meeting these requisites. This work propose a generic CMOS Front-End Self-Powered In-Vivo Implantable Biomedical Device, based on a threeelectrode amperometric biosensor approach, capable of detecting threshold values for targeted concentrations of pathogens, ions, oxygen concentration, etc. Given the speed with which diabetes can spread, as diabetes is the fastest growing disease in the world, the nano-enabled implantable device for in-vivo biomedical analysis needs to be introduced into the global diabetes care devices market. In the case of glucose monitoring, the detection of a threshold decrease in the glucose level it is mandatory to avoid critic situations like the hypoglycemia. Although the case study reported in this paper is complex because it involves multiple organizations and sources of data, it contributes to extend experience to the best practices and models on nanotechnology applications and commercialization.

JTD Keywords: Biomedical equipment, Diseases, Nanotechnology


Valle-Delgado, J. J., Alfonso-Prieto, M., de Groot, N. S., Ventura, S., Samitier, J., Rovira, C., Fernàndez-Busquets, X., (2010). Modulation of A beta(42) fibrillogenesis by glycosaminoglycan structure FASEB Journal , 24, (11), 4250-4261

The role of amyloid beta (A beta) peptide in the onset and progression of Alzheimer's disease is linked to the presence of soluble A beta species. Sulfated glycosaminoglycans (GAGs) promote A beta fibrillogenesis and reduce the toxicity of the peptide in neuronal cell cultures, but a satisfactory rationale to explain these effects at the molecular level has not been provided yet. We have used circular dichroism, Fourier transform infrared spectroscopy, fluorescence microscopy and spectroscopy, protease digestion, atomic force microscopy (AFM), and molecular dynamics simulations to characterize the association of the 42-residue fragment A beta(42) with sulfated GAGs, hyaluronan, chitosan, and poly(vinyl sulfate) (PVS). Our results indicate that the formation of stable A beta(42) fibrils is promoted by polymeric GAGs with negative charges placed in-frame with the 4.8-angstrom separating A beta(42) monomers within protofibrillar beta-sheets. Incubation of A beta(42) with excess sulfated GAGs and hyaluronan increased amyloid fibril content and resistance to proteolysis 2- to 5-fold, whereas in the presence of the cationic polysaccharide chitosan, A beta(42) fibrillar species were reduced by 25% and sensitivity to protease degradation increased similar to 3-fold. Fibrils of intermediate stability were obtained in the presence of PVS, an anionic polymer with more tightly packed charges than GAGs. Important structural differences between A beta(42) fibrils induced by PVS and A beta(42) fibrils obtained in the presence of GAGs and hyaluronan were observed by AFM, whereas mainly precursor protofibrillar forms were detected after incubation with chitosan. Computed binding energies per peptide from -11.2 to -13.5 kcal/mol were calculated for GAGs and PVS, whereas a significantly lower value of -7.4 kcal/mol was obtained for chitosan. Taken together, our data suggest a simple and straightforward mechanism to explain the role of GAGs as enhancers of the formation of insoluble A beta(42) fibrils trapping soluble toxic forms.

JTD Keywords: Alzheimer's disease, Amyloid fibril structure, Fibrillogenesis enhancers and inhibitors, Polysaccharides


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.

JTD 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


Gavín, R., Ferrer, Isidro, del Río, J. A., (2010). Involvement of Dab1 in APP processing and [beta]-amyloid deposition in sporadic Creutzfeldt-Jakob patients Neurobiology of Disease , 37, (2), 324-329

Alzheimer's disease and prion pathologies (e.g., Creutzfeldt-Jakob disease (CJD)) display profound neural lesions associated with aberrant protein processing and extracellular amyloid deposits. Dab1 has been implicated in the regulation of amyloid precursor protein (APP), but a direct link between human prion diseases and Dab1/APP interactions has not been published. Here we examined this putative relationship in 17 cases of sporadic CJD (sCJD) post-mortem. Biochemical analyses of brain tissue revealed two groups, which also correlated with PrPsc types 1 and 2. One group with PrPsc type 1 showed increased Dab1 phosphorylation and lower [beta]CTF production with an absence of A[beta] deposition. The second sCJD group, which carried PrPsc type 2, showed lower levels of Dab1 phosphorylation and [beta]CTF production, and A[beta] deposition. Thus, the present observations suggest a correlation between Dab1 phosphorylation, A[beta] deposition and PrPsc type in sCJD.

JTD Keywords: Prionopathies, Amyloid plaques, Alzheimer's disease, Dab1


Fernàndez-Busquets, X., Ponce, J., Bravo, R., Arimon, M., Martianez, T., Gella, A., Cladera, J., Durany, N., (2010). Modulation of amyloid beta peptide(1-42) cytotoxicity and aggregation in vitro by glucose and chondroitin sulfate Current Alzheimer Research , 7, (5), 428-438

One mechanism leading to neurodegeneration during Alzheimer's Disease (AD) is amyloid beta peptide (A beta)-induced neurotoxicity. Among the factors proposed to potentiate A beta toxicity is its covalent modification through carbohydrate-derived advanced glycation endproducts (AGEs). Other experimental evidence, though, indicates that certain polymeric carbohydrates like the glycosaminoglycan (GAG) chains found in proteoglycan molecules attenuate the neurotoxic effect of A beta in primary neuronal cultures. Pretreatment of the 42-residue A beta fragment (A beta(1-42)) with the ubiquitous brain carbohydrates, glucose, fructose, and the GAG chondroitin sulfate B (CSB) inhibits A beta beta(1-42)-induced apoptosis and reduces the peptide neurotoxicity on neuroblastoma cells, a cytoprotective effect that is partially reverted by AGE inhibitors such as pyridoxamine and L-carnosine. Thioflavin T fluorescence measurements indicate that at concentrations close to physiological, only CSB promotes the formation of A beta amyloid fibril structure. Atomic force microscopy imaging and Western blot analysis suggest that glucose favours the formation of globular oligomeric structures derived from aggregated species. Our data suggest that at short times carbohydrates reduce A beta(1-42) toxicity through different mechanisms both dependent and independent of AGE formation.

JTD Keywords: Alzheimer's disease, Advanced glycation endproducts, Amyloid fibrils, Amyloid beta peptide, Apoptosis, Carbohydrates, Glycosaminoglycans


Iranzo, A., Isetta, V., Molinuevo, J. L., Serradell, M., Navajas, D., Farre, R., Santamaria, J., (2010). Electroencephalographic slowing heralds mild cognitive impairment in idiopathic REM sleep behavior disorder Sleep Medicine , 11, (6), 534-539

Objective: Patients with idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD) may show electroencephalographic (EEG) slowing reflecting cortical dysfunction and are at risk for developing neurological conditions characterized by cognitive dysfunction including mild cognitive impairment (MCI), dementia with Lewy bodies and Parkinson's disease with associated dementia. We hypothesized that those IRBD patients who later developed MCI had pronounced cortical EEG slowing at presentation. Methods: Power EEG spectral analysis was blindly quantified from the polysomnographic studies of 23 IRBD patients without cognitive complaints and 10 healthy controls without RBD. After a mean clinical follow-up of 2.40 +/- 1.55 years, 10 patients developed MCI (RBD + MCI) and the remaining 13 remained idiopathic. Results: Patients with RBD + MCI had marked EEG slowing (increased delta and theta activity) in central and occipital regions during wakefulness and REM sleep, particularly in the right hemisphere, when compared with controls and, to a lesser extent, with IRBD subjects who remained idiopathic. The EEG spectral pattern of the RBD + MCI group was similar to that seen in patients with dementia with Lewy bodies and Parkinson's disease associated with dementia. Conclusion: Our findings suggest that the presence of marked EEG slowing on spectral analysis might be indicative of the short-term development of MCI in patients initially diagnosed with IRBD.

JTD Keywords: Idiopathic REM sleep behavior disorder, Power EEG spectral analysis, Mild cognitive impairment, REM sleep, Parkinson's disease, Dementia with Lewy bodies


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


Correa, R., Laciar, E., Arini, P., Jané, R., (2010). Analysis of QRS loop in the Vectorcardiogram of patients with Chagas' disease Engineering in Medicine and Biology Society (EMBC) 32nd Annual International Conference of the IEEE , IEEE (Buenos Aires, Argentina) , 2561-2564

In the present work, we have studied the QRS loop in the Vectorcardiogram (VCG) of 95 chronic chagasic patients classified in different groups (I, II and III) according to their degree of myocardial damage. For comparison, the VCGs of 11 healthy subjects used as control group (Group O) were also examined. The QRS loop was obtained for each patient from the XYZ orthogonal leads of their High-Resolution Electrocardiogram (HRECG) records. In order to analyze the variations of QRS loop in each detected beat, it has been proposed in this study the following vectorcardiographic parameters a) Maximum magnitude of the cardiac depolarization vector, b) Volume, c) Area of QRS loop, d) Ratio between the Area and Perimeter, e) Ratio between the major and minor axes of the QRS loop and f) QRS loop Energy. It has been found that one or more indexes exhibited statistical differences (p<0.05) between groups 0-II, O-III, I-II, I-III and II-III. We concluded that the proposed method could be use as complementary diagnosis technique to evaluate the degree of myocardial damage in chronic chagasic patients.

JTD Keywords: Practical, Experimental/ bioelectric phenomena, Diseases, Electrocardiography, Medical signal, Processing/ QRS loop, Vectorcardiogram, Cardiac depolarization vector, Myocardial damage, Chagas disease, Complementary diagnosis technique, High-resolution electrocardiogram


Garde, A., Sörnmo, L., Jané, R., Giraldo, B. F., (2010). Correntropy-based nonlinearity test applied to patients with chronic heart failure Engineering in Medicine and Biology Society (EMBC) 32nd Annual International Conference of the IEEE , IEEE (Buenos Aires, Argentina) , 2399-2402

In this study we propose the correntropy function as a discriminative measure for detecting nonlinearities in the respiratory pattern of chronic heart failure (CHF) patients with periodic or nonperiodic breathing pattern (PB or nPB, respectively). The complexity seems to be reduced in CHF patients with higher risk level. Correntropy reflects information on both, statistical distribution and temporal structure of the underlying dataset. It is a suitable measure due to its capability to preserve nonlinear information. The null hypothesis considered is that the analyzed data is generated by a Gaussian linear stochastic process. Correntropy is used in a statistical test to reject the null hypothesis through surrogate data methods. Various parameters, derived from the correntropy and correntropy spectral density (CSD) to characterize the respiratory pattern, presented no significant differences when extracted from the iteratively refined amplitude adjusted Fourier transform (IAAFT) surrogate data. The ratio between the powers in the modulation and respiratory frequency bands R was significantly different in nPB patients, but not in PB patients, which reflects a higher presence of nonlinearities in nPB patients than in PB patients.

JTD Keywords: Practical, Theoretical or Mathematical, Experimental/cardiology diseases, Fourier transforms, Medical signal processing, Pattern classification, Pneumodynamics, Spectral analysis, Statistical analysis, Stochastic processes/ correntropy based nonlinearity test, Chronic heart failure, Correntropy function, Respiratory pattern nonlinearities, CHF patients, Nonperiodic breathing pattern, Dataset statistical distribution, Dataset temporal structure, Nonlinear information, Null hypothesis, Gaussian linear stochastic process, Statistical test, Correntropy spectral density, Iteratively refined amplitude adjusted Fourier transform, Surrogate data, Periodic breathing pattern


Torres, A., Sarlabous, L., Fiz, j A., Gea, J., Marti nez-Llorens, J. M., Morera, J., Jané, R., (2010). Noninvasive measurement of inspiratory muscle performance by means of diaphragm muscle mechanomyographic signals in COPD patients during an incremental load respiratory test Engineering in Medicine and Biology Society (EMBC) 32nd Annual International Conference of the IEEE , IEEE (Buenos Aires, Argentina) , 2493-2496

The study of mechanomyographic (MMG) signals of respiratory muscles is a promising noninvasive technique in order to evaluate the respiratory muscular effort and efficiency. In this work, the MMG signal of the diaphragm muscle it is evaluated in order to assess the respiratory muscular function in Chronic Obstructive Pulmonary Disease (COPD) patients. The MMG signals from left and right hemidiaphragm were acquired using two capacitive accelerometers placed on both left and right sides of the costal wall surface. The MMG signals and the inspiratory pressure signal were acquired while the COPD patients carried out an inspiratory load respiratory test. The population of study is composed of a group of 6 patients with severe COPD (FEV1>50% ref and DLCO<50% ref). We have found high positive correlation coefficients between the maximum inspiratory pressure (IPmax) developed in a respiratory cycle and different amplitude parameters of both left and right MMG signals (RMS, left: 0.68+/-0.11 - right: 0.69+/-0.12; Re nyi entropy, left: - 0.73+/-0.10 - right: 0.77+/-0.08; Multistate Lempel-Ziv, left: 0.73+/-0.17 - right: 0.74+/-0.08), and negative correlation between the Pmax and the maximum frequency of the MMG signal spectrum (left: -0.39+/-0.19 - right: -0.65+/-0.09). Furthermore, we found that the slope of the evolution of the MMG amplitude parameters, as the load increases during the respiratory test, has positive correlation with the %FEV1/FVC pulmonary function test parameter of the six COPD patients analyzed (RMS, left: 0.38 - right: 0.41; Re nyi entropy, left: 0.45 - right: 0.63; Multistate Lempel-Ziv, left: 0.39 - right: 0.64). These results suggest that the information provided by MMG signals could be used in order to evaluate the respiratory effort and the muscular efficiency in COPD patients.

JTD Keywords: Accelerometers, Biomechanics, Biomedical measurement, Diseases, Medical signal processing, Muscle


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


Guix, F. X., Ill-Raga, G., Bravo, R., Nakaya, T., de Fabritiis, G., Coma, M., Miscione, G. P., Villa-Freixa, J., Suzuki, T., Fernàndez-Busquets, X., Valverde, M. A., de Strooper, B., Munoz, F. J., (2009). Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation Brain , 132, (5), 1335-1345

Alzheimer's disease neuropathology is characterized by neuronal death, amyloid beta-peptide deposits and neurofibrillary tangles composed of paired helical filaments of tau protein. Although crucial for our understanding of the pathogenesis of Alzheimer's disease, the molecular mechanisms linking amyloid beta-peptide and paired helical filaments remain unknown. Here, we show that amyloid beta-peptide-induced nitro-oxidative damage promotes the nitrotyrosination of the glycolytic enzyme triosephosphate isomerase in human neuroblastoma cells. Consequently, nitro-triosephosphate isomerase was found to be present in brain slides from double transgenic mice overexpressing human amyloid precursor protein and presenilin 1, and in Alzheimer's disease patients. Higher levels of nitro-triosephosphate isomerase (P < 0.05) were detected, by Western blot, in immunoprecipitates from hippocampus (9 individuals) and frontal cortex (13 individuals) of Alzheimer's disease patients, compared with healthy subjects (4 and 9 individuals, respectively). Triosephosphate isomerase nitrotyrosination decreases the glycolytic flow. Moreover, during its isomerase activity, it triggers the production of the highly neurotoxic methylglyoxal (n = 4; P < 0.05). The bioinformatics simulation of the nitration of tyrosines 164 and 208, close to the catalytic centre, fits with a reduced isomerase activity. Human embryonic kidney (HEK) cells overexpressing double mutant triosephosphate isomerase (Tyr164 and 208 by Phe164 and 208) showed high methylglyoxal production. This finding correlates with the widespread glycation immunostaining in Alzheimer's disease cortex and hippocampus from double transgenic mice overexpressing amyloid precursor protein and presenilin 1. Furthermore, nitro-triosephosphate isomerase formed large beta-sheet aggregates in vitro and in vivo, as demonstrated by turbidometric analysis and electron microscopy. Transmission electron microscopy (TEM) and atomic force microscopy studies have demonstrated that nitro-triosephosphate isomerase binds tau monomers and induces tau aggregation to form paired helical filaments, the characteristic intracellular hallmark of Alzheimer's disease brains. Our results link oxidative stress, the main etiopathogenic mechanism in sporadic Alzheimer's disease, via the production of peroxynitrite and nitrotyrosination of triosephosphate isomerase, to amyloid beta-peptide-induced toxicity and tau pathology.

JTD Keywords: Alzheimer's disease, Amyloid β-peptide, Tau protein, Triosephosphate isomerase, Peroxynitrite


Carreras, A., Almendros, I., Acerbi, I., Montserrat, J. M., Navajas, D., Farre, R., (2009). Obstructive apneas induce early release of mesenchymal stem cells into circulating blood Sleep , 32, (1), 117-119

STUDY OBJECTIVES: To investigate whether noninvasive application of recurrent airway obstructions induces early release of mesenchymal stem cells into the circulating blood in a rat model of obstructive sleep apnea. DESIGN: Prospective controlled animal study. SETTING: University laboratory. PATIENTS OR PARTICIPANTS: Twenty male Sprague-Dawley rats (250-300 g). INTERVENTIONS: A specially designed nasal mask was applied to the anesthetized rats. Ten rats were subjected to a pattern of recurrent obstructive apneas (60 per hour, lasting 15 seconds each) for 5 hours. Ten anesthetized rats were used as controls. MEASUREMENTS AND RESULTS: Mesenchymal stem cells from the blood and bone marrow samples were isolated and cultured to count the total number of colony-forming unit fibroblasts (CFU-F) of adherent cells after 9 days in culture. The number of CFU-F from circulating blood was significantly (P = 0.02) higher in the rats subjected to recurrent obstructive apneas (5.00 +/- 1.16; mean +/- SEM) than in controls (1.70 +/- 0.72). No significant (P = 0.54) differences were observed in CFU-F from bone marrow. CONCLUSIONS: Application of a pattern of airway obstructions similar to those experienced by patients with sleep apnea induced an early mobilization of mesenchymal stem cells into circulating blood.

JTD Keywords: Adipocytes/cytology, Animals, Blood Cell Count, Bone Marrow Cells/ cytology, Cell Adhesion/physiology, Cell Count, Cell Differentiation/physiology, Cell Division/physiology, Disease Models, Animal, Fibroblasts/cytology, Male, Mesenchymal Stem Cells/ cytology, Osteocytes/cytology, Rats, Rats, Sprague-Dawley, Sleep Apnea, Obstructive/ blood, Stem Cells/cytology


Puig, F., Gavara, N., Sunyer, R., Carreras, A., Farre, R., Navajas, D., (2009). Stiffening and contraction induced by dexamethasone in alveolar epithelial cells Experimental Mechanics , 49, (1), 47-55

The structural integrity of the alveolar monolayer, which is compromised during lung inflammation, is determined by the balance between cell-cell and cell-matrix tethering forces and the centripetal forces owing to cell viscoelasticity and contraction. Dexamethasone is an anti-inflammatory glucocorticoid with protective effects in lung injury. To determine the effects of Dexamethasone on the stiffness and contractility of alveolar epithelial cells. Cell stiffness (G') and average traction exerted by the cell (T) were measured by magnetic twisting cytometry and by traction microscopy, respectively. A549 cells were treated 24 h with Dexamethasone (1 mu M) or vehicle (control). G' and T were measured before and 5 min after challenge with the inflammatory mediator Thrombin (0.5 U/ml). Changes induced by Dexamethasone in actin cytoskeleton polymerization were assessed by the fluorescent ratio between F-actin and G-actin obtained by staining cells with phalloidin and DNase I. Dexamethasone significantly increased G' and T by 56% (n = 11; p < 0.01) and by 80% (n = 17; p < 0.05), respectively. Dexamethasone also increased F/G-actin ratio from 2.68 +/- 0.07 to 2.96 +/- 0.09 (n = 10; p < 0.05). The relative increase in stiffness and contraction induced by Thrombin in control cells was significantly (p < 0.05) reduced by Dexamethasone treatment: from 190 to 98% in G' and from 318 to 105% in T. The cytoskeleton remodelling and the increase in cell stiffness and contraction induced by Dexamethasone could account for its protective effect in the alveolar epithelium when subjected to inflammatory challenge.

JTD Keywords: Cell mechanics, Cytoskeleton, Magnetic twisting cytometry, Traction microscopy, Respiratory diseases


Planell, J. A., Navarro, M., (2009). Challenges in bone repair Bone repair biomaterials (ed. Planell, J. A., Lacroix, D., Best, S., Merolli, A.), Woodhead (Cambridge, UK) , 3-24

A fundamental aspect of the rapidly expanding medical care sector, bone repair continues to benefit from emerging technological developments. This text provides researchers and students with a comprehensive review of the materials science and engineering principles behind these developments. The first part reviews the fundamentals of bone repair and regeneration. Further chapters discuss the science and properties of biomaterials used in bone repair, including both metals and biocomposites. Final chapters analyze device considerations such as implant lifetime and failure, and discuss potential applications, as well as the ethical issues that continually confront researchers and clinicians.

JTD Keywords: Social impact of musculoskeletal disease, Economic burden of musculoskeletal disease, Social aspects of dental and maxillofacial conditions, Some clinical challenges of bone repair, Conclusions and future trends, Sources of further information and advice


Bravo, R., Arimon, M., Valle-Delgado, J. J., Garcia, R., Durany, N., Castel, S., Cruz, M., Ventura, S., Fernàndez-Busquets, X., (2008). Sulfated polysaccharides promote the assembly of amyloid beta(1-42) peptide into stable fibrils of reduced cytotoxicity Journal of Biological Chemistry , 283, (47), 32471-32483

The histopathological hallmarks of Alzheimer disease are the self-aggregation of the amyloid beta peptide (A beta) in extracellular amyloid fibrils and the formation of intraneuronal Tau filaments, but a convincing mechanism connecting both processes has yet to be provided. Here we show that the endogenous polysaccharide chondroitin sulfate B (CSB) promotes the formation of fibrillar structures of the 42-residue fragment, A beta(1-42). Atomic force microscopy visualization, thioflavin T fluorescence, CD measurements, and cell viability assays indicate that CSB-induced fibrils are highly stable entities with abundant beta-sheet structure that have little toxicity for neuroblastoma cells. We propose a wedged cylinder model for A beta(1-42) fibrils that is consistent with the majority of available data, it is an energetically favorable assembly that minimizes the exposure of hydrophobic areas, and it explains why fibrils do not grow in thickness. Fluorescence measurements of the effect of different A beta(1-42) species on Ca2+ homeostasis show that weakly structured nodular fibrils, but not CSB-induced smooth fibrils, trigger a rise in cytosolic Ca2+ that depends on the presence of both extracellular and intracellular stocks. In vitro assays indicate that such transient, local Ca2+ increases can have a direct effect in promoting the formation of Tau filaments similar to those isolated from Alzheimer disease brains.

JTD Keywords: AFM, Alzheimers-disease, Chondroitin sulfate, Heparan-sulfate, Lipid-bilayers, Beta-peptide, In-vitro, Neurodegenerative diseases, Extracellular-matrix, Prion protein


Morell, M., Bravo, R., Espargaro, A., Sisquella, X., Aviles, F. X., Fernàndez-Busquets, X., Ventura, S., (2008). Inclusion bodies: Specificity in their aggregation process and amyloid-like structure Biochimica et Biophysica Acta - Molecular Cell Research , 1783, (10), 1815-1825

The accumulation of aggregated protein in the cell is associated with the pathology of many diseases and constitutes a major concern in protein production. Intracellular aggregates have been traditionally regarded as nonspecific associations of misfolded polypeptides. This view is challenged by studies demonstrating that, in vitro, aggregation often involves specific interactions. However, little is known about the specificity of in vivo protein deposition. Here, we investigate the degree of in vivo co-aggregation between two self-aggregating proteins, A beta A2 amyloid peptide and foot-and-mouth disease virus VP1 capsid protein, in prokaryotic cells. In addition, the ultrastructure of intracellular aggregates is explored to decipher whether amyloid fibrils and intracellular protein inclusions share structural properties. The data indicate that in vivo protein aggregation exhibits a remarkable specificity that depends on the establishment of selective interactions and results in the formation of oligomeric and fibrillar structures displaying amyloid-like properties. These features allow prokaryotic A beta A2 intracellular aggregates to act as effective seeds in the formation of A beta A2 amyloid fibrils. overall, our results suggest that conserved mechanisms underlie protein aggregation in different organisms. They also have important implications for biotechnological and biomedical applications of recombinant polypeptides.

JTD Keywords: Protein aggregation, Inclusion bodies, Conformational diseases, Amyloid fibrils, Protein folding


Arimon, M., Grimminger, V., Sanz, F., Lashuel, H. A., (2008). Hsp104 targets multiple intermediates on the amyloid pathway and suppresses the seeding capacity of A beta fibrils and protofibrils Journal of Molecular Biology , 384, (5), 1157-1173

The heat shock protein Hsp104 has been reported to possess the ability to. modulate protein aggregation and toxicity and to "catalyze" the disaggregation and recovery of protein aggregates, including amyloid fibrils, in yeast, Escherichia coli, mammalian cell cultures, and animal models of Huntington's disease and Parkinson's disease. To provide mechanistic insight into the molecular mechanisms by which Hsp104 modulates aggregation and fibrillogenesis, the effect of Hsp104 on the fibrillogenesis of amyloid beta (A(3) was investigated by characterizing its ability to interfere with oligomerization and fibrillogenesis of different species along the amyloid-formation pathway of A beta. To probe the disaggregation activity of Hsp104, its ability to dissociate preformed protofibrillar and fibrillar aggregates of A beta was assessed in the presence and in the absence of ATP. Our results show that Hsp104 inhibits the fibrillization of monomeric and protofibrillar forms of A beta in a concentration-dependent but ATP-independent manner. Inhibition of A beta fibrillization by Hsp104 is observable up to Hsp104/A beta stoichiometric ratios of 1:1000, suggesting a preferential interaction of Hsp104 with aggregation intermediates (e.g., oligomers, protofibrils, small fibrils) on the pathway of A beta amyloid formation. This hypothesis is consistent with our observations that Hsp104 (i) interacts with A beta protofibrils, (ii) inhibits conversion of protofibrils into amyloid fibrils, (iii) arrests fibril elongation and reassembly, and (iv) abolishes the capacity of protofibrils and sonicated fibrils to seed the fibrillization of monomeric A beta. Together, these findings suggest that the strong inhibition of A beta fibrillization by Hsp104 is mediated by its ability to act at different stages and target multiple intermediates on the pathway to amyloid formation.

JTD Keywords: Amyloid formation A beta, Hsp104, Disaggregation, Alzheimer's diseases