Year 11

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Arsiwalla, X. D., Bote, R. M., Verschure, P., (2019). Beyond neural coding? Lessons from perceptual control theory The Behavioral and brain sciences 42, e217

Pointing to similarities between challenges encountered in today's neural coding and twentieth-century behaviorism, we draw attention to lessons learned from resolving the latter. In particular, Perceptual Control Theory posits behavior as a closed-loop control process with immediate and teleological causes. With two examples, we illustrate how these ideas may also address challenges facing current neural coding paradigms.

Ballester, B. R., Maier, M., Duff, A., Cameirão, M., Bermúdez, S., Duarte, E., Cuxart, A., Rodríguez, S., San Segundo Mozo, R. M., Verschure, P., (2019). A critical time window for recovery extends beyond one-year post-stroke Journal of neurophysiology 122, (1), 350-357

The impact of rehabilitation on post-stroke motor recovery and its dependency on the patient's chronicity remain unclear. The field has widely accepted the notion of a proportional recovery rule with a "critical window for recovery" within the first 3-6 mo poststroke. This hypothesis justifies the general cessation of physical therapy at chronic stages. However, the limits of this critical window have, so far, been poorly defined. In this analysis, we address this question, and we further explore the temporal structure of motor recovery using individual patient data from a homogeneous sample of 219 individuals with mild to moderate upper-limb hemiparesis. We observed that improvement in body function and structure was possible even at late chronic stages. A bootstrapping analysis revealed a gradient of enhanced sensitivity to treatment that extended beyond 12 mo poststroke. Clinical guidelines for rehabilitation should be revised in the context of this temporal structure. NEW & NOTEWORTHY Previous studies in humans suggest that there is a 3- to 6-mo "critical window" of heightened neuroplasticity poststroke. We analyze the temporal structure of recovery in patients with hemiparesis and uncover a precise gradient of enhanced sensitivity to treatment that expands far beyond the limits of the so-called critical window. These findings highlight the need for providing therapy to patients at the chronic and late chronic stages.

Keywords: Motor recovery, Neuroplasticity, Neurorehabilitation, Stroke recovery, Virtual reality

Montero, Joan, Gstalder, Cécile, Kim, Daniel J., Sadowicz, Dorota, Miles, Wayne, Manos, Michael, Cidado, Justin R., Paul Secrist, J., Tron, Adriana E., Flaherty, Keith, Stephen Hodi, F., Yoon, Charles H., Letai, Anthony, Fisher, David E., Haq, Rizwan, (2019). Destabilization of NOXA mRNA as a common resistance mechanism to targeted therapies Nature Communications 10, (1), 5157

Most targeted cancer therapies fail to achieve complete tumor regressions or attain durable remissions. To understand why these treatments fail to induce robust cytotoxic responses despite appropriately targeting oncogenic drivers, here we systematically interrogated the dependence of cancer cells on the BCL-2 family of apoptotic proteins after drug treatment. We observe that multiple targeted therapies, including BRAF or EGFR inhibitors, rapidly deplete the pro-apoptotic factor NOXA, thus creating a dependence on the anti-apoptotic protein MCL-1. This adaptation requires a pathway leading to destabilization of the NOXA mRNA transcript. We find that interruption of this mechanism of anti-apoptotic adaptive resistance dramatically increases cytotoxic responses in cell lines and a murine melanoma model. These results identify NOXA mRNA destabilization/MCL-1 adaptation as a non-genomic mechanism that limits apoptotic responses, suggesting that sequencing of MCL-1 inhibitors with targeted therapies could overcome such widespread and clinically important resistance.

Keywords: Cancer therapeutic resistance, Melanoma, Targeted therapies

Rey-Vinolas, S., Castaño, O., Ruiz-Macarrilla, L., Llorens, X., Mora, J. M., Engel, E., Mateos-Timoneda, M. A., (2019). Development of a novel automatable fabrication method based on electrospinning co electrospraying for rotator cuff augmentation patches PLoS ONE 14, (11), e0224661

Rotator cuff tear is one of the most common shoulder diseases. Rotator cuff augmentation (RCA) is trying to solve the high retear failure percentage after the surgery procedures (20–90%). The ideal augmentation patch must provide a temporal mechanical support during the healing process. In this work, we proposed a simple method for the fabrication of synthetic RCA patches. This method combines the use of electrospraying to produce poly-L-lactic-co-ε-caprolactone (PLC) films in an organogel form and electrospinning to produce poly(lactic) acid (PLA) nanofibers. The device consists in a combination of layers, creating a multilayered construct, enabling the possibility of tuning its mechanical properties and thickness. Besides, both techniques are simple to escalate for industrial production. A complete characterization has been performed to optimize the involved number of layers and production time of PLC films and PLA nanofibers fabrication, obtaining a final optimal configuration for RCA devices. Structural, mechanical and suture properties were evaluated. Also, the possibility of surface functionalization to improve the bioactivity of the scaffold was studied, adding aligned electrospun PLA nanofibers on the surface of the device to mimic the natural tendon topography. Surface modification was characterized by culturing adult normal human dermal fibroblasts. Lack of toxicity was detected for material presented, and cell alignment shape orientation guided by aligned fibers, mimicking tendon structure, was obtained. Cell proliferation and protein production were also evaluated.

Palmisano, I., Danzi, M. C., Hutson, T. H., Zhou, L., McLachlan, E., Serger, E., Shkura, K., Srivastava, P. K., Hervera, A., Neill, N. O., Liu, T., Dhrif, H., Wang, Z., Kubat, M., Wuchty, S., Merkenschlager, M., Levi, L., Elliott, E., Bixby, J. L., Lemmon, V. P., Di Giovanni, S., (2019). Epigenomic signatures underpin the axonal regenerative ability of dorsal root ganglia sensory neurons Nature Neuroscience 22, (11), 1913-1924

Axonal injury results in regenerative success or failure, depending on whether the axon lies in the peripheral or the CNS, respectively. The present study addresses whether epigenetic signatures in dorsal root ganglia discriminate between regenerative and non-regenerative axonal injury. Chromatin immunoprecipitation for the histone 3 (H3) post-translational modifications H3K9ac, H3K27ac and H3K27me3; an assay for transposase-accessible chromatin; and RNA sequencing were performed in dorsal root ganglia after sciatic nerve or dorsal column axotomy. Distinct histone acetylation and chromatin accessibility signatures correlated with gene expression after peripheral, but not central, axonal injury. DNA-footprinting analyses revealed new transcriptional regulators associated with regenerative ability. Machine-learning algorithms inferred the direction of most of the gene expression changes. Neuronal conditional deletion of the chromatin remodeler CCCTC-binding factor impaired nerve regeneration, implicating chromatin organization in the regenerative competence. Altogether, the present study offers the first epigenomic map providing insight into the transcriptional response to injury and the differential regenerative ability of sensory neurons.

Keywords: Cell biology, Computational biology and bioinformatics, Molecular biology, Neuroscience

Barba, A., Diez-Escudero, A., Espanol, M., Bonany, M., Sadowska, J. M., Guillem-Marti, J., Öhman-Mägi, C., Persson, C., Manzanares, M. C., Franch, J., Ginebra, M. P., (2019). Impact of biomimicry in the design of osteoinductive bone substitutes: Nanoscale matters ACS Applied Materials and Interfaces 11, (9), 8818-8830

Bone apatite consists of carbonated calcium-deficient hydroxyapatite (CDHA) nanocrystals. Biomimetic routes allow fabricating synthetic bone grafts that mimic biological apatite. In this work, we explored the role of two distinctive features of biomimetic apatites, namely, nanocrystal morphology (plate vs needle-like crystals) and carbonate content, on the bone regeneration potential of CDHA scaffolds in an in vivo canine model. Both ectopic bone formation and scaffold degradation were drastically affected by the nanocrystal morphology after intramuscular implantation. Fine-CDHA foams with needle-like nanocrystals, comparable in size to bone mineral, showed a markedly higher osteoinductive potential and a superior degradation than chemically identical coarse-CDHA foams with larger plate-shaped crystals. These findings correlated well with the superior bone-healing capacity showed by the fine-CDHA scaffolds when implanted intraosseously. Moreover, carbonate doping of CDHA, which resulted in small plate-shaped nanocrystals, accelerated both the intrinsic osteoinduction and the bone healing capacity, and significantly increased the cell-mediated resorption. These results suggest that tuning the chemical composition and the nanostructural features may allow the material to enter the physiological bone remodeling cycle, promoting a tight synchronization between scaffold degradation and bone formation.

Keywords: Biomimetic, Calcium phosphate, Carbonated apatite, Foaming, Nanostructure, Osteogenesis, Osteoinduction

Rao, T. N., Hansen, N., Hilfiker, J., Rai, S., Majewska, J. M., Lekovic, D., Gezer, D., Andina, N., Galli, S., Cassel, T., Geier, F., Delezie, J., Nienhold, R., Hao-Shen, H., Beisel, C., Di Palma, S., Dimeloe, S., Trebicka, J., Wolf, D., Gassmann, M., Fan, T. W. M., Lane, A. N., Handschin, C., Dirnhofer, S., Kröger, N., Hess, C., Radimerski, T., Koschmieder, S., Cokic, V. P., Skoda, R. C., (2019). JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms Blood 134, (21), 1832-1846

Increased energy requirement and metabolic reprogramming are hallmarks of cancer cells. We show that metabolic alterations in hematopoietic cells are fundamental to the pathogenesis of mutant JAK2–driven myeloproliferative neoplasms (MPNs). We found that expression of mutant JAK2 augmented and subverted metabolic activity of MPN cells, resulting in systemic metabolic changes in vivo, including hypoglycemia, adipose tissue atrophy, and early mortality. Hypoglycemia in MPN mouse models correlated with hyperactive erythropoiesis and was due to a combination of elevated glycolysis and increased oxidative phosphorylation. Modulating nutrient supply through high-fat diet improved survival, whereas high-glucose diet augmented the MPN phenotype. Transcriptomic and metabolomic analyses identified numerous metabolic nodes in JAK2-mutant hematopoietic stem and progenitor cells that were altered in comparison with wild-type controls. We studied the consequences of elevated levels of Pfkfb3, a key regulatory enzyme of glycolysis, and found that pharmacological inhibition of Pfkfb3 with the small molecule 3PO reversed hypoglycemia and reduced hematopoietic manifestations of MPNs. These effects were additive with the JAK1/2 inhibitor ruxolitinib in vivo and in vitro. Inhibition of glycolysis by 3PO altered the redox homeostasis, leading to accumulation of reactive oxygen species and augmented apoptosis rate. Our findings reveal the contribution of metabolic alterations to the pathogenesis of MPNs and suggest that metabolic dependencies of mutant cells represent vulnerabilities that can be targeted for treating MPNs.

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

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

Keywords: Inflammation, Macrophages, Glucocorticoid, Polymersomes

Santos-Pata, Diogo, Zucca, Riccardo, López-Carral, Héctor, Verschure, P., (2019). Modulating grid cell scale and intrinsic frequencies via slow high-threshold conductances: A simplified model Neural Networks 119, 66-73

Grid cells in the medial entorhinal cortex (MEC) have known spatial periodic firing fields which provide a metric for the representation of self-location and path planning. The hexagonal tessellation pattern of grid cells scales up progressively along the MEC’s layer II dorsal-to-ventral axis. This scaling gradient has been hypothesized to originate either from inter-population synaptic dynamics as postulated by attractor networks, or from projected theta frequency waves to different axis levels, as in oscillatory models. Alternatively, cellular dynamics and specifically slow high-threshold conductances have been proposed to have an impact on the grid cell scale. To test the hypothesis that intrinsic hyperpolarization-activated cation currents account for both the scaled gradient and the oscillatory frequencies observed along the dorsal-to-ventral axis, we have modeled and analyzed data from a population of grid cells simulated with spiking neurons interacting through low-dimensional attractor dynamics. We observed that the intrinsic neuronal membrane properties of simulated cells were sufficient to induce an increase in grid scale and potentiate differences in the membrane potential oscillatory frequency. Overall, our results suggest that the after-spike dynamics of cation currents may play a major role in determining the grid cells’ scale and that oscillatory frequencies are a consequence of intrinsic cellular properties that are specific to different levels of the dorsal-to-ventral axis in the MEC layer II.

Keywords: Grid cells, Entorhinal, Hyperpolarization, Navigation, Space

Cendra, Maria del Mar, Blanco-Cabra, Núria, Pedraz, Lucas, Torrents, Eduard, (2019). Optimal environmental and culture conditions allow the in vitro coexistence of Pseudomonas aeruginosa and Staphylococcus aureus in stable biofilms Scientific Reports 9, (1), 16284

The coexistence between species that occurs in some infections remains hard to achieve in vitro since bacterial fitness differences eventually lead to a single organism dominating the mixed culture. Pseudomonas aeruginosa and Staphylococcus aureus are major pathogens found growing together in biofilms in disease-affected lungs or wounds. Herein, we tested and analyzed different culture media, additives and environmental conditions to support P. aeruginosa and S. aureus coexistence in vitro. We have unraveled the potential of DMEM to support the growth of these two organisms in mature cocultured biofilms (three days old) in an environment that dampens the pH rise. Our conditions use equal initial inoculation ratios of both strains and allow the stable formation of separate S. aureus microcolonies that grow embedded in a P. aeruginosa biofilm, as well as S. aureus biofilm overgrowth when bovine serum albumin is added to the system. Remarkably, we also found that S. aureus survival is strictly dependent on a well-characterized phenomenon of oxygen stratification present in the coculture biofilm. An analysis of differential tolerance to gentamicin and ciprofloxacin treatment, depending on whether P. aeruginosa and S. aureus were growing in mono- or coculture biofilms, was used to validate our in vitro coculture conditions.

Keywords: Applied microbiology, Biofilms

Labay, C., Hamouda, I., Tampieri, F., Ginebra, M. P., Canal, C., (2019). Production of reactive species in alginate hydrogels for cold atmospheric plasma-based therapies Scientific Reports 9, (1), 16160

In the last years, great advances have been made in therapies based in cold atmospheric plasmas (CAP). CAP generate reactive oxygen and nitrogen species (RONS) which can be transferred to liquids. These CAP activated liquids display the same biological efficacy (i.e. on killing cancer cells) as CAP themselves, opening the door for minimally invasive therapies. However, injection of a liquid in the body results in fast diffusion due to extracellular fluids and blood flow. Therefore, the development of efficient vehicles which allow local confinement and delivery of RONS to the diseased site is a fundamental requirement. In this work, we investigate the generation of RONS (H2O2, NO2−, short-lived RONS) in alginate hydrogels by comparing two atmospheric pressure plasma jets: kINPen and a helium needle, at a range of plasma treatment conditions (time, gas flow, distance to the sample). The physic-chemical properties of the hydrogels remain unchanged by the plasma treatment, while the hydrogel shows several-fold larger capacity for generation of RONS than a typical isotonic saline solution. Part of the RONS are quickly released to a receptor media, so special attention has to be put on the design of hydrogels with in-situ crosslinking. Remarkably, the hydrogels show capacity for sustained release of the RONS. The plasma-treated hydrogels remain fully biocompatible (due the fact that the species generated by plasma are previously washed away), indicating that no cytotoxic modifications have occurred on the polymer. Moreover, the RONS generated in alginate solutions showed cytotoxic potential towards bone cancer cells. These results open the door for the use of hydrogel-based biomaterials in CAP-associated therapies.

Keywords: Biomedical materials, Plasma physics

Farré, R., Navajas, D., Gozal, D., Montserrat, J. M., (2019). Telematic multi-physician decision-making for improving CPAP prescription in sleep apnoea Archivos de Bronconeumología Archivos de Bronconeumologia , 55, (11), 604-606

Telematic multi-physician decision-making for improving CPAP prescription in sleep apnoea.

Good, M., Trepat, X., (2018). Cell parts to complex processes, from the bottom up Nature 563, (7730), 188-189

Engineering approaches allow biological structures and behaviours to be reconstituted in vitro. A biologist and a physicist discuss the potential and limitations of this bottom-up philosophy in providing insights into complex biological processes.

Keywords: Biophysics, Complexity, Engineering

Torres, M., Campillo, N., Nonaka, P.N., Montserrat, J.M., Gozal, D., Martínez-García, M.A., Campos-Rodriguez, F., Navajas, D., Farré, R., Almendros, I., (2018). Aging reduces intermittent hypoxia-induced lung carcinoma growth in a mouse model of sleep apnea American Journal of Respiratory and Critical Care Medicine 198, (9), 1234-1236

Thottacherry, Joseph Jose, Kosmalska, Anita Joanna, Elosegui-Artola, Alberto, Pradhan, Susav, Sharma, Sumit, Singh, Parvinder P., Guadamillas, Marta C., Chaudhary, Natasha, Vishwakarma, Ram, Trepat, Xavier, del Pozo, Miguel A., Parton, Robert G., Pullarkat, Pramod, Roca-Cusachs, Pere, Mayor, Satyajit, (2018). Mechanochemical feedback and control of endocytosis and membrane tension Nature Communications 9, 4217

Plasma membrane tension is an important factor that regulates many key cellular processes. Membrane trafficking is tightly coupled to membrane tension and can modulate the latter by addition or removal of the membrane. However, the cellular pathway(s) involved in these processes are poorly understood. Although a number of endocytic processes function simultaneously at the cell surface, we find that a dynamin and clathrin-independent pathway, the CLIC/GEEC (CG) pathway, is rapidly and specifically upregulated upon reduction of tension. On the other hand, inhibition of the CG pathway results in lower membrane tension, while up regulation significantly enhances membrane tension. We find that vinculin, a well-studied mechanotransducer, mediates the tension-dependent regulation of the CG pathway. Vinculin negatively regulates a key CG pathway regulator, GBF1, at the plasma membrane in a tension dependent manner. Thus, the CG pathway operates in a negative feedback loop with membrane tension which leads to a homeostatic regulation of membrane tension.

Piano, Salvatore, Schmidt, Hartmut H., Ariza, Xavier, Amoros, Alex, Romano, Antonietta, Hüsing-Kabar, Anna, Solà , Elsa, Gerbes, Alexander, Bernardi, Mauro, Alessandria, Carlo, Scheiner, Bernhard, Tonon, Marta, Maschmeier, Miriam, Solè, Cristina, Trebicka, Jonel, Gustot, Thierry, Nevens, Frederik, Arroyo, Vicente, Gines, Pere, Angeli, Paolo, (2018). Association between grade of acute on chronic liver failure and response to terlipressin and albumin in patients with hepatorenal syndrome Clinical Gastroenterology and Hepatology 16, (11), 1792-1800

Type 1 hepatorenal syndrome (HRS) is the most high-risk type of renal failure in patients with cirrhosis. Terlipressin and albumin are effective treatments for type 1 HRS. However, the effects of acute on chronic liver failure (ACLF) grade on response to treatment are not clear. We aimed to identify factors associated with response to treatment with terlipressin and albumin in patients with type 1 HRS (reduction in serum level of creatinine to below 1.5 mg/dL at the end of treatment) and factors associated with death within 90 days of HRS diagnosis (90-day mortality).

Gumí-Audenis, Berta, Costa, Luca, Ferrer-Tasies, Lidia, Ratera, Imma, Ventosa, Nora, Sanz, Fausto, Giannotti, M. I., (2018). Pulling lipid tubes from supported bilayers unveils the underlying substrate contribution to the membrane mechanics Nanoscale 10, 14763-14770

Cell processes like endocytosis, membrane resealing, signaling and transcription involve conformational changes which depend on the chemical composition and the physicochemical properties of the lipid membrane. The better understanding of the mechanical role of lipids in cell membrane force-triggered and sensing mechanisms has recently become the focus of attention. Different membrane models and experimental methodologies are commonly explored. While general approaches involve controlled vesicle deformation using micropipettes or optical tweezers, due to the local and dynamic nature of the membrane, high spatial resolution atomic force microscopy (AFM) has been widely used to study the mechanical compression and indentation of supported lipid bilayers (SLBs). However, the substrate contribution remains unkown. Here, we demonstrate how pulling lipid tubes with an AFM out of model SLBs can be used to assess the nanomechanics of SLBs through the evaluation of the tube growing force (Ftube), allowing for very local evaluation with high spatial and force resolution of the lipid membrane tension. We first validate this approach to determine the contribution of different phospholipids, by varying the membrane composition, in both one-component and phase-segregated membranes. Finally, we successfully assess the contribution of the underlying substrate to the membrane mechanics, demonstrating that SLB models may represent an intermediate scenario between a free membrane (blebs) and a cytoskeleton supported membrane.

Contreras, M. D. M., Jurado-Campos, N., Sánchez-Carnerero Callado, C., Arroyo-Manzanares, N., Fernández, L., Casano, S., Marco, S., Arce, L., Ferreiro-Vera, C., (2018). Thermal desorption-ion mobility spectrometry: A rapid sensor for the detection of cannabinoids and discrimination of Cannabis sativa L. chemotypes Sensors and Actuators B: Chemical 273, 1413-1424

Existing analytical techniques used for the determination of cannabinoids in Cannabis sativa L. (Cannabis) plants mostly rely on chromatography-based methods. As a rapid alternative for the direct analysis of them, thermal desorption (TD)-ion mobility spectrometry (IMS) was used for obtaining spectral fingerprints of single cannabinoids from Cannabis plant extracts and from plant residues on hands after their manipulation. The ionization source was 63Ni, with automatic switchable polarity. Although in both ionization modes there were signals in the TD-IMS spectra of the plant extracts and residues that could be assigned to concrete cannabinoids and chemotypes, most of them could not be clearly distinguished. Alternatively, the global spectral data of the plant extracts and residues were pre-processed and then, using principal component analysis (PCA)-linear discriminant analysis (LDA), grouped in function of their chemotype in a more feasible way. Using this approach, the possibility of false positive responses was also studied analyzing other non-Cannabis plants and tobacco, which were clustered in a different group to those of Cannabis. Therefore, TD-IMS, as analytical tool, and PCA-LDA, as a strategy for data reduction and pattern recognition, can be applied for on-site chemotaxonomic discrimination of Cannabis varieties and detection of illegal marijuana since the IMS equipment is portable and the analysis time is highly short.

Keywords: Cannabis sativa L., Cannabinoids, Chemometrics, ChemotypeIon mobility spectrometry

Martí Coma-Cros, E., Biosca, A., Marques, J., Carol, L., Urbán, P., Berenguer, D., Riera, M. C., Delves, M., Sinden, R. E., Valle-Delgado, J. J., Spanos, L., Siden-Kiamos, I., Pérez, P., Paaijmans, K., Rottmann, M., Manfredi, A., Ferruti, P., Ranucci, E., Fernàndez-Busquets, X., (2018). Polyamidoamine nanoparticles for the oral administration of antimalarial drugs Pharmaceutics 10, (4), 225

Current strategies for the mass administration of antimalarial drugs demand oral formulations to target the asexual Plasmodium stages in the peripheral bloodstream, whereas recommendations for future interventions stress the importance of also targeting the transmission stages of the parasite as it passes between humans and mosquitoes. Orally administered polyamidoamine (PAA) nanoparticles conjugated to chloroquine reached the blood circulation and cured Plasmodium yoelii-infected mice, slightly improving the activity of the free drug and inducing in the animals immunity against malaria. Liquid chromatography with tandem mass spectrometry analysis of affinity chromatography-purified PAA ligands suggested a high adhesiveness of PAAs to Plasmodium falciparum proteins, which might be the mechanism responsible for the preferential binding of PAAs to Plasmodium-infected erythrocytes vs. non-infected red blood cells. The weak antimalarial activity of some PAAs was found to operate through inhibition of parasite invasion, whereas the observed polymer intake by macrophages indicated a potential of PAAs for the treatment of certain coinfections such as Plasmodium and Leishmania. When fluorescein-labeled PAAs were fed to females of the malaria mosquito vectors Anopheles atroparvus and Anopheles gambiae, persistent fluorescence was observed in the midgut and in other insect’s tissues. These results present PAAs as a versatile platform for the encapsulation of orally administered antimalarial drugs and for direct administration of antimalarials to mosquitoes, targeting mosquito stages of Plasmodium.

Keywords: Anopheles, Antimalarial drugs, Malaria, Mosquitoes, Nanomedicine, Nanotechnology, Plasmodium, Polyamidoamines, Polymers, Targeted drug delivery

Zamora, R., Korff, S., Mi, Q., Barclay, D., Schimunek, L., Zucca, R., Arsiwalla, X. D., Simmons, R. L., Verschure, P., Billiar, T. R., Vodovotz, Y., (2018). A computational analysis of dynamic, multi-organ inflammatory crosstalk induced by endotoxin in mice PLoS Computational Biology 14, (11), e1006582

Bacterial lipopolysaccharide (LPS) induces an acute inflammatory response across multiple organs, primarily via Toll-like receptor 4 (TLR4). We sought to define novel aspects of the complex spatiotemporal dynamics of LPS-induced inflammation using computational modeling, with a special focus on the timing of pathological systemic spillover. An analysis of principal drivers of LPS-induced inflammation in the heart, gut, lung, liver, spleen, and kidney to assess organ-specific dynamics, as well as in the plasma (as an assessment of systemic spillover), was carried out using data on 20 protein-level inflammatory mediators measured over 0-48h in both C57BL/6 and TLR4-null mice. Using a suite of computational techniques, including a time-interval variant of Principal Component Analysis, we confirm key roles for cytokines such as tumor necrosis factor-α and interleukin-17A, define a temporal hierarchy of organ-localized inflammation, and infer the point at which organ-localized inflammation spills over systemically. Thus, by employing a systems biology approach, we obtain a novel perspective on the time- and organ-specific components in the propagation of acute systemic inflammation.

Caddeo, Carla, Manca, Maria Letizia, Peris, José Esteban, Usach, Iris, Diez-Sales, Octavio, Matos, Maria, Fernàndez-Busquets, Xavier, Fadda, Anna Maria, Manconi, Maria, (2018). Tocopherol-loaded transfersomes: In vitro antioxidant activity and efficacy in skin regeneration International Journal of Pharmaceutics 551, (1), 34-41

Transfersomes were prepared by using different polysorbates (i.e., Tween 20, 40, 60 and 80) and loaded with tocopherol acetate, a naturally-occurring phenolic compound with antioxidant activity. The vesicles showed unilamellar morphology, small size (∼85 nm), low polydispersity index (≤0.27), and high entrapment efficiency, which increased as a function of the length of the Tween fatty acid chain (from 72% to 90%). The long-term stability of the formulations was evaluated by means of the Turbiscan™ technology, which indicated their good stability, irrespective of the Tween used. The vesicles efficiently delivered tocopherol to the skin, and showed biocompatibility in vitro in keratinocytes and fibroblasts. Regardless of the Tween used, the transfersomes were able to protect skin cells from the oxidative damage induced by hydrogen peroxide. Additionally, transfersomes promoted cell proliferation and migration, which resulted in an acceleration of skin wound closure. These results demonstrated that tocopherol-loaded transfersomes bear potential as topical delivery system with antioxidant activity and wound healing properties.

Keywords: Tocopherol, Transfersomes, Tween, Skin delivery, Antioxidant activity, Skin wound

Silva, N., Riveros, A., Yutronic, N., Lang, E., Chornik, B., Guerrero, S., Samitier, J., Jara, P., Kogan, M. J., (2018). Photothermally controlled methotrexate release system using β-cyclodextrin and gold nanoparticles Nanomaterials 8, (12), 985

The inclusion compound (IC) of cyclodextrin (CD) containing the antitumor drug Methotrexate (MTX) as a guest molecule was obtained to increase the solubility of MTX and decrease its inherent toxic effects in nonspecific cells. The IC was conjugated with gold nanoparticles (AuNPs), obtained by a chemical method, creating a ternary intelligent delivery system for MTX molecules, based on the plasmonic properties of the AuNPs. Irradiation of the ternary system, with a laser wavelength tunable with the corresponding surface plasmon of AuNPs, causes local energy dissipation, producing the controlled release of the guest from CD cavities. Finally, cell viability was evaluated using MTS assays for β-CD/MTX and AuNPs + β-CD/MTX samples, with and without irradiation, against HeLa tumor cells. The irradiated sample of the ternary system AuNPs + β-CD/MTX produced a diminution in cell viability attributed to the photothermal release of MTX.

Keywords: Cyclodextrin, Delivery system, Gold nanoparticles, Inclusion compound, Irradiation, Laser, Methotrexate, Photothermal release

Hurtado del Pozo, Carmen, Garreta, Elena, Izpisúa Belmonte, Juan Carlos, Montserrat, Nuria, (2018). Modeling epigenetic modifications in renal development and disease with organoids and genome editing Disease Models & Mechanisms 11, (11), 035048

Understanding epigenetic mechanisms is crucial to our comprehension of gene regulation in development and disease. In the past decades, different studies have shown the role of epigenetic modifications and modifiers in renal disease, especially during its progression towards chronic and end-stage renal disease. Thus, the identification of genetic variation associated with chronic kidney disease has resulted in better clinical management of patients. Despite the importance of these findings, the translation of genotype–phenotype data into gene-based medicine in chronic kidney disease populations still lacks faithful cellular or animal models that recapitulate the key aspects of the human kidney. The latest advances in the field of stem cells have shown that it is possible to emulate kidney development and function with organoids derived from human pluripotent stem cells. These have successfully recapitulated not only kidney differentiation, but also the specific phenotypical traits related to kidney function. The combination of this methodology with CRISPR/Cas9 genome editing has already helped researchers to model different genetic kidney disorders. Nowadays, CRISPR/Cas9-based approaches also allow epigenetic modifications, and thus represent an unprecedented tool for the screening of genetic variants, epigenetic modifications or even changes in chromatin structure that are altered in renal disease. In this Review, we discuss these technical advances in kidney modeling, and offer an overview of the role of epigenetic regulation in kidney development and disease.

Lozano-García, Manuel, Sarlabous, Leonardo, Moxham, John, Rafferty, Gerrard F., Torres, Abel, Jané, Raimon, Jolley, Caroline J., (2018). Surface mechanomyography and electromyography provide non-invasive indices of inspiratory muscle force and activation in healthy subjects Scientific Reports 8, (1), 16921

The current gold standard assessment of human inspiratory muscle function involves using invasive measures of transdiaphragmatic pressure (Pdi) or crural diaphragm electromyography (oesEMGdi). Mechanomyography is a non-invasive measure of muscle vibration associated with muscle contraction. Surface electromyogram and mechanomyogram, recorded transcutaneously using sensors placed over the lower intercostal spaces (sEMGlic and sMMGlic respectively), have been proposed to provide non-invasive indices of inspiratory muscle activation, but have not been directly compared to gold standard Pdi and oesEMGdi measures during voluntary respiratory manoeuvres. To validate the non-invasive techniques, the relationships between Pdi and sMMGlic, and between oesEMGdi and sEMGlic were measured simultaneously in 12 healthy subjects during an incremental inspiratory threshold loading protocol. Myographic signals were analysed using fixed sample entropy (fSampEn), which is less influenced by cardiac artefacts than conventional root mean square. Strong correlations were observed between: mean Pdi and mean fSampEn |sMMGlic| (left, 0.76; right, 0.81), the time-integrals of the Pdi and fSampEn |sMMGlic| (left, 0.78; right, 0.83), and mean fSampEn oesEMGdi and mean fSampEn sEMGlic (left, 0.84; right, 0.83). These findings suggest that sMMGlic and sEMGlic could provide useful non-invasive alternatives to Pdi and oesEMGdi for the assessment of inspiratory muscle function in health and disease.

Peyman, Zirak, Clara, Gregori-Pla, Igor, Blanco, Ana, Fortuna, Gianluca, Cotta, Pau, Bramon, Isabel, Serra, Anna, Mola, Jordi, Solà-Soler, Beatriz, F. Giraldo-Giraldo, Turgut, Durduran, Mercedes, Mayos, (2018). Characterization of the microvascular cerebral blood flow response to obstructive apneic events during night sleep Neurophotonics 5, (4), 045003

Obstructive apnea causes periodic changes in cerebral and systemic hemodynamics, which may contribute to the increased risk of cerebrovascular disease of patients with obstructive sleep apnea (OSA) syndrome. The improved understanding of the consequences of an apneic event on the brain perfusion may improve our knowledge of these consequences and then allow for the development of preventive strategies. Our aim was to characterize the typical microvascular, cortical cerebral blood flow (CBF) changes in an OSA population during an apneic event. Sixteen patients (age 58  ±  8  years, 75% male) with a high risk of severe OSA were measured with a polysomnography device and with diffuse correlation spectroscopy (DCS) during one night of sleep with 1365 obstructive apneic events detected. All patients were later confirmed to suffer from severe OSA syndrome with a mean of 83  ±  15 apneas and hypopneas per hour. DCS has been shown to be able to characterize the microvascular CBF response to each event with a sufficient contrast-to-noise ratio to reveal its dynamics. It has also revealed that an apnea causes a peak increase of microvascular CBF (30  ±  17  %  ) at the end of the event followed by a drop (−20  ±  12  %  ) similar to what was observed in macrovascular CBF velocity of the middle cerebral artery. This study paves the way for the utilization of DCS for further studies on these populations.

Keywords: Sleep disorder breathing, Cerebral blood flow, Brain perfusion, Diffuse correlation spectroscopy

Farré, N., Jorba, I., Torres, M., Falcones, B., Martí-Almor, J., Farré, R., Almendros, I., Navajas, D., (2018). Passive stiffness of left ventricular myocardial tissue is reduced by ovariectomy in a post-menopause mouse model Frontiers in Physiology 9, Article 1545

Background: Heart failure (HF) – a very prevalent disease with high morbidity and mortality – usually presents with diastolic dysfunction. Although post-menopause women are at increased risk of HF and diastolic dysfunction, poor attention has been paid to clinically and experimentally investigate this group of patients. Specifically, whether myocardial stiffness is affected by menopause is unknown. Aim: To investigate whether loss of female sexual hormones modifies the Young’s modulus (E) of left ventricular (LV) myocardial tissue in a mouse model of menopause induced by ovariectomy (OVX). Methods: After 6 months of bilateral OVX, eight mice were sacrificed, fresh LV myocardial strips were prepared (∼8 × 1 × 1 mm), and their passive stress–stretch relationship was measured. E was computed by exponential fitting of the stress–stretch relationship. Subsequently, to assess the relative role of cellular and extracellular matrix components in determining OVX-induced changes in E, the tissues strips were decellularized and subjected to the same stretching protocol to measure E. A control group of eight sham-OVX mice was simultaneously studied. Results: E (kPa; m ± SE) in OVX mice was ∼twofold lower than in controls (11.7 ± 1.8 and 22.1 ± 4.4, respectively; p < 0.05). No significant difference between groups was found in E of the decellularized tissue (31.4 ± 12.05 and 40.9 ± 11.5, respectively; p = 0.58). Conclusion: Loss of female sexual hormones in an OVX model induces a reduction in the passive stiffness of myocardial tissue, suggesting that active relaxation should play a counterbalancing role in diastolic dysfunction in post-menopausal women with HF.

Keywords: Decellularized tissue, Female hormones, Heart tissue, Ovariectomy, Stress-strain

Pujol, E., Blanco-Cabra, N., Julián, E., Leiva, R., Torrents, E., Vázquez, S., (2018). Pentafluorosulfanyl-containing triclocarban analogs with potent antimicrobial activity Molecules 23, (11), 2853

Concerns have been raised about the long-term accumulating effects of triclocarban, a polychlorinated diarylurea widely used as an antibacterial soap additive, in the environment and in human beings. Indeed, the Food and Drug Administration has recently banned it from personal care products. Herein, we report the synthesis, antibacterial activity and cytotoxicity of novel N,N′-diarylureas as triclocarban analogs, designed by reducing one or more chlorine atoms of the former and/or replacing them by the novel pentafluorosulfanyl group, a new bioisostere of the trifluoromethyl group, with growing importance in drug discovery. Interestingly, some of these pentafluorosulfanyl-bearing ureas exhibited high potency, broad spectrum of antimicrobial activity against Gram-positive bacterial pathogens, and high selectivity index, while displaying a lower spontaneous mutation frequency than triclocarban. Some lines of evidence suggest a bactericidal mode of action for this family of compounds.

Keywords: Antibacterial, Gram-positive, N,N'-diarylureas, Pentafluorosulfanyl, Staphylococcus aureus, Triclocarban

Fonollosa, Jordi, Solórzano, Ana, Marco, Santiago, (2018). Chemical sensor systems and associated algorithms for fire detection: A review Sensors 18, (2), 553

Indoor fire detection using gas chemical sensing has been a subject of investigation since the early nineties. This approach leverages the fact that, for certain types of fire, chemical volatiles appear before smoke particles do. Hence, systems based on chemical sensing can provide faster fire alarm responses than conventional smoke-based fire detectors. Moreover, since it is known that most casualties in fires are produced from toxic emissions rather than actual burns, gas-based fire detection could provide an additional level of safety to building occupants. In this line, since the 2000s, electrochemical cells for carbon monoxide sensing have been incorporated into fire detectors. Even systems relying exclusively on gas sensors have been explored as fire detectors. However, gas sensors respond to a large variety of volatiles beyond combustion products. As a result, chemical-based fire detectors require multivariate data processing techniques to ensure high sensitivity to fires and false alarm immunity. In this paper, we the survey toxic emissions produced in fires and defined standards for fire detection systems. We also review the state of the art of chemical sensor systems for fire detection and the associated signal and data processing algorithms. We also examine the experimental protocols used for the validation of the different approaches, as the complexity of the test measurements also impacts on reported sensitivity and specificity measures. All in all, further research and extensive test under different fire and nuisance scenarios are still required before gas-based fire detectors penetrate largely into the market. Nevertheless, the use of dynamic features and multivariate models that exploit sensor correlations seems imperative

Keywords: Fire detection, Gas sensor, Pattern recognition, Sensor fusion, Machine learning, Toxicants, Carbon monoxide, Hydrogen cyanide, Standard test fires, Transducers, Smoke

Moulin-Frier, C., Fischer, T., Petit, M., Pointeau, G., Puigbo, J., Pattacini, U., Low, S. C., Camilleri, D., Nguyen, P., Hoffmann, M., Chang, H. J., Zambelli, M., Mealier, A., Damianou, A., Metta, G., Prescott, T. J., Demiris, Y., Dominey, P. F., Verschure, P. F. M. J., (2018). DAC-h3: A proactive robot cognitive architecture to acquire and express knowledge about the world and the self IEEE Transactions on Cognitive and Developmental Systems 10, (4), 1005-1022

This paper introduces a cognitive architecture for a humanoid robot to engage in a proactive, mixed-initiative exploration and manipulation of its environment, where the initiative can originate from both the human and the robot. The framework, based on a biologically-grounded theory of the brain and mind, integrates a reactive interaction engine, a number of state-of-the art perceptual and motor learning algorithms, as well as planning abilities and an autobiographical memory. The architecture as a whole drives the robot behavior to solve the symbol grounding problem, acquire language capabilities, execute goal-oriented behavior, and express a verbal narrative of its own experience in the world. We validate our approach in human-robot interaction experiments with the iCub humanoid robot, showing that the proposed cognitive architecture can be applied in real time within a realistic scenario and that it can be used with naive users.

Keywords: Autobiographical Memory., Biology, Cognition, Cognitive Robotics, Computer architecture, Distributed Adaptive Control, Grounding, Human-Robot Interaction, Humanoid robots, Robot sensing systems, Symbol Grounding

Miret-Casals, L., Baelo, A., Julián, E., Astola, J., Lobo-Ruiz, A., Albericio, F., Torrents, E., (2018). Hydroxylamine derivatives as a new paradigm in the search of antibacterial agents ACS Omega 3, (12), 17057-17069

Serious infections caused by bacteria that are resistant to commonly used antibiotics have become a major global healthcare problem in the 21st century. Multidrug-resistant bacteria causing severe infections mainly grow in complex bacterial communities known as biofilms, in which bacterial resistance to antibacterial agents and to the host immune system is strengthened. As drug resistance is becoming a threatening problem, it is necessary to develop new antimicrobial agents with novel mechanisms of action. Here, we designed and synthesized a small library of N-substituted hydroxylamine (N-HA) compounds with antibacterial activity. These compounds, acting as radical scavengers, inhibit the bacterial ribonucleotide reductase (RNR) enzyme. RNR enzyme is essential for bacterial proliferation during infection, as it provides the building blocks for DNA synthesis and repair. We demonstrate the broad antimicrobial effect of several drug candidates against a variety of Gram-positive and Gram-negative bacteria, together with low toxicity toward eukaryotic cells. Furthermore, the most promising compounds can reduce the biomass of an established biofilm on Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli. This study settles the starting point to develop new N-hydroxylamine compounds as potential effective antibacterial agents to fight against drug-resistant pathogenic bacteria.

Miquel, Joan, Santana, F., Palau, E., Vinagre, M., Langohr, K., Casals, A., Torrens, C., (2018). Retaining or excising the supraspinatus tendon in complex proximal humeral fractures treated with reverse prosthesis: a biomechanical analysis in two different designs Archives of Orthopaedic and Trauma Surgery 138, (11), 1533-1539

We aimed to biomechanically evaluate the effect of the supraspinatus tendon on tuberosity stability using two different reverse shoulder arthroplasty (RSA) models for complex proximal humeral fractures (PHFs).

Keywords: Tuberosity reconstruction, Reverse shoulder arthroplasty, Supraspinatus, Cadaveric study, Rotator cuff excision, Complex proximal humeral fractures

Pacheco, D., Verschure, P. F. M. J., (2018). Long-term spatial clustering in free recall Memory 26, (6), 798–806

We explored the influence of space on the organisation of items in long-term memory. In two experiments, we asked our participants to explore a virtual environment and memorise discrete items presented at specific locations. Memory for those items was later on tested in immediate (T1) and 24 hours delayed (T2) free recall tests, in which subjects were asked to recall as many items as possible in any order. In experiment 2, we further examined the contribution of active and passive navigation in recollection dynamics. Results across experiments revealed a significant tendency for participants to consecutively recall items that were encountered in proximate locations during learning. Moreover, the degree of spatial organisation and the total number of items recalled were positively correlated in the immediate and the delayed tests. Results from experiment 2 indicated that the spatial clustering of items was independent of navigation types. Our results highlight the long-term stability of spatial clustering effects and their correlation with recall performance, complementing previous results collected in immediate or briefly delayed tests.

Keywords: Free recall, Spatial clustering, Spatial memory, Spatial navigation, Virtual reality

Burgués, Javier, Hernandez, Victor, Lilienthal, Achim J., Marco, Santiago, (2018). 3D Gas distribution with and without artificial airflow: An experimental study with a grid of metal oxide semiconductor gas sensors Proceedings EUROSENSORS 2018 , MDPI (Graz, Austria) 2, (13), 911

Gas distribution modelling can provide potentially life-saving information when assessing the hazards of gaseous emissions and for localization of explosives, toxic or flammable chemicals. In this work, we deployed a three-dimensional (3D) grid of metal oxide semiconductor (MOX) gas sensors deployed in an office room, which allows for novel insights about the complex patterns of indoor gas dispersal. 12 independent experiments were carried out to better understand dispersion patters of a single gas source placed at different locations of the room, including variations in height, release rate and air flow profiles. This dataset is denser and richer than what is currently available, i.e., 2D datasets in wind tunnels. We make it publicly available to enable the community to develop, validate, and compare new approaches related to gas sensing in complex environments.

Keywords: MOX, Metal oxide, Flow visualization, Gas sensors, Gas distribution mapping, Sensor grid, 3D, Gas source localization, Indoor

Rodríguez-Pérez, Raquel, Padilla, Marta, Marco, S., (2018). The need of external validation for metabolomics predictive models Volatile Organic Compound Analysis in Biomedical Diagnosis Applications (ed. Cumeras, R., Correig, X.), Apple Academic Press (New York, USA) PART III: COMPUTATIONAL TOOLS, 225-252

Over the last decade, metabolomics research has produced thousands of research works. Many of them were describing the ability of machine learning methods to detect diverse health conditions based on massspectrometry, nuclear magnetic resonance or artificial olfaction analysis of body fluids.

Hristova-Panusheva, K., Keremidarska-Markova, M., Altankov, G., Krasteva, N., (2017). Age-related changes in adhesive phenotype of bone marrow-derived mesenchymal stem cells on extracellular matrix proteins Journal of New Results in Science , 6, (1), 11-19

Mesenchymal stem cells (MSCs) are a promising cell source for cell-based therapies because of their self-renewal and multi-lineage differentiation potential. Unlike embryonic stem cells adult stem cells are subject of aging processes and the concomitant decline in their function. Age-related changes in MSCs have to be well understood in order to develop clinical techniques and therapeutics based on these cells. In this work we have studied the effect of aging on adhesive behaviour of bone marrow-derived MSC and MG- 63 osteoblastic cells onto three extracellular matrix proteins: fibronectin (FN), vitronectin (VN) and collagen I (Coll I). The results revealed substantial differences in adhesive behaviour of both cell types during 21 days in culture. Bone-marrow derived MSCs decreased significantly their adhesive affinity to all studied proteins after 7th day in culture with further incubation. In contrast, MG-63 cells, demonstrated a stable cell adhesive phenotype with high affinity to FN and Coll I and low affinity to vitronectin over the whole culture period. These data suggest that adhesive behaviour of MSCs to matrix proteins is affected by aging processes unlike MG-63 cells and the age-related changes have to be considered when expanding adult stem cells for clinical applications.

Keywords: Cell morphology, Cell attachment and spreading, Fibronectin, Vitronectin, Collagen I

Rodriguez-Franco, P., Brugués, A., Marin-Llaurado, A., Conte, V., Solanas, G., Batlle, E., Fredberg, J. J., Roca-Cusachs, P., Sunyer, R., Trepat, X., (2017). Long-lived force patterns and deformation waves at repulsive epithelial boundaries Nature Materials 16, (10), 1029-1036

For an organism to develop and maintain homeostasis, cell types with distinct functions must often be separated by physical boundaries. The formation and maintenance of such boundaries are commonly attributed to mechanisms restricted to the cells lining the boundary. Here we show that, besides these local subcellular mechanisms, the formation and maintenance of tissue boundaries involves long-lived, long-ranged mechanical events. Following contact between two epithelial monolayers expressing, respectively, EphB2 and its ligand ephrinB1, both monolayers exhibit oscillatory patterns of traction forces and intercellular stresses that tend to pull cell-matrix adhesions away from the boundary. With time, monolayers jam, accompanied by the emergence of deformation waves that propagate away from the boundary. This phenomenon is not specific to EphB2/ephrinB1 repulsion but is also present during the formation of boundaries with an inert interface and during fusion of homotypic epithelial layers. Our findings thus unveil a global physical mechanism that sustains tissue separation independently of the biochemical and mechanical features of the local tissue boundary.

Keywords: Biological physics, Cellular motility

Elosegui-Artola, A., Andreu, I., Beedle, A. E. M., Lezamiz, A., Uroz, M., Kosmalska, A. J., Oria, R., Kechagia, J. Z., Rico-Lastres, P., Le Roux, A. L., Shanahan, C. M., Trepat, X., Navajas, D., Garcia-Manyes, S., Roca-Cusachs, P., (2017). Force triggers YAP nuclear entry by regulating transport across nuclear pores Cell , 171, (6), 1397-1410

YAP is a mechanosensitive transcriptional activator with a critical role in cancer, regeneration, and organ size control. Here, we show that force applied to the nucleus directly drives YAP nuclear translocation by decreasing the mechanical restriction of nuclear pores to molecular transport. Exposure to a stiff environment leads cells to establish a mechanical connection between the nucleus and the cytoskeleton, allowing forces exerted through focal adhesions to reach the nucleus. Force transmission then leads to nuclear flattening, which stretches nuclear pores, reduces their mechanical resistance to molecular transport, and increases YAP nuclear import. The restriction to transport is further regulated by the mechanical stability of the transported protein, which determines both active nuclear transport of YAP and passive transport of small proteins. Our results unveil a mechanosensing mechanism mediated directly by nuclear pores, demonstrated for YAP but with potential general applicability in transcriptional regulation. Force-dependent changes in nuclear pores control protein access to the nucleus.

Keywords: Atomic force microscopy, Hippo pathway, Mechanosensing, Mechanotransduction, Molecular mechanical stability, Nuclear mechanics, Nuclear pores, Nuclear transport, Rigidity sensing, Transcription regulation

Feiner-Gracia, Natalia, Buzhor, Marina, Fuentes, Edgar, Pujals, S., Amir, Roey J., Albertazzi, Lorenzo, (2017). Micellar stability in biological media dictates internalization in living cells Journal of the American Chemical Society 139, (46), 16677-16687

The dynamic nature of polymeric assemblies makes their stability in biological media a crucial parameter for their potential use as drug delivery systems in vivo. Therefore, it is essential to study and understand the behavior of self-assembled nanocarriers under conditions that will be encountered in vivo such as extreme dilutions and interactions with blood proteins and cells. Herein, using a combination of fluorescence spectroscopy and microscopy, we studied four amphiphilic PEG–dendron hybrids and their self-assembled micelles in order to determine their structure–stability relations. The high molecular precision of the dendritic block enabled us to systematically tune the hydrophobicity and stability of the assembled micelles. Using micelles that change their fluorescent properties upon disassembly, we observed that serum proteins bind to and interact with the polymeric amphiphiles in both their assembled and monomeric states. These interactions strongly affected the stability and enzymatic degradation of the micelles. Finally, using spectrally resolved confocal imaging, we determined the relations between the stability of the polymeric assemblies in biological media and their cell entry. Our results highlight the important interplay between molecular structure, micellar stability, and cell internalization pathways, pinpointing the high sensitivity of stability–activity relations to minor structural changes and the crucial role that these relations play in designing effective polymeric nanostructures for biomedical applications.

Perez-Mockus, Gantas, Mazouni, Khalil, Roca, Vanessa, Corradi, Giulia, Conte, Vito, Schweisguth, François, (2017). Spatial regulation of contractility by Neuralized and Bearded during furrow invagination in Drosophila Nature Communications 8, (1), 1594

Embryo-scale morphogenesis arises from patterned mechanical forces. During Drosophila gastrulation, actomyosin contractility drives apical constriction in ventral cells, leading to furrow formation and mesoderm invagination. It remains unclear whether and how mechanical properties of the ectoderm influence this process. Here, we show that Neuralized (Neur), an E3 ubiquitin ligase active in the mesoderm, regulates collective apical constriction and furrow formation. Conversely, the Bearded (Brd) proteins antagonize maternal Neur and lower medial–apical contractility in the ectoderm: in Brd-mutant embryos, the ventral furrow invaginates properly but rapidly unfolds as medial MyoII levels increase in the ectoderm. Increasing contractility in the ectoderm via activated Rho similarly triggers furrow unfolding whereas decreasing contractility restores furrow invagination in Brd-mutant embryos. Thus, the inhibition of Neur by Brd in the ectoderm differentiates the mechanics of the ectoderm from that of the mesoderm and patterns the activity of MyoII along the dorsal–ventral axis.

Keywords: Drosophila, Gastrulation, Morphogenesis

Feiner-Gracia, Natalia, Beck, Michaela, Pujals, Sílvia, Tosi, Sébastien, Mandal, Tamoghna, Buske, Christian, Linden, Mika, Albertazzi, Lorenzo, (2017). Super-resolution microscopy unveils dynamic heterogeneities in nanoparticle protein corona Small 13, (41), 1701631

The adsorption of serum proteins, leading to the formation of a biomolecular corona, is a key determinant of the biological identity of nanoparticles in vivo. Therefore, gaining knowledge on the formation, composition, and temporal evolution of the corona is of utmost importance for the development of nanoparticle-based therapies. Here, it is shown that the use of super-resolution optical microscopy enables the imaging of the protein corona on mesoporous silica nanoparticles with single protein sensitivity. Particle-by-particle quantification reveals a significant heterogeneity in protein absorption under native conditions. Moreover, the diversity of the corona evolves over time depending on the surface chemistry and degradability of the particles. This paper investigates the consequences of protein adsorption for specific cell targeting by antibody-functionalized nanoparticles providing a detailed understanding of corona-activity relations. The methodology is widely applicable to a variety of nanostructures and complements the existing ensemble approaches for protein corona study.

Keywords: Heterogeneity, Mesoporous silica nanoparticles, Protein corona, Super-resolution imaging, Targeting

Ojosnegros', Samuel, Cutrale, Francesco, Rodríguez, Daniel, Otterstrom, Jason J., Chiu, Chi Li, Hortigüela, Verónica, Tarantino, Carolina, Seriola', Anna, Mieruszynski, Stephen, Martínez, Elena, Lakadamyali, Melike, Raya, Angel, Fraser, Scott E., (2017). Eph-ephrin signaling modulated by polymerization and condensation of receptors Proceedings of the National Academy of Sciences of the United States of America 114, (50), 13188-13193

Eph receptor signaling plays key roles in vertebrate tissue boundary formation, axonal pathfinding, and stem cell regeneration by steering cells to positions defined by its ligand ephrin. Some of the key events in Eph-ephrin signaling are understood: ephrin binding triggers the clustering of the Eph receptor, fostering transphosphorylation and signal transduction into the cell. However, a quantitative and mechanistic understanding of how the signal is processed by the recipient cell into precise and proportional responses is largely lacking. Studying Eph activation kinetics requires spatiotemporal data on the number and distribution of receptor oligomers, which is beyond the quantitative power offered by prevalent imaging methods. Here we describe an enhanced fluorescence fluctuation imaging analysis, which employs statistical resampling to measure the Eph receptor aggregation distribution within each pixel of an image. By performing this analysis over time courses extending tens of minutes, the information-rich 4D space (x, y, oligomerization, time) results were coupled to straightforward biophysical models of protein aggregation. This analysis reveals that Eph clustering can be explained by the combined contribution of polymerization of receptors into clusters, followed by their condensation into far larger aggregates. The modeling reveals that these two competing oligomerization mechanisms play distinct roles: polymerization mediates the activation of the receptor by assembling monomers into 6- to 8-mer oligomers; condensation of the preassembled oligomers into large clusters containing hundreds of monomers dampens the signaling. We propose that the polymerization–condensation dynamics creates mechanistic explanation for how cells properly respond to variable ligand concentrations and gradients.

Keywords: Eph, Ephrin, Receptor tyrosine kinase, Gradients, Cell communication

Moles, E., Galiano, S., Gomes, A., Quiliano, M., Teixeira, C., Aldana, I., Gomes, P., Fernàndez-Busquets, X., (2017). ImmunoPEGliposomes for the targeted delivery of novel lipophilic drugs to red blood cells in a falciparum malaria murine model Biomaterials 145, 178-191

Most drugs currently entering the clinical pipeline for severe malaria therapeutics are of lipophilic nature, with a relatively poor solubility in plasma and large biodistribution volumes. Low amounts of these compounds do consequently accumulate in circulating Plasmodium-infected red blood cells, exhibiting limited antiparasitic activity. These drawbacks can in principle be satisfactorily dealt with by stably encapsulating drugs in targeted nanocarriers. Here this approach has been adapted for its use in immunocompetent mice infected by the Plasmodium yoelii 17XL lethal strain, selected as a model for human blood infections by Plasmodium falciparum. Using immunoliposomes targeted against a surface protein characteristic of the murine erythroid lineage, the protocol has been applied to two novel antimalarial lipophilic drug candidates, an aminoquinoline and an aminoalcohol. Large encapsulation yields of >90% were obtained using a citrate-buffered pH gradient method and the resulting immunoliposomes reached in vivo erythrocyte targeting and retention efficacies of >80%. In P. yoelii-infected mice, the immunoliposomized aminoquinoline succeeded in decreasing blood parasitemia from severe to uncomplicated malaria parasite densities (i.e. from ≥25% to ca. 5%), whereas the same amount of drug encapsulated in non-targeted liposomes had no significant effect on parasite growth. Pharmacokinetic analysis indicated that this good performance was obtained with a rapid clearance of immunoliposomes from the circulation (blood half-life of ca. 2 h), suggesting a potential for improvement of the proposed model.

Keywords: Immunoliposomes, Malaria, Nanomedicine, Plasmodium falciparum, Plasmodium yoelii 17XL, Targeted drug delivery

Schieber, R., Lasserre, F., Hans, M., Fernández-Yagüe, M., Díaz-Ricart, M., Escolar, G., Ginebra, M. P., Mücklich, F., Pegueroles, M., (2017). Direct laser interference patterning of CoCr alloy surfaces to control endothelial cell and platelet response for cardiovascular applications Advanced Healthcare Materials 6, (19), 1700327

The main drawbacks of cardiovascular bare-metal stents (BMS) are in-stent restenosis and stent thrombosis as a result of an incomplete endothelialization after stent implantation. Nano- and microscale modification of implant surfaces is a strategy to recover the functionality of the artery by stimulating and guiding molecular and biological processes at the implant/tissue interface. In this study, cobalt-chromium (CoCr) alloy surfaces are modified via direct laser interference patterning (DLIP) in order to create linear patterning onto CoCr surfaces with different periodicities (≈3, 10, 20, and 32 μm) and depths (≈20 and 800 nm). Changes in surface topography, chemistry, and wettability are thoroughly characterized before and after modification. Human umbilical vein endothelial cells' adhesion and spreading are similar for all patterned and plain CoCr surfaces. Moreover, high-depth series induce cell elongation, alignment, and migration along the patterned lines. Platelet adhesion and aggregation decrease in all patterned surfaces compared to CoCr control, which is associated with changes in wettability and oxide layer characteristics. Cellular studies provide evidence of the potential of DLIP topographies to foster endothelialization without enhancement of platelet adhesion, which will be of high importance when designing new BMS in the future.

Keywords: CoCr, Direct laser interference patterning, Endothelial cells, Linear surface pattern, Platelets

Wu, Bi-Yi, Sheng, Xin-Qing, Fabregas, Rene, Hao, Yang, (2017). Full-wave modeling of broadband near field scanning microwave microscopy Scientific Reports 7, (1), 16064

A three-dimensional finite element numerical modeling for the scanning microwave microscopy (SMM) setup is applied to study the full-wave quantification of the local material properties of samples. The modeling takes into account the radiation and scattering losses of the nano-sized probe neglected in previous models based on low-frequency assumptions. The scanning techniques of approach curves and constant height are implemented. In addition, we conclude that the SMM has the potential for use as a broadband dielectric spectroscopy operating at higher frequencies up to THz. The results demonstrate the accuracy of previous models. We draw conclusions in light of the experimental results.

Schillers, H., Rianna, C., Schäpe, J., Luque, T., Doschke, H., Wälte, M., Uriarte, J. J., Campillo, N., Michanetzis, G. P. A., Bobrowska, J., Dumitru, A., Herruzo, E. T., Bovio, S., Parot, P., Galluzzi, M., Podestà, A., Puricelli, L., Scheuring, S., Missirlis, Y., Garcia, R., Odorico, M., Teulon, J. M., Lafont, F., Lekka, M., Rico, F., Rigato, A., Pellequer, J. L., Oberleithner, H., Navajas, D., Radmacher, M., (2017). Standardized nanomechanical atomic force microscopy procedure (SNAP) for measuring soft and biological samples Scientific Reports 7, (1), 5117

We present a procedure that allows a reliable determination of the elastic (Young's) modulus of soft samples, including living cells, by atomic force microscopy (AFM). The standardized nanomechanical AFM procedure (SNAP) ensures the precise adjustment of the AFM optical lever system, a prerequisite for all kinds of force spectroscopy methods, to obtain reliable values independent of the instrument, laboratory and operator. Measurements of soft hydrogel samples with a well-defined elastic modulus using different AFMs revealed that the uncertainties in the determination of the deflection sensitivity and subsequently cantilever's spring constant were the main sources of error. SNAP eliminates those errors by calculating the correct deflection sensitivity based on spring constants determined with a vibrometer. The procedure was validated within a large network of European laboratories by measuring the elastic properties of gels and living cells, showing that its application reduces the variability in elastic moduli of hydrogels down to 1%, and increased the consistency of living cells elasticity measurements by a factor of two. The high reproducibility of elasticity measurements provided by SNAP could improve significantly the applicability of cell mechanics as a quantitative marker to discriminate between cell types and conditions.

Nedjari, Salima, Awaja, Firas, Altankov, George, (2017). Three dimensional honeycomb patterned fibrinogen based nanofibers induce substantial osteogenic response of mesenchymal stem cells Scientific Reports 7, (1), 15947

Stem cells therapy offers a viable alternative for treatment of bone disorders to the conventional bone grafting. However clinical therapies are still hindered by the insufficient knowledge on the conditions that maximize stem cells differentiation. Hereby, we introduce a novel 3D honeycomb architecture scaffold that strongly support osteogenic differentiation of human adipose derived mesenchymal stem cells (ADMSCs). The scaffold is based on electrospun hybrid nanofibers consisting of poly (L-lactide ε-caprolactone) and fibrinogen (PLCL/FBG). Classical fibers orientations, random or aligned were also produced and studied for comparison. The overall morphology of ADMSC’s generally followed the nanofibers orientation and dimensionality developing regular focal adhesions and direction-dependent actin cytoskeleton bundles. However, there was an initial tendency for cells rounding on honeycomb scaffolds before ADMSCs formed a distinct bridging network. This specific cells organization appeared to have significant impact on the differentiation potential of ADMSCs towards osteogenic lineage, as indicated by the alkaline phosphatase production, calcium deposition and specific genes expression. Collectively, it was observed synergistic effect of nanofibers with honeycomb architecture on the behavior of ADMSCs entering osteogenic path of differentiation which outlines the potential benefits from insertion of such bioinspired geometrical cues within scaffolds for bone tissue engineering.

Fraioli, R., Tsimbouri, P. M., Fisher, L. E., Nobbs, A. H., Su, B., Neubauer, S., Rechenmacher, F., Kessler, H., Ginebra, M. P., Dalby, M. J., Manero, J. M., Mas-Moruno, C., (2017). Towards the cell-instructive bactericidal substrate: Exploring the combination of nanotopographical features and integrin selective synthetic ligands Scientific Reports 7, (1), 16363

Engineering the interface between biomaterials and tissues is important to increase implant lifetime and avoid failures and revision surgeries. Permanent devices should enhance attachment and differentiation of stem cells, responsible for injured tissue repair, and simultaneously discourage bacterial colonization; this represents a major challenge. To take first steps towards such a multifunctional surface we propose merging topographical and biochemical cues on the surface of a clinically relevant material such as titanium. In detail, our strategy combines antibacterial nanotopographical features with integrin selective synthetic ligands that can rescue the adhesive capacity of the surfaces and instruct mesenchymal stem cell (MSC) response. To this end, a smooth substrate and two different high aspect ratio topographies have been produced and coated either with an αvβ3-selective peptidomimetic, an α5β1-selective peptidomimetic, or an RGD/PHSRN peptidic molecule. Results showed that antibacterial effects of the substrates could be maintained when tested on pathogenic Pseudomonas aeruginosa. Further, functionalization increased MSC adhesion to the surfaces and the αvβ3-selective peptidomimetic-coated nanotopographies promoted osteogenesis. Such a dual physicochemical approach to achieve multifunctional surfaces represents a first step in the design of novel cell-instructive biomaterial surfaces.

Keywords: Bioinspired materials, Biomaterials – cells

Gugutkov, D., Gustavsson, J., Cantini, M., Salmeron-Sánchez, M., Altankov, G., (2017). Electrospun fibrinogen-PLA nanofibres for vascular tissue engineering Journal of Tissue Engineering and Regenerative Medicine 11, (10), 2774-2784

Here we report on the development of a new type of hybrid fibrinogen-polylactic acid (FBG-PLA) nanofibres (NFs) with improved stiffness, combining the good mechanical properties of PLA with the excellent cell recognition properties of native FBG. We were particularly interested in the dorsal and ventral cell response to the nanofibres' organization (random or aligned), using human umbilical endothelial cells (HUVECs) as a model system. Upon ventral contact with random NFs, the cells developed a stellate-like morphology with multiple projections. The well-developed focal adhesion complexes suggested a successful cellular interaction. However, time-lapse analysis shows significantly lowered cell movements, resulting in the cells traversing a relatively short distance in multiple directions. Conversely, an elongated cell shape and significantly increased cell mobility were observed in aligned NFs. To follow the dorsal cell response, artificial wounds were created on confluent cell layers previously grown on glass slides and covered with either random or aligned NFs. Time-lapse analysis showed significantly faster wound coverage (within 12 h) of HUVECs on aligned samples vs. almost absent directional migration on random ones. However, nitric oxide (NO) release shows that endothelial cells possess lowered functionality on aligned NFs compared to random ones, where significantly higher NO production was found. Collectively, our studies show that randomly organized NFs could support the endothelization of implants while aligned NFs would rather direct cell locomotion for guided neovascularization.

Keywords: Electrospun nanofibers, Endothelial cells, Fibrinogen, Guided cellular behavior, Polylactic acid, Vascular tissue engineering

Wang, Y., van Merwyk, L., Tönsing, K., Walhorn, V., Anselmetti, D., Fernàndez-Busquets, X., (2017). Biophysical characterization of the association of histones with single-stranded DNA Biochimica et Biophysica Acta (BBA) - General Subjects , 1861, (11), 2739-2749

Background: Despite the profound current knowledge of the architecture and dynamics of nucleosomes, little is known about the structures generated by the interaction of histones with single-stranded DNA (ssDNA), which is widely present during replication and transcription. Methods: Non-denaturing gel electrophoresis, transmission electron microscopy, atomic force microscopy, magnetic tweezers. Results: Histones have a high affinity for ssDNA in 0.15 M NaCl ionic strength, with an apparent binding constant similar to that calculated for their association with double-stranded DNA (dsDNA). The length of DNA (number of nucleotides in ssDNA or base pairs in dsDNA) associated with a fixed core histone mass is the same for both ssDNA and dsDNA. Although histone-ssDNA complexes show a high tendency to aggregate, nucleosome-like structures are formed at physiological salt concentrations. Core histones are able to protect ssDNA from digestion by micrococcal nuclease, and a shortening of ssDNA occurs upon its interaction with histones. The purified (+) strand of a cloned DNA fragment of nucleosomal origin has a higher affinity for histones than the purified complementary (−) strand. Conclusions: At physiological ionic strength histones have high affinity for ssDNA, possibly associating with it into nucleosome-like structures. General significance: In the cell nucleus histones may spontaneously interact with ssDNA to facilitate their participation in the replication and transcription of chromatin.

Keywords: Electrophoresis, Force spectroscopy, Histones, Magnetic tweezers, Nucleosome, Single-stranded DNA

Campillo, N., Falcones, B., Montserrat, J. M., Gozal, D., Obeso, A., Gallego-Martin, T., Navajas, D., Almendros, I., Farré, R., (2017). Frequency and magnitude of intermittent hypoxia modulate endothelial wound healing in a cell culture model of sleep apnea Journal of Applied Physiology , 123, (5), 1047-1054

Intermittent hypoxia (IH) has been implicated in the cardiovascular consequences of obstructive sleep apnea (OSA). However, the lack of suitable experimental systems has precluded assessment as to whether IH is detrimental, protective, or both for the endothelium. The aim of the work was to determine the effects of frequency and amplitude of IH oxygenation swings on aortic endothelial wound healing. Monolayers of human primary endothelial cells were wounded and subjected to constant oxygenation (1%, 4%, 13%, or 20% O2) or IH at different frequencies (0.6, 6, or 60 cycles/h) and magnitude ranges (13–4% O2 or 20–1% O2), using a novel well-controlled system, with wound healing being measured after 24 h. Cell monolayer repair was similar at 20% O2 and 13% O2, but was considerably increased (approximately twofold) in constant hypoxia at 4% O2. The magnitude and frequency of IH considerably modulated wound healing. Cycles ranging 13–4% O2 at the lowest frequency (0.6 cycles/h) accelerated endothelial wound healing by 102%. However, for IH exposures consisting of 20% to 1% O2 oscillations, wound closure was reduced compared with oscillation in the 13–4% range (by 74% and 44% at 6 cycles/h and 0.6 cycles/h, respectively). High-frequency IH patterns simulating severe OSA (60 cycles/h) did not significantly modify endothelial wound closure, regardless of the oxygenation cycle amplitude. In conclusion, the frequency and magnitude of hypoxia cycling in IH markedly alter wound healing responses and emerge as key factors determining how cells will respond in OSA. NEW & NOTEWORTHY Intermittent hypoxia (IH) induces cardiovascular consequences in obstructive sleep apnea (OSA) patients. However, the vast array of frequencies and severities of IH previously employed in OSA-related experimental studies has led to controversial results on the effects of IH. By employing an optimized IH experimental system here, we provide evidence that the frequency and magnitude of IH markedly alter human aortic endothelial wound healing, emerging as key factors determining how cells respond in OSA.

Keywords: Sleep apnea, Repair, Endothelium, Hypoxia, Reoxygenation

Mohammadi, M. H., Obregón, R., Ahadian, S., Ramón-Azcón, J., Radisic, M., (2017). Engineered muscle tissues for disease modeling and drug screening applications Current Pharmaceutical Design , 23, (20), 2991-3004

Animal models have been the main resources for drug discovery and prediction of drugs’ pharmacokinetic responses in the body. However, noticeable drawbacks associated with animal models include high cost, low reproducibility, low physiological similarity to humans, and ethical problems. Engineered tissue models have recently emerged as an alternative or substitute for animal models in drug discovery and testing and disease modeling. In this review, we focus on skeletal muscle and cardiac muscle tissues by first describing their characterization and physiology. Major fabrication technologies (i.e., electrospinning, bioprinting, dielectrophoresis, textile technology, and microfluidics) to make functional muscle tissues are then described. Finally, currently used muscle tissue models in drug screening are reviewed and discussed.

Keywords: Cardiac muscle, Drug screening, Engineering muscle, Human pharmacological response, Physiological similarity, Skeletal muscle

Zaffino, R. L., Mir, M., Samitier, J., (2017). Oligonucleotide probes functionalization of nanogap electrodes Electrophoresis , 38, (21), 2712-2720

Nanogap electrodes have attracted a lot of consideration as promising platform for molecular electronic and biomolecules detection. This is mainly for their higher aspect ratio, and because their electrical properties are easily accessed by current-voltage measurements. Nevertheless, application of standard current-voltages measurements used to characterize nanogap response, and/or to modify specific nanogap electrodes properties, represents an issue. Since the strength of electrical fields in nanoscaled devices can reach high values, even at low voltages. Here, we analyzed the effects induced by different methods of surface modification of nanogap electrodes, in test-voltage application, employed for the electrical detection of a desoxyribonucleic acid (DNA) target. Nanogap electrodes were functionalized with two antisymmetric oligo-probes designed to have 20 terminal bases complementary to the edges of the target, which after hybridization bridges the nanogap, closing the electrical circuit. Two methods of functionalization were studied for this purpose; a random self-assembling of a mixture of the two oligo-probes (OPs) used in the platform, and a selective method that controls the position of each OP at selected side of nanogap electrodes. We used for this aim, the electrophoretic effect induced on negatively charged probes by the application of an external direct current voltage. The results obtained with both functionalization methods where characterized and compared in terms of electrode surface covering, calculated by using voltammetry analysis. Moreover, we contrasted the electrical detection of a DNA target in the nanogap platform either in site-selective and in randomly assembled nanogap. According to our results, a denser, although not selective surface functionalization, is advantageous for such kind of applications.

Keywords: Biosensor bioelectronics, DNA electrophoresis, Nanogap electrodes, Self-assembled monolayers, Site-selective deposition

Tezanos, E., Badiola, M., Samitier, J., (2017). 3D Bioprinted muscle on a chip CASEIB Proceedings XXXV Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2017) , Sociedad Española de Ingeniería Biomédica (Valencia, Spain) , XXXX (falta pdf)

Rodriguez, J., Voss, A., Caminal, P., Bayes-Genis, A., Giraldo, B. F., (2017). Characterization and classification of patients with different levels of cardiac death risk by using Poincaré plot analysis Engineering in Medicine and Biology Society (EMBC) 39th Annual International Conference of the IEEE , IEEE (Seogwipo, South Korea) , 1332-1335

Cardiac death risk is still a big problem by an important part of the population, especially in elderly patients. In this study, we propose to characterize and analyze the cardiovascular and cardiorespiratory systems using the Poincaré plot. A total of 46 cardiomyopathy patients and 36 healthy subjets were analyzed. Left ventricular ejection fraction (LVEF) was used to stratify patients with low risk (LR: LVEF > 35%, 16 patients), and high risk (HR: LVEF ≤ 35%, 30 patients) of heart attack. RR, SBP and TTot time series were extracted from the ECG, blood pressure and respiratory flow signals, respectively. Parameters that describe the scatterplott of Poincaré method, related to short- and long-term variabilities, acceleration and deceleration of the dynamic system, and the complex correlation index were extracted. The linear discriminant analysis (LDA) and the support vector machines (SVM) classification methods were used to analyze the results of the extracted parameters. The results showed that cardiac parameters were the best to discriminate between HR and LR groups, especially the complex correlation index (p = 0.009). Analising the interaction, the best result was obtained with the relation between the difference of the standard deviation of the cardiac and respiratory system (p = 0.003). When comparing HR vs LR groups, the best classification was obtained applying SVM method, using an ANOVA kernel, with an accuracy of 98.12%. An accuracy of 97.01% was obtained by comparing patients versus healthy, with a SVM classifier and Laplacian kernel. The morphology of Poincaré plot introduces parameters that allow the characterization of the cardiorespiratory system dynamics.

Keywords: Time series analysis, Electrocardiography, Support vector machines, Kernel, Standards, Correlation, RF signals

Castillo, Y., Blanco, D., Whitney, J., Mersky, B., Jané, R., (2017). Characterization of a tooth microphone coupled to an oral appliance device: A new system for monitoring OSA patients Engineering in Medicine and Biology Society (EMBC) 39th Annual International Conference of the IEEE , IEEE (Seogwipo, South Korea) , 1543-1546

Obstructive sleep apnea (OSA) is a highly prevalent chronic disease, especially in elderly and obese populations. Despite constituting a serious health, social and economic problem, most patients remain undiagnosed and untreated due to limitations in current equipment. In this work, we propose a novel method to diagnose OSA and monitor therapy adherence and effectiveness at home in a non-invasive and inexpensive way: combining acoustic analysis of breathing and snoring sounds with oral appliance therapy (OA). Audiodontics has introduced a new sensor, a tooth microphone coupled to an OA device, which is the main pillar of this system. The objective of this work is to characterize the response of this sensor, comparing it with a commercial tracheal microphone (Biopac transducer). Signals containing OSA-related sounds were acquired simultaneously with the two microphones for that purpose. They were processed and analyzed in time, frequency and time-frequency domains, in a custom MATLAB interface. We carried out a single-event approach focused on breaths, snores and apnea episodes. We found that the quality of the signals obtained by both microphones was quite similar, although the tooth microphone spectrum concentrated more energy at the high-frequency band. This opens a new field of study about high-frequency components of snores and breathing sounds. These characteristics, together with its intraoral position, wireless option and combination with customizable OAs, give the tooth microphone a great potential to reduce the impact of sleep disorders, by enabling prompt detection and continuous monitoring of patients at home.

Keywords: Microphones, Teeth, Sleep apnea, Time-frequency analysis, Signal to noise ratio, Monitoring, Acoustics

Castillo, Y., Camara, M. A., Blanco-Almazan, D., Jane, R., (2017). Characterization of microphones for snoring and breathing events analysis in mHealth Engineering in Medicine and Biology Society (EMBC) 39th Annual International Conference of the IEEE , IEEE (Seogwipo, South Korea) , 1547-1550

Obstructive sleep apnea (OSA) is one of the most common sleep disorders, especially in elderly population. Despite its high prevalence and severe consequences, most patients remain undiagnosed due to serious limitations on the existing equipment. Efforts are being done to find cost-effective alternatives and mHealth solutions could play a key role. One promising approach in this context is the acoustic analysis of snoring. The sensor it requires is a microphone, which is widely available in different models and even integrated in smartphones. The objective of this work is to characterize and compare the responses of two commercial tracheal microphones and a mHealth-based microphone, as a proof-of-concept to evaluate their potential as sensors for OSA detection. To do that, we designed an experimental protocol to study OSA-related events (breaths, snores and apneas) simulated by 4 subjects. Test signals were simultaneously recorded with different microphones and posteriorly processed and analyzed. We accurately characterized the frequency response of the two commercial microphones, finding that one of them was too restrictive (bandwidth 50-250 Hz) and thus not suitable as snoring sensor for high-frequency acoustic analysis. Regarding smartphones, we studied the Samsung Galaxy S5 microphone. We found that, when located over the thorax, it provided quality signals comparable to those of tracheal microphones, with a broader frequency response. Further work is required, but this preliminary study suggests that acoustic analysis of snoring through mHealth solutions can be a feasible alternative to screen and monitor OSA patients at home.

Garcia-Castellote, D., Torres, A., Estrada, L., Sarlabous, L., Jane, R., (2017). Evaluation of indirect measures of neural inspiratory time from invasive and noninvasive recordings of respiratory activity Engineering in Medicine and Biology Society (EMBC) 39th Annual International Conference of the IEEE , IEEE (Seogwipo, South Korea) , 341-344

Measuring diaphragmatic electromyography (EMGdi) provides an indirect quantification of neural respiratory drive and allows the delimitation of diaphragm neural activation and deactivation during inspiration. EMGdi recordings have been incorporated in novel modes of assisted mechanical ventilation, such as neurally adjusted ventilatory assist (NAVA), to trigger and cycle-off the ventilator. The EMGdi signal improves the assistance delivered by more conventional ventilatory modes, in which the ventilator is synchronized with the patient employing a pneumatic triggering. In this work, we evaluate the time delay between the onset and offset of inspiratory activity estimated from EMGdi and three respiratory mechanical signals: the respiratory flow (FL), the transdiaphragmatic pressure (Pdi) and the diaphragm length (Ldi) signals. To this purpose, these signals were acquired in three mongrel dogs surgically instrumented under general anesthesia. Onsets and offsets were estimated manually and by automatic algorithms on these signals. The highest delays were obtained between EMGdi and FL (100 ms) while the lowest delays were obtained between EMGdi and Pdi (8 ms). Moreover, differences between manual and automatic estimations showed a mean absolute error lower than 45 ms. In conclusion, our study points out that both EMGdi and Pdi signals detect the onset and offset of inspiratory activity earlier than the FL signal, and would therefore be better for the improvement of patient-ventilator synchrony.

Keywords: Estimation, Ventilation, Anesthesia, Dogs, Manuals, Power harmonic filters

Badiola, M., Hervera, A., López, J., Segura, Miriam, del Río, J. A., Samitier, J., (2017). In-vitro Peripheral Nervous System on a chip CASEIB Proceedings XXXV Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2017) , Sociedad Española de Ingeniería Biomédica (Valencia, Spain) , XXXX (falta pdf)

Camara, M. A., Castillo, Y., Blanco-Almazan, D., Estrada, L., Jane, R., (2017). MHealth tools for monitoring Obstructive Sleep Apnea patients at home: Proof-of-concept Engineering in Medicine and Biology Society (EMBC) 39th Annual International Conference of the IEEE , IEEE (Seogwipo, South Korea) , 1555-1558

Obstructive Sleep Apnea (OSA) is a sleep disorder that affects mainly the adult and elderly population. Due to the high percentage of patients who remain undiagnosed and untreated because of limitations of current diagnosis methods, the management of OSA is an important social, scientific and economic problem that will be difficult to be assumed by health systems. On the other hand, smartphone platforms (mHealth systems) are being considered as an innovative solution, thanks to the integration of the essential sensors to obtain clinically relevant parameters in the same device or in combination with wireless wearable devices.

Keywords: Sleep apnea, Microphones, Monitoring, Sensors, Accelerometers, Biomedical monitoring, Band-pass filters

Schulz, S., Legorburu Cladera, B., Giraldo, B., Bolz, M., Bar, K. J., Voss, A., (2017). Neuronal desynchronization as marker of an impaired brain network Engineering in Medicine and Biology Society (EMBC) 39th Annual International Conference of the IEEE , IEEE (Seogwipo, South Korea) , 2251-2254

Synchronization is a central key feature of neural information processing and communication between different brain areas. Disturbance of oscillatory brain rhythms and decreased synchronization have been associated with different disorders including schizophrenia. The aim of this study was to investigate whether synchronization (in relaxed conditions with no stimuli) between different brain areas within the delta, theta, alpha (alpha1, alpha2), beta (beta1, beta2), and gamma bands is altered in patients with a neurological disorder in order to generate significant cortical enhancements. To achieve this, we investigated schizophrenic patients (SZO; N=17, 37.5±10.4 years, 15 males) and compared them to healthy subjects (CON; N=21, 36.7±13.4 years, 15 males) applying the phase locking value (PLV). We found significant differences between SZO and CON in different brain areas of the theta, alpha1, beta2 and gamma bands. These areas are related to the central and parietal lobes for the theta band, the parietal lobe for the alpha1, the parietal and frontal for the beta2 and the frontal-central for the gamma band. The gamma band revealed the most significant differences between CON and SZO. PLV were 61.7% higher on average in SZO in most of the clusters when compared to CON. The related brain areas are directly related to cognition skills which are proved to be impaired in SZO. The results of this study suggest that synchronization in SZO is also altered when the patients were not asked to perform a task that requires their cognitive skills (i.e., no stimuli are applied - in contrast to other findings).

Keywords: Synchronization, Electroencephalography, Electrodes, Brain, Time series analysis, Oscillators, Frequency synchronization

Trapero, J. I., Arizmendi, C. J., Gonzalez, H., Forero, C., Giraldo, B. F., (2017). Nonlinear dynamic analysis of the cardiorespiratory system in patients undergoing the weaning process Engineering in Medicine and Biology Society (EMBC) 39th Annual International Conference of the IEEE , IEEE (Seogwipo, South Korea) , 3493-3496

In this work, the cardiorespiratory pattern of patients undergoing extubation process is studied. First, the respiratory and cardiac signals were resampled, next the Symbolic Dynamics (SD) technique was implemented, followed of a dimensionality reduction applying Forward Selection (FS) and Moving Window with Variance Analysis (MWVA) methods. Finally, the Linear Discriminant Analysis (LDA) and Support Vector Machines (SVM) classifiers were used. The study analyzed 153 patients undergoing weaning process, classified into 3 groups: Successful Group (SG: 94 patients), Failed Group (FG: 39 patients), and patients who had been successful during the extubation and had to be reintubated before 48 hours, Reintubated Group (RG: 21 patients). According to the results, the best classification present an accuracy higher than 88.98 ± 0.013% in all proposed combinations.

Keywords: Support vector machines, Standards, Time series analysis, Resonant frequency, Nonlinear dynamical systems, Ventilation

Sola-Soler, J., Giraldo, B. F., Fiz, J. A., Jane, R., (2017). Relationship between heart rate excursion and apnea duration in patients with Obstructive Sleep Apnea Engineering in Medicine and Biology Society (EMBC) 39th Annual International Conference of the IEEE , IEEE (Seogwipo, South Korea) , 1539-1542

Obstructive Sleep Apnea (OSA) is a sleep disorder with a high prevalence in the general population. It is a risk factor for many cardiovascular diseases, and an independent risk factor for cerebrovascular diseases such as stroke. After an apnea episode, both arterial blood pressure and cerebral blood flow velocity change in function of the apnea duration (AD). We hypothesized that the relative excursion in heart rate (AHR), defined as the percentage difference between the maximum and the minimum heart rate values associated to an obstructive apnea event, is also related to AD. In this work we studied the relationship between apnea-related AHR and AD in a population of eight patients with severe OSA. AHR and AD showed a moderate but statistically significant correlation (p <; 0.0001) in a total of 1454 obstructive apneas analyzed. The average heart rate excursion for apneas with AD ≥ 30s (ΔHR = 31.29 ± 6.64%) was significantly greater (p = 0.0002) than for apneas with AD ∈ [10,20)s (ΔHR = 18.14±3.08%). We also observed that patients with similar Apnea-Hypopnea Index (AHI) may exhibit remarkably different distributions of AHR and AD, and that patients with a high AHI need not have a higher average AHR than others with a lower severity index. We conclude that the overall apnea-induced heart rate excursion is partially explained by the duration of apnoeic episodes, and it may be a simple measure of the cardiovascular stress associated with OSA that is not directly reflected in the AHI.

Keywords: Heart rate, Sleep apnea, Correlation, Indexes, Sociology, Blood vessels

Morer, A., Basas, J., Colominas, S., Ratia, C., Gomis, X., Abellà, J., Torrents, E., Larrosa, N., Almirante, B., Gavaldà, J., (2017). Actividad de la electrólisis con corriente eléctrica directa continua de bajo amperaje en infecciones por biopelículas y por microorganismos XDR Gram-negativos Enfermedades Infecciosas y Microbiología Clínica XXI Congreso de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC) , Elsevier (Málaga, Spain) 35, (Espec. Cong. 1), 41

Necesitamos nuevas estrategias para combatir la resistencia a los antibióticos. Las infecciones crónicas asociadas con dispositivos médicos se asocian con una morbimortalidad significativa. Nuestro objetivo fue desarrollar una nueva estrategia frente a infecciones productoras de biopelículas y aquellas producidas por microorganismos gramnegativos XDR mediante el uso de una corriente eléctrica directa continua de bajo amperaje (CD). Esta estrategia se evaluó en presencia de suero fisiológico como electrolito para aproximarse a la situación in vivo.

Basas, J., Morer, A., Ratia, C., Rojo, E., Larrosa, N., Oliver, A., Cantón, R., Ferrer, R., Gomis, X., Grau, S., Vima, J., Torrents, E., Almirante, B., Gavaldà, J., (2017). Eficacia in vitro e in vivo de distintas combinaciones antibióticas para el tratamiento nebulizado de neumonía aguda frente a clones de alto riesgo de Pseudomonas aeruginosa. Enfermedades Infecciosas y Microbiología Clínica Enfermedades Infecciosas y Microbiología Clínica XXI Congreso de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC) , Elsevier (Málaga, Spain) 35, (Espec. Cong. 1), 126

El tratamiento de las infecciones respiratorias por cepas extremadamente resistentes (XDR) de P. aeruginosa (sólo sensibles a colistina/amikacina) es complicado, en ocasiones ineficaz y/o nefrotóxico. La nebulización con antibióticos parece una estrategia terapéutica adecuada frente a ese tipo de infecciones.

Garreta, Elena, Marco, Andres, Izpisua Belmonte, Juan Carlos, Montserrat, Nuria, (2016). Genome editing in human pluripotent stem cells: a systematic approach unrevealing pancreas development and disease Stem Cell Investigation , 4, (11), 1-4

Although mouse models have represented a major tool for understanding and predicting molecular mechanisms responsible for several human genetic diseases, still species-specific differences between mouse and humans in their biochemical and physiological characteristics represent a major hurdle when translating promising findings into the human setting (1). For instance, in several types of maturity onset diabetes of the young (MODY; autosomal dominant), mice with heterozygous mutations do not develop diabetes (2). In this regard, the derivation of human embryonic stem cells (hESCs) in 1998 represented an unprecedented opportunity for human disease modelling, and a promising source for cell replacement therapies (3). Later on, the possibility to generate patient-derived induced pluripotent stem cells (iPSCs) has opened new venues for the potential translation of stem-cell related studies into the clinic (4).

Parmar, Jemish, Vilela, Diana, Sanchez, Samuel, (2016). Tubular microjets: Fabrication, factors affecting the motion and mechanism of propulsion The European Physical Journal: Special Topics , 225, (11), 2255-2267

Artificial micro- and nano-swimmers are interesting systems for both fundamental understandings of swimming at low Reynolds numbers and for their promising applications in many fields, such as environmental and biomedical fields. Different architectures of self-propelled systems present various propulsion mechanisms. Among them, tubular microjets are widely used for different applications. Here, we briefly describe the fabrication of microjets by rolling up thin film and electrodeposition techniques and the principles behind these processes. Different parameters affecting the motion of microjets and existing theoretical models about microjet propulsion are discussed.

Van Der Hofstadt, Marc, Fabregas, Rene, Millan, Ruben, Juarez, Antonio, Fumagalli, Laura, Gomila, Gabriel, (2016). Internal hydration properties of single bacterial endospores probed by electrostatic force microscopy ACS Nano 10, (12), 11327–11336

We show that the internal hydration properties of single Bacillus cereus endospores in air under different relative humidity (RH) conditions can be determined through the measurement of its electric permittivity by means of quantitative electrostatic force microscopy (EFM). We show that an increase in the RH from 0% to 80% induces a large increase in the equivalent homogeneous relative electric permittivity of the bacterial endospores, from ~4 up to ~17, accompanied only by a small increase in the endospore height, of just a few nanometers. These results correlate the increase of the moisture content of the endospore with the corresponding increase of environmental RH. 3D finite element numerical calculations, which include the internal structure of the endospores, indicate that the moisture is mainly accumulated in the external layers of the endospore, hence preserving the core of the endospore at low hydration levels. This mechanism is different from what we observe for vegetative bacterial cells of the same species, in which the cell wall at high humid atmospheric conditions is not able to preserve the cytoplasmic region at low hydration levels. These results show the potential of quantitative EFM under environmental humidity control to study the hygroscopic properties of small scale biological (and non-biological) entities and to determine its internal hydration state. A better understanding of nano-hygroscopic properties can be of relevance in the study of essential biological processes and in the design of bio-nanotechnological applications.

Moles, E., Moll, K., Ch'ng, J. H., Parini, P., Wahlgren, M., Fernàndez-Busquets, X., (2016). Development of drug-loaded immunoliposomes for the selective targeting and elimination of rosetting Plasmodium falciparum-infected red blood cells Journal of Controlled Release 241, 57-67

Parasite proteins exported to the surface of Plasmodium falciparum-parasitized red blood cells (pRBCs) have a major role in severe malaria clinical manifestation, where pRBC cytoadhesion and rosetting processes have been strongly linked with microvascular sequestration while avoiding both spleen filtration and immune surveillance. The parasite-derived and pRBC surface-exposed PfEMP1 protein has been identified as one of the responsible elements for rosetting and, therefore, considered as a promising vaccine candidate for the generation of rosette-disrupting antibodies against severe malaria. However, the potential role of anti-rosetting antibodies as targeting molecules for the functionalization of antimalarial drug-loaded nanovectors has never been studied. Our manuscript presents a proof-of-concept study where the activity of an immunoliposomal vehicle with a dual performance capable of specifically recognizing and disrupting rosettes while simultaneously eliminating those pRBCs forming them has been assayed in vitro. A polyclonal antibody against the NTS-DBL1α N-terminal domain of a rosetting PfEMP1 variant has been selected as targeting molecule and lumefantrine as the antimalarial payload. After 30 min incubation with 2 μM encapsulated drug, a 70% growth inhibition for all parasitic forms in culture (IC50: 414 nM) and a reduction in ca. 60% of those pRBCs with a rosetting phenotype (IC50: 747 nM) were achieved. This immunoliposomal approach represents an innovative combination therapy for the improvement of severe malaria therapeutics having a broader spectrum of activity than either anti-rosetting antibodies or free drugs on their own.

Keywords: Combination therapy, Immunoliposomes, Malaria, Nanomedicine, Rosetting, Targeted drug delivery

Vila, M., García, A., Girotti, A., Alonso, M., Rodríguez-Cabello, J. C., González-Vázquez, A., Planell, J. A., Engel, E., Buján, J., Garcíaa-Honduvilla, N., Vallet-Regí, M., (2016). 3D silicon doped hydroxyapatite scaffolds decorated with Elastin-like Recombinamers for bone regenerative medicine Acta Biomaterialia 45, 349-356

The current study reports on the manufacturing by rapid prototyping technique of three-dimensional (3D) scaffolds based on silicon substituted hydroxyapatite with Elastin-like Recombinamers (ELRs) functionalized surfaces. Silicon doped hydroxyapatite (Si-HA), with Ca10(PO4)5.7(SiO4)0.3(OH)1.7h0.3 nominal formula, was surface functionalized with two different types of polymers designed by genetic engineering: ELR-RGD that contain cell attachment specific sequences and ELR-SNA15/RGD with both hydroxyapatite and cells domains that interact with the inorganic phase and with the cells, respectively. These hybrid materials were subjected to in vitro assays in order to clarify if the ELRs coating improved the well-known biocompatible and bone regeneration properties of calcium phosphates materials. The in vitro tests showed that there was a total and homogeneous colonization of the 3D scaffolds by Bone marrow Mesenchymal Stromal Cells (BMSCs). In addition, the BMSCs were viable and able to proliferate and differentiate into osteoblasts. Statement of Significance Bone tissue engineering is an area of increasing interest because its main applications are directly related to the rising life expectancy of the population, which promotes higher rates of several bone pathologies, so innovative strategies are needed for bone tissue regeneration therapies. Here we use the rapid prototyping technology to allow moulding ceramic 3D scaffolds and we use different bio-polymers for the functionalization of their surfaces in order to enhance the biological response. Combining the ceramic material (silicon doped hydroxyapatite, Si-HA) and the Elastin like Recombinamers (ELRs) polymers with the presence of the integrin-mediate adhesion domain alone or in combination with SNA15 peptide that possess high affinity for hydroxyapatite, provided an improved Bone marrow Mesenchymal Stromal Cells (BMSCs) differentiation into osteoblastic linkage.

Keywords: Bone marrow Mesenchymal Stromal Cells (BMSCs), Bone repair, Elastin-like Recombinamers (ELRs), Rapid prototyped 3D scaffolds, Silicon doped hydroxyapatite (Si-HA), Tissue engineering

Guivernau, B., Bonet, J., Valls-Comamala, V., Bosch-Morató, M., Godoy, J. A., Inestrosa, N. C., Perálvarez-Marín, A., Fernàndez-Busquets, X., Andreu, D., Oliva, B., Muñoz, F. J., (2016). Amyloid-β peptide nitrotyrosination stabilizes oligomers and enhances NMDAR-mediated toxicity Journal of Neuroscience , 36, (46), 11693-11703

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the pathological aggregation of the amyloid-β peptide (Aβ). Monomeric soluble Aβ can switch from helicoidal to β-sheet conformation, promoting its assembly into oligomers and subsequently to amyloid fibrils. Oligomers are highly toxic to neurons and have been reported to induce synaptic transmission impairments. The progression from oligomers to fibrils forming senile plaques is currently considered a protective mechanism to avoid the presence of the highly toxic oligomers. Protein nitration is a frequent post-translational modification under AD nitrative stress conditions. Aβ can be nitrated at tyrosine 10 (Y10) by peroxynitrite. Based on our analysis of ThT binding, Western blot and electron and atomic force microscopy, we report that Aβ nitration stabilizes soluble, highly toxic oligomers and impairs the formation of fibrils. We propose a mechanism by which fibril elongation is interrupted upon Y10 nitration: Nitration disrupts fibril-forming folds by preventing H14-mediated bridging, as shown with an Aβ analog containing a single residue (H to E) replacement that mimics the behavior of nitrated Aβ related to fibril formation and neuronal toxicity. The pathophysiological role of our findings in AD was highlighted by the study of these nitrated oligomers on mouse hippocampal neurons, where an increased NMDAR-dependent toxicity of nitrated Aβ oligomers was observed. Our results show that Aβ nitrotyrosination is a post-translational modification that increases Aβ synaptotoxicity.

Keywords: Alzheimer, Amyloid, Nitrotyrosination, NMDA Rc, Oligomers, Peroxynitrite

Fonollosa, J., Fernández, L., Gutiérrez-Gálvez, A., Huerta, R., Marco, S., (2016). Calibration transfer and drift counteraction in chemical sensor arrays using Direct Standardization Sensors and Actuators B: Chemical 236, 1044-1053

Inherent variability of chemical sensors makes it necessary to calibrate chemical detection systems individually. This shortcoming has traditionally limited usability of systems based on metal oxide gas sensor arrays and prevented mass-production for some applications. Here, aiming at exploring calibration transfer between chemical sensor arrays, we exposed five twin 8-sensor detection units to different concentration levels of ethanol, ethylene, carbon monoxide, or methane. First, we built calibration models using data acquired with a master unit. Second, to explore the transferability of the calibration models, we used Direct Standardization to map the signals of a slave unit to the space of the master unit in calibration. In particular, we evaluated the transferability of the calibration models to other detection units, and within the same unit measuring days apart. Our results show that signals acquired with one unit can be successfully mapped to the space of a reference unit. Hence, calibration models trained with a master unit can be extended to slave units using a reduced number of transfer samples, diminishing thereby calibration costs. Similarly, signals of a sensing unit can be transformed to match sensor behavior in the past to mitigate drift effects. Therefore, the proposed methodology can reduce calibration costs in mass-production and delay recalibrations due to sensor aging. Acquired dataset is made publicly available.

Keywords: Calibration transfer, Chemical sensors, Direct Standardization, Electronic nose, MOX sensors, Public dataset

Noori, M., Aragonès, A. C., Di Palma, G., Darwish, N., Bailey, S. W. D., Al-Galiby, Q., Grace, I., Amabilino, D. B., González-Campo, A., Díez-Pérez, I., Lambert, C. J., (2016). Tuning the electrical conductance of metalloporphyrin supramolecular wires Scientific Reports 6, 37352

In contrast with conventional single-molecule junctions, in which the current flows parallel to the long axis or plane of a molecule, we investigate the transport properties of M(II)-5,15-diphenylporphyrin (M-DPP) single-molecule junctions (M=Co, Ni, Cu, or Zn divalent metal ions), in which the current flows perpendicular to the plane of the porphyrin. Novel STM-based conductance measurements combined with quantum transport calculations demonstrate that current-perpendicular-to-the-plane (CPP) junctions have three-orders-of-magnitude higher electrical conductances than their current-in-plane (CIP) counterparts, ranging from 2.10-2 G0 for Ni-DPP up to 8.10-2 G0 for Zn-DPP. The metal ion in the center of the DPP skeletons is strongly coordinated with the nitrogens of the pyridyl coated electrodes, with a binding energy that is sensitive to the choice of metal ion. We find that the binding energies of Zn-DPP and Co-DPP are significantly higher than those of Ni-DPP and Cu-DPP. Therefore when combined with its higher conductance, we identify Zn-DPP as the favoured candidate for high-conductance CPP single-molecule devices.

Asadipour, N., Trepat, X., Muñoz, J. J., (2016). Porous-based rheological model for tissue fluidisation Journal of the Mechanics and Physics of Solids 96, 535-549

It has been experimentally observed that cells exhibit a fluidisation process when subjected to a transient stretch, with an eventual recovery of the mechanical properties upon removal of the applied deformation. This fluidisation process is characterised by a decrease of the storage modulus and an increase of the phase angle. We propose a rheological model which is able to reproduce this combined mechanical response. The model is described in the context of continua and adapted to a cell-centred particle system that simulates cell–cell interactions. Mechanical equilibrium is coupled with two evolution laws: (i) one for the reference configuration, and (ii) another for the porosity or polymer density. The first law depends on the actual strain of the tissue, while the second assumes different remodelling rates during porosity increase and decrease. The theory is implemented on a particle based model and tested on a stretching experiment. The numerical results agree with the experimental measurements for different stretching magnitudes.

Keywords: Cell remodelling, Cell rheology, Fluidisation, Softening, Viscoelasticity

Nonaka, Paula N., Uriarte, Juan J., Campillo, Noelia, Oliveira, Vinicius R., Navajas, Daniel, Farré, Ramon, (2016). Lung bioengineering: physical stimuli and stem/progenitor cell biology interplay towards biofabricating a functional organ Respiratory Research , 17, (1), 161

A current approach to obtain bioengineered lungs as a future alternative for transplantation is based on seeding stem cells on decellularized lung scaffolds. A fundamental question to be solved in this approach is how to drive stem cell differentiation onto the different lung cell phenotypes. Whereas the use of soluble factors as agents to modulate the fate of stem cells was established from an early stage of the research with this type of cells, it took longer to recognize that the physical microenvironment locally sensed by stem cells (e.g. substrate stiffness, 3D architecture, cyclic stretch, shear stress, air-liquid interface, oxygenation gradient) also contributes to their differentiation. The potential role played by physical stimuli would be particularly relevant in lung bioengineering since cells within the organ are physiologically subjected to two main stimuli required to facilitate efficient gas exchange: air ventilation and blood perfusion across the organ. The present review focuses on describing how the cell mechanical microenvironment can modulate stem cell differentiation and how these stimuli could be incorporated into lung bioreactors for optimizing organ bioengineering.

Meacci, G., Wolfenson, H., Liu, S., Stachowiak, M. R., Iskratsch, T., Mathur, A., Ghassemi, S., Gauthier, N., Tabdanov, E., Lohner, J., Gondarenko, A., Chander, A. C., Roca-Cusachs, P., O'Shaughnessy, B., Hone, J., Sheetz, M. P., (2016). α-Actinin links extracellular matrix rigidity-sensing contractile units with periodic cell-edge retractions Molecular Biology of the Cell , 27, (22), 3471-3479

During spreading and migration, the leading edges of cells undergo periodic protrusion--retraction cycles. The functional purpose of these cycles is unclear. Here, using submicrometer polydimethylsiloxane pillars as substrates for cell spreading, we show that periodic edge retractions coincide with peak forces produced by local contractile units (CUs) that assemble and disassemble along the cell edge to test matrix rigidity. We find that, whereas actin rearward flow produces a relatively constant force inward, the peak of local contractile forces by CUs scales with rigidity. The cytoskeletal protein α-Actinin is shared between these two force-producing systems. It initially localizes to the CUs and subsequently moves inward with the actin flow. Knockdown of α-Actinin causes aberrant rigidity sensing, loss of CUs, loss of protrusion-retraction cycles, and, surprisingly, enables the cells to proliferate on soft matrices. We present a model based on these results in which local CUs drive rigidity sensing and adhesion formation.

Caddeo, C., Nacher, A., Vassallo, A., Armentano, M. F., Pons, R., Fernàndez-Busquets, X., Carbone, C., Valenti, D., Fadda, A. M., Manconi, M., (2016). Effect of quercetin and resveratrol co-incorporated in liposomes against inflammatory/oxidative response associated with skin cancer International Journal of Pharmaceutics 513, (1-2), 153-163

The present investigation reports the development of liposomes for the co-delivery of naturally occurring polyphenols, namely quercetin and resveratrol. Small, spherical, uni/bilamellar vesicles were produced, as demonstrated by light scattering, cryo-TEM, SAXS. The incorporation of quercetin and resveratrol in liposomes did not affect their intrinsic antioxidant activity, as DPPH radical was almost completely inhibited. The cellular uptake of the polyphenols was higher when they were formulated in liposomes, and especially when co-loaded rather than as single agents, which resulted in a superior ability to scavenge ROS in fibroblasts. The in vivo efficacy of the polyphenols in liposomes was assessed in a mouse model of skin lesion. The topical administration of liposomes led to a remarkable amelioration of the tissue damage, with a significant reduction of oedema and leukocyte infiltration. Therefore, the proposed approach based on polyphenol vesicular formulation may be of value in the treatment of inflammation/oxidative stress associated with pre-cancerous/cancerous skin lesions.

Keywords: Antioxidant, Fibroblast, Liposome, Quercetin, Resveratrol, Skin lesion

Fonte, Pedro, Andrade, Fernanda, Azevedo, Cláudia, Pinto, João, Seabra, Vítor, van de Weert, Marco, Reis, Salette, Sarmento, Bruno, (2016). Effect of the freezing step in the stability and bioactivity of protein-loaded PLGA nanoparticles upon lyophilization Pharmaceutical Research , 33, (11), 2777-2793

The freezing step in lyophilization is the most determinant for the quality of biopharmaceutics. Using insulin as model of therapeutic protein, our aim was to evaluate the freezing effect in the stability and bioactivity of insulin-loaded PLGA nanoparticles. The performance of trehalose, sucrose and sorbitol as cryoprotectants was evaluated.

Ramón Valencia, J. L., García-Sánchez, A., Roca-Dorda, J., Giraldo, B. F., (2016). Análisis de la señal ECG en pacientes con enfermedad de Párkinson CASEIB Proceedings XXXIV Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2016) , Sociedad Española de Ingeniería Biomédica (Valencia, Spain) , 552-555

La enfermedad del Párkinson es un tipo de trastorno del movimiento, causado por la degeneración de las células dopaminérgicas. La variabilidad del ritmo cardíaco en estos pacientes se puede ver alterada como consecuencia de la actividad motora. El estudio de esta variabilidad puede ayudar en el diagnóstico y análisis de la evolución de la enfermedad en estos pacientes. En este estudio se propone el análisis de parámetros extraídos de la señal electrocardiográfica en pacientes enfermos de Párkinson, con el propósito de obtener índices que puedan ser indicadores de esta enfermedad. Se propone un protocolo para registrar la señal ECG considerando 4 actividades diferentes. Se registraron 19 pacientes y 16 sujetos sanos. Las señales fueron analizadas en el dominio temporal considerando los intervalos RR de la señal ECG, y en el dominio frecuencial, considerando las bandas de muy baja (VLF: 0-0.05 Hz), baja (LF: 0.05-0.15 Hz) y alta (HF: 0.15-0.4 Hz) frecuencia, respectivamente. De acuerdo con los resultados obtenidos, el índice de la actividad simpática presentó diferencias estadísticamente significativas al comparar pacientes versus sanos, durante las 4 actividades desarrolladas. El intervalo RR también es un indicador de la variación de la actividad cardíaca en los pacientes, especialmente al compararlos en el estado basal. Índices que relacionen parámetros temporales y frecuenciales podrían ser un claro indicador de la actividad cardiovascular de los pacientes enfermos de Párkinson.

Rodriguez, J., Voss, A., Caminal, P., Bayés-Genís, A., Giraldo, B. F., (2016). Caracterización de pacientes con diferentes niveles de riesgo cardiovascular mediante diagramas de Poincaré CASEIB Proceedings XXXIV Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2016) , Sociedad Española de Ingeniería Biomédica (Valencia, Spain) , 396-399

En este trabajo se propone caracterizar la dinámica no-lineal de los sistemas cardíaco, vascular y respiratorio a partir de los diagramas de Poincaré. Se han analizado 46 pacientes con cardiomiopatía isquémica (ICM) o dilatada (DCM), y 35 sujetos sanos. De acuerdo con su fracción de eyección ventricular izquierda (LVEF), los pacientes también fueron clasificados en un grupo de alto riesgo (HR: LVEF ≤ 35%, 30 pacientes) y otro de bajo riesgo (LR: LVEF > 35%, 16 pacientes). A partir de las señales electrocardiográfica, de flujo respiratorio y de presión sanguínea se han obtenido los datos relacionados con el tiempo entre latidos cardíacos (RR), entre valores máximos de presión sistólica (SBP), y la duración del ciclo respiratorio (TTot). Estas series temporales han sido representadas mediante los diagramas de Poincaré, y caracterizadas teniendo en cuenta su desviación a largo plazo (SD1) y su cambio instantáneo (SD2). De acuerdo con los resultados obtenidos, los parámetros de las series cardíaca y de presión sanguínea, relacionados con las diagonales longitudinales y transversales del diagrama de Poincaré, son los que mejor diferencian entre pacientes con HR vs LR. Para la clasificación de pacientes isquémicos vs dilatados, los mejores parámetros se obtuvieron a partir de las series respiratorias y están relacionados con las distancias de la desviación estándar a la línea de identidad. Los cambios en estas relaciones representan una mayor aceleración en la dinámica respiratoria de los pacientes con cardiomiopatía isquémica.

Ràfols-de-Urquía, M., Estévez-Piorno, J., Torres, A., Estrada, L., Jané, R., (2016). Evaluación de un dispositivo inalámbrico para el registro de la actividad electromiográfica del músculo diafragma CASEIB Proceedings XXXIV Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2016) , Sociedad Española de Ingeniería Biomédica (Valencia, Spain) , 244-247

La evaluación clínica y deportiva requiere el desarrollo de sistemas de adquisición de señales biomédicas de alta calidad. Sin embargo, estos sistemas implican una gran limitación: los datos deben ser registrados en laboratorios. En los últimos años se han desarrollado dispositivos inalámbricos multimodales que pueden poner fin a estos problemas. En este proyecto se han evaluado señales electromiográficas de los músculos respiratorios, en especial del diafragma (EMGdi), obtenidas a partir de un dispositivo inalámbrico. De forma simultánea se han adquirido las mismas señales con un sistema estándar de adquisición de señales biomédicas, para realizar un estudio comparativo de parámetros e información fisiológica extraída de dichas señales. Las señales han sido registradas en 9 sujetos sanos que siguieron un protocolo respiratorio. Estas señales han sido filtradas y procesadas usando técnicas basadas en el dominio frecuencial y temporal. El ritmo cardíaco ha sido estimado tanto a partir de la medida directa del registro ECG, como indirectamente a partir de las señales electromiografícas respiratorias, mientras que el ritmo respiratorio y la fuerza del músculo han sido estimados a partir de la amplitud de las señales EMGdi durante la contracción respiratoria. Los resultados obtenidos de los datos registrados por sistemas inalámbricos son muy similares a los obtenidos mediante sistemas convencionales con cables, demostrando ser una alternativa que permite adquisiciones y estudios fuera de los laboratorios en situaciones mucho más reales.

Estévez-Piorno, J., Ràfols-de-Urquía, M., Torres, A., Estrada, L., Jané, R., (2016). Evaluación del registro y transmisión de señales electromiográficas mediante un dispostivo inalámbrico CASEIB Proceedings XXXIV Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2016) , Sociedad Española de Ingeniería Biomédica (Valencia, Spain) , 556-559

Obstructive sleep apnea (OSA) is a highly prevalent chronic disease, especially in elderly and obese population. Despite constituting a huge health and economic problem, most patients remain undiagnosed due to limitations in current strategies. Therefore, it is essential to find cost-effective diagnostic alternatives. One of these novel approaches is the analysis of acoustic snoring signals. Snoring is an early symptom of OSA which carries pathophysiological information of high diagnostic value. For this reason, the main objective of this work is to study the characteristics of single snores of different types, from healthy and OSA subjects. To do that, we analyzed snoring signals from previous databases and developed an experimental protocol to record simulated OSA-related sounds and characterize the response of two commercial tracheal microphones. Automatic programs for filtering, downsampling, event detection and time-frequency analysis were built in MATLAB. We found that time-frequency maps and spectral parameters (central, mean and peak frequency and energy in the 100-500 Hz band) allow distinguishing regular snores of healthy subjects from non-regular snores and snores of OSA subjects. Regarding the two commercial microphones, we found that one of them was a suitable snoring sensor, while the other had a too restricted frequency response. Future work shall include a higher number of episodes and subjects, but our study has contributed to show how important the differences between regular and non-regular snores can be for OSA diagnosis, and how much clinically relevant information can be extracted from time-frequency maps and spectral parameters of single snores.

Julian, S., Callicó, F., Giraldo, B. F., Juanola, A., López, D., Rodiera, J., (2016). Segmentación del nodo vesical a partir del plano transversal de imágenes ecográficas de la región suprapúbica CASEIB Proceedings XXXIV Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2016) , Sociedad Española de Ingeniería Biomédica (Valencia, Spain) , 278-281

La retención urinaria después de una cirugía anestésica puede provocar sobre-distensión vesical, impidiendo al paciente miccionar de forma voluntaria. La cateterización es el método más utilizado para solucionar este problema. El método es aplicado cuando el volumen vesical es superior a 300 ml. En este trabajo propone un método para la binarización y segmentación del nodo vesical a partir de una imagen ecográfica de la región suprapúbica transversal. Se han analizado 180 imágenes (80 de entrenamiento y 100 de validación), segmentadas utilizando el método de nivel de gris. Las imágenes fueron caracterizadas a partir de las líneas vertical, horizontal y las dos diagonales. Los valores obtenidos fueron comparados con los medidos con el ecógrafo, con un 72% de acierto. Se ha propuesto un método radial para el cierre de aperturas lateral e interior. Ajustados el brillo y la profundidad de la imagen, y el control morfológico se obtuvo hasta un 83% de correcta segmentación del área vesical en el grupo validación de la muestra. Estos resultados son la base para el cálculo del volumen de orina en vejiga y la decisión de cateterizar un paciente con retención urinaria.

Castillo, Y., Blanco, D., Cámara, M.A., Jané, R., (2016). Study of time-frequency characteristics of single snores: extracting new information for sleep apnea diagnosis CASEIB Proceedings XXXIV Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2016) , Sociedad Española de Ingeniería Biomédica (Valencia, Spain) , 105-108

Obstructive sleep apnea (OSA) is a highly prevalent chronic disease, especially in elderly and obese population. Despite constituting a huge health and economic problem, most patients remain undiagnosed due to limitations in current strategies. Therefore, it is essential to find cost-effective diagnostic alternatives. One of these novel approaches is the analysis of acoustic snoring signals. Snoring is an early symptom of OSA which carries pathophysiological information of high diagnostic value. For this reason, the main objective of this work is to study the characteristics of single snores of different types, from healthy and OSA subjects. To do that, we analyzed snoring signals from previous databases and developed an experimental protocol to record simulated OSA-related sounds and characterize the response of two commercial tracheal microphones. Automatic programs for filtering, downsampling, event detection and time-frequency analysis were built in MATLAB. We found that time-frequency maps and spectral parameters (central, mean and peak frequency and energy in the 100-500 Hz band) allow distinguishing regular snores of healthy subjects from non-regular snores and snores of OSA subjects. Regarding the two commercial microphones, we found that one of them was a suitable snoring sensor, while the other had a too restricted frequency response. Future work shall include a higher number of episodes and subjects, but our study has contributed to show how important the differences between regular and non-regular snores can be for OSA diagnosis, and how much clinically relevant information can be extracted from time-frequency maps and spectral parameters of single snores.

Malandrino, Andrea, Pozo, Jose Maria, Castro-Mateos, Isaac, Frangi, Alejandro F., van Rijsbergen, Marc M., Ito, Keita, Wilke, Hans-Joachim, Dao, Tien Tuan, Ho Ba Tho, Marie-Christine, Noailly, Jerome, (2015). On the relative relevance of subject-specific geometries and degeneration-specific mechanical properties for the study of cell death in human intervertebral disc models Frontiers in Bioengineering and Biotechnology 3, (Article 5), 1-15

Capturing patient- or condition-specific intervertebral disk (IVD) properties in finite element models is outmost important in order to explore how biomechanical and biophysical processes may interact in spine diseases. However, disk degenerative changes are often modeled through equations similar to those employed for healthy organs, which might not be valid. As for the simulated effects of degenerative changes, they likely depend on specific disk geometries. Accordingly, we explored the ability of continuum tissue models to simulate disk degenerative changes. We further used the results in order to assess the interplay between these simulated changes and particular IVD morphologies, in relation to disk cell nutrition, a potentially important factor in disk tissue regulation. A protocol to derive patient-specific computational models from clinical images was applied to different spine specimens. In vitro, IVD creep tests were used to optimize poro-hyperelastic input material parameters in these models, in function of the IVD degeneration grade. The use of condition-specific tissue model parameters in the specimen-specific geometrical models was validated against independent kinematic measurements in vitro. Then, models were coupled to a transport-cell viability model in order to assess the respective effects of tissue degeneration and disk geometry on cell viability. While classic disk poro-mechanical models failed in representing known degenerative changes, additional simulation of tissue damage allowed model validation and gave degeneration-dependent material properties related to osmotic pressure and water loss, and to increased fibrosis. Surprisingly, nutrition-induced cell death was independent of the grade-dependent material properties, but was favored by increased diffusion distances in large IVDs. Our results suggest that in situ geometrical screening of IVD morphology might help to anticipate particular mechanisms of disk degeneration.

Keywords: Intervertebral Disc Degeneration, Finite element modelling, Lumbar spine, Poroelasticity, Damage model, Subject-specific modelling, Disc cell nutrition

Moles, Ernest, Valle-Delgado, Juan José, Urbán, Patricia, Azcárate, Isabel G., Bautista, José M., Selva, Javier, Egea, Gustavo, Ventura, Salvador, Fernàndez-Busquets, Xavier, (2015). Possible roles of amyloids in malaria pathophysiology Future Science OA , 1, (2), FSO43

The main therapeutic and prophylactic tools against malaria have been locked for more than a century in the classical approaches of using drugs targeting metabolic processes of the causing agent, the protist Plasmodium spp., and of designing vaccines against chosen antigens found on the parasite’s surface. Given the extraordinary resources exhibited by Plasmodium to escape these traditional strategies, which have not been able to free humankind from the scourge of malaria despite much effort invested in them, new concepts have to be explored in order to advance toward eradication of the disease. In this context, amyloid-forming proteins and peptides found in the proteome of the pathogen should perhaps cease being regarded as mere anomalous molecules. Their likely functionality in the pathophysiology of Plasmodium calls for attention being paid to them as a possible Achilles’ heel of malaria. Here we will give an overview of Plasmodium-encoded amyloid-forming polypeptides as potential therapeutic targets and toxic elements, particularly in relation to cerebral malaria and the blood–brain barrier function. We will also discuss the recent finding that the genome of the parasite contains an astonishingly high proportion of prionogenic domains.

Keywords: Amyloids, Intrinsically unstructured proteins, Malaria, Prions

Sánchez-Ferrero, Aitor, Mata, Álvaro, Mateos-Timoneda, Miguel A., Rodríguez-Cabello, José C., Alonso, Matilde, Planell, Josep, Engel, Elisabeth, (2015). Development of tailored and self-mineralizing citric acid-crosslinked hydrogels for in situ bone regeneration Biomaterials 68, 42-53

Bone tissue engineering demands alternatives overcoming the limitations of traditional approaches in the context of a constantly aging global population. In the present study, elastin-like recombinamers hydrogels were produced by means of carbodiimide-catalyzed crosslinking with citric acid, a molecule suggested to be essential for bone nanostructure. By systematically studying the effect of the relative abundance of reactive species on gelation and hydrogel properties such as functional groups content, degradation and structure, we were able to understand and to control the crosslinking reaction to achieve hydrogels mimicking the fibrillary nature of the extracellular matrix. By studying the effect of polymer concentration on scaffold mechanical properties, we were able to produce hydrogels with a stiffness value of 36.13 ± 10.72 kPa, previously suggested to be osteoinductive. Microstructured and mechanically-tailored hydrogels supported the growth of human mesenchymal stem cells and led to higher osteopontin expression in comparison to their non-tailored counterparts. Additionally, tailored hydrogels were able to rapidly self-mineralize in biomimetic conditions, evidencing that citric acid was successfully used both as a crosslinker and a bioactive molecule providing polymers with calcium phosphate nucleation capacity.

Keywords: Biomimetic material, Biomineralisation, Bone tissue engineering, Cross-linking, Hydrogel, Mesenchymal stem cell

Dols-Perez, Aurora, Gramse, Georg, Calo, Annalisa, Gomila, Gabriel, Fumagalli, Laura, (2015). Nanoscale electric polarizability of ultrathin biolayers on insulator substrates by electrostatic force microscopy Nanoscale 7, 18327-18336

We measured and quantified the local electric polarization properties of ultrathin (~ 5 nm) biolayers on mm-thick mica substrates. We achieved it by scanning a sharp conductive tip (< 10 nm radius) of an electrostatic force microscope over the biolayers and quantifying sub-picoNewton electric polarization forces with a sharp-tip model implemented using finite-element numerical calculations. We obtained relative dielectric constants ?r = 3.3, 2.4 and 1.9 for bacteriorhodopsin, dioleoylphosphatidylcholine (DOPC) and cholesterol layers, chosen as representative of the main cell membrane components, with an error below 10% and a spatial resolution down to ~ 50 nm. The ability of using insulating substrates common in biophysics research, such as mica or glass, instead of metallic substrates, offers both a general platform to determine the dielectric properties of biolayers and a wider compatibility with other characterization techniques, such as optical microscopy. This opens up new possibilities for biolayer research at the nanoscale, including nanoscale label-free composition mapping.

Vincent, Romaric, Bazellières, Elsa, Pérez-González, Carlos, Uroz, Marina, Serra-Picamal, Xavier, Trepat, Xavier, (2015). Active tensile modulus of an epithelial monolayer Physical Review Letters 115, (24), 248103

A general trait of cell monolayers is their ability to exert contractile stresses on their surroundings. The scaling laws that link such contractile stresses with the size and geometry of constituent cells remain largely unknown. In this Letter, we show that the active tension of an epithelial monolayer scales linearly with the size of the constituent cells, a surprisingly simple relationship. The slope of this relationship defines an active tensile modulus, which depends on the concentration of myosin and spans more than 2 orders of magnitude across cell types and molecular perturbations.

Teller, Sara, Tahirbegi, Islam Bogachan, Mir, M., Samitier, Josep, Soriano, Jordi, (2015). Magnetite-Amyloid-β deteriorates activity and functional organization in an in vitro model for Alzheimer’s disease Scientific Reports 5, 17261

The understanding of the key mechanisms behind human brain deterioration in Alzheimer’ disease (AD) is a highly active field of research. The most widespread hypothesis considers a cascade of events initiated by amyloid-β peptide fibrils that ultimately lead to the formation of the lethal amyloid plaques. Recent studies have shown that other agents, in particular magnetite, can also play a pivotal role. To shed light on the action of magnetite and amyloid-β in the deterioration of neuronal circuits, we investigated their capacity to alter spontaneous activity patterns in cultured neuronal networks. Using a versatile experimental platform that allows the parallel monitoring of several cultures, the activity in controls was compared with the one in cultures dosed with magnetite, amyloid-β and magnetite-amyloid-β complex. A prominent degradation in spontaneous activity was observed solely when amyloid-β and magnetite acted together. Our work suggests that magnetite nanoparticles have a more prominent role in AD than previously thought, and may bring new insights in the understanding of the damaging action of magnetite-amyloid-β complex. Our experimental system also offers new interesting perspectives to explore key biochemical players in neurological disorders through a controlled, model system manner.

Urbán, Patricia, Ranucci, Elisabetta, Fernàndez-Busquets, Xavier, (2015). Polyamidoamine nanoparticles as nanocarriers for the drug delivery to malaria parasite stages in the mosquito vector Nanomedicine 10, (22), 3401-3414

Malaria is arguably one of the main medical concerns worldwide because of the numbers of people affected, the severity of the disease and the complexity of the life cycle of its causative agent, the protist Plasmodium spp. With the advent of nanoscience, renewed hopes have appeared of finally obtaining the long sought-after magic bullet against malaria in the form of a nanovector for the targeted delivery of antimalarial compounds exclusively to Plasmodium-infected cells, thus increasing drug efficacy and minimizing the induction of resistance to newly developed therapeutic agents. Polyamidoamine-derived nanovectors combine into a single chemical structure drug encapsulating capacity, antimalarial activity, low unspecific toxicity, specific targeting to Plasmodium, optimal in vivo activity and affordable synthesis cost. After having shown their efficacy in targeting drugs to intraerythrocytic parasites, now polyamidoamines face the challenge of spearheading a new generation of nanocarriers aiming at the malaria parasite stages in the mosquito vector.

Fonollosa, Jordi, Neftci, Emre, Rabinovich, Mikhail, (2015). Learning of chunking sequences in cognition and behavior PLoS Computational Biology 11, (11), e1004592

We often learn and recall long sequences in smaller segments, such as a phone number 858 534 22 30 memorized as four segments. Behavioral experiments suggest that humans and some animals employ this strategy of breaking down cognitive or behavioral sequences into chunks in a wide variety of tasks, but the dynamical principles of how this is achieved remains unknown. Here, we study the temporal dynamics of chunking for learning cognitive sequences in a chunking representation using a dynamical model of competing modes arranged to evoke hierarchical Winnerless Competition (WLC) dynamics. Sequential memory is represented as trajectories along a chain of metastable fixed points at each level of the hierarchy, and bistable Hebbian dynamics enables the learning of such trajectories in an unsupervised fashion. Using computer simulations, we demonstrate the learning of a chunking representation of sequences and their robust recall. During learning, the dynamics associates a set of modes to each information-carrying item in the sequence and encodes their relative order. During recall, hierarchical WLC guarantees the robustness of the sequence order when the sequence is not too long. The resulting patterns of activities share several features observed in behavioral experiments, such as the pauses between boundaries of chunks, their size and their duration. Failures in learning chunking sequences provide new insights into the dynamical causes of neurological disorders such as Parkinson’s disease and Schizophrenia.

Maynou, Joan, Pairo, Erola, Marco, Santiago, Perera, Alexandre, (2015). Sequence information gain based motif analysis BMC Bioinformatics , 16, (1), 377

BACKGROUND:The detection of regulatory regions in candidate sequences is essential for the understanding of the regulation of a particular gene and the mechanisms involved. This paper proposes a novel methodology based on information theoretic metrics for finding regulatory sequences in promoter regions.RESULTS:This methodology (SIGMA) has been tested on genomic sequence data for Homo sapiens and Mus musculus. SIGMA has been compared with different publicly available alternatives for motif detection, such as MEME/MAST, Biostrings (Bioconductor package), MotifRegressor, and previous work such Qresiduals projections or information theoretic based detectors. Comparative results, in the form of Receiver Operating Characteristic curves, show how, in 70 % of the studied Transcription Factor Binding Sites, the SIGMA detector has a better performance and behaves more robustly than the methods compared, while having a similar computational time. The performance of SIGMA can be explained by its parametric simplicity in the modelling of the non-linear co-variability in the binding motif positions.CONCLUSIONS:Sequence Information Gain based Motif Analysis is a generalisation of a non-linear model of the cis-regulatory sequences detection based on Information Theory. This generalisation allows us to detect transcription factor binding sites with maximum performance disregarding the covariability observed in the positions of the training set of sequences. SIGMA is freely available to the public at

Gumí-Audenis, B., Carlà, F., Vitorino, M. V., Panzarella, A., Porcar, L., Boilot, M., Guerber, S., Bernard, P., Rodrigues, M. S., Sanz, F., Giannotti, M. I., Costa, L., (2015). Custom AFM for X-ray beamlines: in situ biological investigations under physiological conditions Journal of Synchrotron Radiation , 22, 1364-1371

A fast atomic force microscope (AFM) has been developed that can be installed as a sample holder for grazing-incidence X-ray experiments at solid/gas or solid/liquid interfaces. It allows a wide range of possible investigations, including soft and biological samples under physiological conditions (hydrated specimens). The structural information obtained using the X-rays is combined with the data gathered with the AFM (morphology and mechanical properties), providing a unique characterization of the specimen and its dynamics in situ during an experiment. In this work, lipid monolayers and bilayers in air or liquid environment have been investigated by means of AFM, both with imaging and force spectroscopy, and X-ray reflectivity. In addition, this combination allows the radiation damage induced by the beam on the sample to be studied, as has been observed on DOPC and DPPC supported lipid bilayers under physiological conditions.

Keywords: In situ atomic force microscopy, Grazing-incidence scattering and reflectivity, Radiation damage, Model lipid membranes

Rajasekaran, Vijaykumar, Aranda, Joan, Casals, Alicia, Pons, Jose L., (2015). An adaptive control strategy for postural stability using a wearable robot Robotics and Autonomous Systems , 73, 16-23

Abstract Wearable robots are expected to expand the use of robotics in rehabilitation since they can widen the assistance application context. An important aspect of a rehabilitation therapy, in terms of lower extremity assistance, is balance control. In this article, we propose and evaluate an adaptive control strategy for robotic rehabilitation therapies to guarantee static stability using a wearable robot. Postural balance control can be implemented either acting on the hip, on the ankle joint or on both, depending on the kind of perturbation acting on the subject: internal or external. Internal perturbations can be produced by any voluntary movement of the body, such as bending the trunk. External perturbations, in the form of an impact force, are applied by the exoskeleton without any prior notice to observe the proactive response of the subject. We have used a 6 degree of freedom planar lower limb exoskeleton, H1, to perform this analysis. The developed control strategy has been designed to provide the necessary assistance, related to balance recovery and postural stability, under the “Assist-as-needed” paradigm. The interaction forces between orthosis and subject are monitored, as they play a relevant role in the definition of assistive and resistive movements to be applied to the joints. The proposed method has been tested with 5 healthy subjects in presence of internal and external disturbances. The results demonstrate that knowing the stability limit of each subject, in combination with a therapeutically selected scaling factor, the proposed adaptive control helps in providing an effective assistance in therapy. This method is efficient in handling the individual and combined effect of external perturbations acting on any joint movements.

Keywords: Exoskeleton controls, Postural stability, Balance controls, Adaptive control

Lozano-Garcia, M., Fiz, J. A., Jané, R., (2015). Análisis de sonidos adventicios continuos en pacientes asmáticos mediante el espectro de Hilbert CASEIB Proceedings XXXIII Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2015) , Sociedad Española de Ingeniería Biomédica (Madrid, Spain) , 179-182

Los sonidos adventicios continuos (CAS) son uno de los principales síntomas del asma. Dada su importancia clínica, el análisis de estas señales requiere del uso de técnicas que permitan segmentarlas y caracterizarlas con una precisión alta. Sin embargo, la mayoría de técnicas propuestas anteriormente estaban basadas en el análisis de Fourier o wavelet, técnicas que tienen una resolución limitada a priori y son altamente dependientes de la amplitud de los CAS. En este estudio se presenta una técnica alternativa para el análisis de CAS basada en el espectro de Hilbert. El método presentado combina la descomposición empírica en modos por conjuntos con el estimador de Kay de la frecuencia instantánea, para obtener una representación tiempo-frecuencia con una alta concentración de energía y una resolución temporal y frecuencial elevada. Con el fin de mostrar las ventajas que ofrece el método presentado, se ha aplicado a cuatro señales de sonidos respiratorios registradas en pacientes asmáticos que contienen distintos tipos de CAS, reforzando la hipótesis confirmada en nuestro estudio previo de que el espectro de Hilbert permite segmentar y caracterizar los CAS con mayor precisión que otras técnicas tradicionales ampliamente utilizadas, como el espectrograma.

Giraldo, B. F., Rodríguez, J., Arcentales, A., Voss, A., Caminal, P., Bayes-Genis, A., (2015). Caracterización de pacientes isquémicos y dilatados a partir de las señales ECG y de presión sanguínea CASEIB Proceedings XXXIII Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2015) , Sociedad Española de Ingeniería Biomédica (Madrid, Spain) , 31-34

Las enfermedades cardiovasculares son una de las principales causas de muerte en países desarrollados. Se han analizado 42 pacientes con cardiomiopatía isquémica (ICM) o dilatada (DCM), clasificados en función de la fracción de eyección ventricular izquierda (LVEF), en grupos de alto riesgo (HR: LVEF

Castillo, Y., Gutiérrez, A., (2015). Determining the tertiary structure of an olfactory receptor CASEIB Proceedings XXXIII Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2015) , Sociedad Española de Ingeniería Biomédica (Madrid, Spain) , 245-248

Olfactory receptors (ORs) are transmembrane proteins that interact with odorant molecules, triggering the first step in the mechanism of olfaction. They also occupy a large part of mammalian genome and their dysfunction is involved in some degenerative diseases. Proteins structure is related to their function, but experimentally determining the three-dimensional structure of ORs is tricky. However, recent advances in bioinformatics have made it easier. The objectives of this project were to computationally model several ORs and to study their interactions with odorants. We carried out a comparative modelling process, using Chimera and Modeller programs as alignment, visualization and 3D reconstruction tools. After validating the models by several procedures, we performed docking experiments with DOCK. We predicted binding pockets location and studied which odorants bind which ORs, comparing our results with electrophysiological measures of olfactory neurons activity. At the end, we successfully built six mouse ORs models and tested them against 24 common odorants, obtaining a good correlation with previous studies and thus validating our protocol. Moreover, we reconstructed eight human ORs which had never been modelled before, though their predicted interactions with 63 odorants were not clearly correlated to previous experimental studies. In this way, we have shown the efficiency of these computational algorithms, which can contribute to the research about biological processes such as the mechanism of olfaction. With small improvements, they could be in an early future a suitable alternative to experimental approaches, leading to accurate protein models in a practical, faster and easier way.

Estrada, L., Torres, A., Garcia-Casado, J., Sarlabous, L., Prats-Boluda, G., Jané, R., (2015). Evaluation of sternocleidomastoid muscle activity by electromyography recorded with concentric ring electrodes CASEIB Proceedings XXXIII Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2015) , Sociedad Española de Ingeniería Biomédica (Madrid, Spain) , 183-186

Los sonidos adventicios continuos (CAS) son uno de los principales síntomas del asma. Dada su importancia clínica, el análisis de estas señales requiere del uso de técnicas que permitan segmentarlas y caracterizarlas con una precisión alta. Sin embargo, la mayoría de técnicas propuestas anteriormente estaban basadas en el análisis de Fourier o wavelet, técnicas que tienen una resolución limitada a priori y son altamente dependientes de la amplitud de los CAS. En este estudio se presenta una técnica alternativa para el análisis de CAS basada en el espectro de Hilbert. El método presentado combina la descomposición empírica en modos por conjuntos con el estimador de Kay de la frecuencia instantánea, para obtener una representación tiempo-frecuencia con una alta concentración de energía y una resolución temporal y frecuencial elevada. Con el fin de mostrar las ventajas que ofrece el método presentado, se ha aplicado a cuatro señales de sonidos respiratorios registradas en pacientes asmáticos que contienen distintos tipos de CAS, reforzando la hipótesis confirmada en nuestro estudio previo de que el espectro de Hilbert permite segmentar y caracterizar los CAS con mayor precisión que otras técnicas tradicionales ampliamente utilizadas, como el espectrograma.

Urra, O., Casals, A., Jané, R., (2015). Visual feedback facilitates intermanual transfer of the motor control of the dominant arm towards the nondominant arm CASEIB Proceedings XXXIII Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2015) , Sociedad Española de Ingeniería Biomédica (Madrid, Spain) , 503-506

Visual feedback (VF) is applied to recover motor skills after stroke. However, the exact mechanisms underlying the beneficial effects of VF remain unclear, limiting its optimal use in clinical practice. We previously reported that the effect of neural mechanisms triggered by VF is reflected in the upperlimb at the level of the control structure (the set of synergies/corresponding activation coefficients used to perform a task). Here, we hypothesize that VF may facilitate the transfer of superior motor programs stored in the dominant hemisphere to optimize the nondominant arm’s motor control. In order to test this hypothesis we have quantified the intermanual transfer (IMT) of the dominant control structure to the nondominant arm during the execution of a complete set of standard rehabilitation routines. We demonstrate that IMT is the main mechanism by which VF increases interlimb similarity and we show that the magnitude of IMT can be up to 75% in neurologically intact subjects. Thus, this study provides sound physiological evidence to encourage the use of VF in stroke rehabilitation.

Rajasekaran, V., Aranda, J., Casals, A., (2015). User intention driven adaptive gait assistance using a wearable exoskeleton Robot 2015: Second Iberian Robotics Conference (ed. Paulo Reis, L., Paulo Moreira, A., Lima, P. U., Montano, L., Muñoz-Martinez, V.), Springer International (Lausanne, Switzerland) 418, 289-301

A user intention based rehabilitation strategy for a lower-limb wearable robot is proposed and evaluated. The control strategy, which involves monitoring the human-orthosis interaction torques, determines the gait initiation instant and modifies orthosis operation for gait assistance, when needed. Orthosis operation is classified as assistive or resistive in function of its evolution with respect to a normal gait pattern. The control algorithm relies on the adaptation of the joints’ stiffness in function of their interaction torques and their deviation from the desired trajectories. An average of recorded gaits obtained from healthy subjects is used as reference input. The objective of this work is to develop a control strategy that can trigger the gait initiation from the user’s intention and maintain the dynamic stability, using an efficient real-time stiffness adaptation for multiple joints, simultaneously maintaining their synchronization. The algorithm has been tested with five healthy subjects showing its efficient behavior in initiating the gait and maintaining the equilibrium while walking in presence of external forces. The work is performed as a preliminary study to assist patients suffering from incomplete Spinal cord injury and Stroke.

Keywords: Adaptive control, Exoskeleton, Gait assistance, Gait initiation, Wearable robot

Aviles, A. I., Sobrevilla, P., Casals, A., (2014). An approach for physiological motion compensation in robotic-assisted cardiac surgery Experimental & Clinical Cardiology , 20, (11), 6713-6724

The lack of physiological motion compensation is a major problem in robotic-assisted cardiac surgery. Since the heart is beating while the surgeon carried out the procedure, dexterity of the surgeon’s and precision are compromised. Due to the operative space and the visibility of the surgical field are reduced, the most practical solution is the use of computer vision techniques. The lack of efficiency and robustness of the existing proposals make physiological motion compensation to be considered an open problem. In this work a novel solution to solve this problem based on the minimization of an energy functional is presented. It is described in the three-dimensional space using the l1−regularized optimization class in which cubic b-splines are used to represent the changes produced on the heart surface. Moreover, the logarithmic barrier function is applied to create an approximation of the total energy in order to avoid its non-differentiability. According to the results, this proposal is able to deal with complex deformations, requires a short computational time and gives a small error.

Keywords: Beating heart surgery, Image analysis, Motion compensation

Eckelt, Kay, Masanas, Helena, Llobet, Artur, Gorostiza, P., (2014). Automated high-throughput measurement of body movements and cardiac activity of Xenopus tropicalis tadpoles Journal of Biological Methods , 1, (2), e9

Xenopus tadpoles are an emerging model for developmental, genetic and behavioral studies. A small size, optical accessibility of most of their organs, together with a close genetic and structural relationship to humans make them a convenient experimental model. However, there is only a limited toolset available to measure behavior and organ function of these animals at medium or high-throughput. Herein, we describe an imaging-based platform to quantify body and autonomic movements of Xenopus tropicalis tadpoles of advanced developmental stages. Animals alternate periods of quiescence and locomotor movements and display buccal pumping for oxygen uptake from water and rhythmic cardiac movements. We imaged up to 24 animals in parallel and automatically tracked and quantified their movements by using image analysis software. Animal trajectories, moved distances, activity time, buccal pumping rates and heart beat rates were calculated and used to characterize the effects of test compounds. We evaluated the effects of propranolol and atropine, observing a dose-dependent bradycardia and tachycardia, respectively. This imaging and analysis platform is a simple, cost-effective high-throughput in vivo assay system for genetic, toxicological or pharmacological characterizations.

Keywords: Xenopus tropicalis, Animal behavior, Cardiac imaging, Motion analysis, Animal tracking, Hhigh-throughput in vivo assay

Tahirbegi, I. B., Mir, M., Schostek, S., Schurr, M., Samitier, J., (2014). In vivo ischemia monitoring array for endoscopic surgery Biosensors and Bioelectronics 61, 124-130

An array with all-solid-state, potentiometric, miniaturized sensors for pH and potassium was developed to be introduced into the stomach or other sectors of the digestive tract by means of flexible endoscopy. These sensors perform continuous and simultaneous measurement of extracellular pH and potassium. This detection seeks to sense ischemia in the gastric mucosa inside the stomach, an event indicative of local microvascular perfusion and tissue oxygenation status. Our array is proposed as a medical tool to identify the occurrence of the ischemia after gastrointestinal or gastroesophageal anastomosis. The stability and feasibility of the miniaturized working and reference electrodes integrated in the array were studied under in vitro conditions, and the behavior of the potassium and pH ion-selective membranes were optimized to work under acidic gastric conditions with high concentrations of HCl. The array was tested in vivo in pigs to measure the ischemia produced by clamping the blood flow into the stomach. Our results indicate that ischemic and reperfusion states can be sensed in vivo and that information on tissue damage can be collected by this sensor array. The device described here provides a miniaturized, inexpensive, and mass producible sensor array for detecting local ischemia caused by unfavorable anastomotic perfusion and will thus contribute to preventing anastomotic leakage and failure caused by tissue necrosis.

Keywords: Endoscopy, Surgery, Tissue, Gastric anastomosis, Gastric conditions, Ion selective sensors, Ischemia, pH detection, Reference electrodes, Simultaneous measurement, Tissue oxygenation, Sensors

Marques, J., Moles, E., Urbán, P., Prohens, R., Busquets, M. A., Sevrin, C., Grandfils, C., Fernàndez-Busquets, X., (2014). Application of heparin as a dual agent with antimalarial and liposome targeting activities toward Plasmodium-infected red blood cells Nanomedicine: Nanotechnology, Biology, and Medicine 10, (8), 1719-1728

Heparin had been demonstrated to have antimalarial activity and specific binding affinity for Plasmodium-infected red blood cells (pRBCs) vs. non-infected erythrocytes. Here we have explored if both properties could be joined into a drug delivery strategy where heparin would have a dual role as antimalarial and as a targeting element of drug-loaded nanoparticles. Confocal fluorescence and transmission electron microscopy data show that after 30. min of being added to living pRBCs fluorescein-labeled heparin colocalizes with the intracellular parasites. Heparin electrostatically adsorbed onto positively charged liposomes containing the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane and loaded with the antimalarial drug primaquine was capable of increasing three-fold the activity of encapsulated drug in Plasmodium falciparum cultures. At concentrations below those inducing anticoagulation of mouse blood in vivo, parasiticidal activity was found to be the additive result of the separate activities of free heparin as antimalarial and of liposome-bound heparin as targeting element for encapsulated primaquine. From the Clinical Editor: Malaria remains an enormous global public health concern. In this study, a novel functionalized heparin formulation used as drug delivery agent for primaquine was demonstrated to result in threefold increased drug activity in cell cultures, and in a murine model it was able to provide these benefits in concentrations below what would be required for anticoagulation. Further studies are needed determine if this approach is applicable in the human disease as well.

Keywords: Heparin, Liposomes, Malaria, Plasmodium, Targeted drug delivery, Heparin, Malaria, Plasmodium, Red blood cell, Targeted drug delivery, Liposomes, 1,2 dioleoyl 3 trimethylammoniopropane, fluorescein, heparin, liposome, nanoparticle, primaquine, adsorption, animal experiment, anticoagulation, antimalarial activity, Article, binding affinity, confocal microscopy, controlled study, drug targeting, encapsulation, erythrocyte, female, fluorescence microscopy, human, human cell, in vivo study, liposomal delivery, mouse, nonhuman, Plasmodium falciparum, transmission electron microscopy

Gramse, G., Kasper, M., Fumagalli, L., Gomila, G., Hinterdorfer, P., Kienberger, F., (2014). Calibrated complex impedance and permittivity measurements with scanning microwave microscopy Nanotechnology 25, (14), 145703 (8)

We present a procedure for calibrated complex impedance measurements and dielectric quantification with scanning microwave microscopy. The calibration procedure works in situ directly on the substrate with the specimen of interest and does not require any specific calibration sample. In the workflow tip-sample approach curves are used to extract calibrated complex impedance values and to convert measured S11 reflection signals into sample capacitance and resistance images. The dielectric constant of thin dielectric SiO2 films were determined from the capacitance images and approach curves using appropriate electrical tip-sample models and the εr value extracted at f = 19.81 GHz is in good agreement with the nominal value of εr ∼ 4. The capacitive and resistive material properties of a doped Si semiconductor sample were studied at different doping densities and tip-sample bias voltages. Following a simple serial model the capacitance-voltage spectroscopy curves are clearly related to the semiconductor depletion zone while the resistivity is rising with falling dopant density from 20 Ω to 20 kΩ. The proposed procedure of calibrated complex impedance measurements is simple and fast and the accuracy of the results is not affected by varying stray capacitances. It works for nanoscale samples on either fully dielectric or highly conductive substrates at frequencies between 1 and 20 GHz.

Keywords: Complex impedance, Dielectric constant, Nanotechnology: calibration, Resistivity, Scanning microwave microscopy

Rajzer, I., Menaszek, E., Kwiatkowski, R., Planell, J. A., Castaño, O., (2014). Electrospun gelatin/poly(ε-caprolactone) fibrous scaffold modified with calcium phosphate for bone tissue engineering Materials Science and Engineering: C 44, 183-190

In this study gelatin (Gel) modified with calcium phosphate nanoparticles (SG5) and polycaprolactone (PCL) were used to prepare a 3D bi-layer scaffold by collecting electrospun PCL and gelatin/SG5 fibers separately in the same collector. The objective of this study was to combine the desired properties of PCL and Gel/SG5 in the same scaffold in order to enhance mineralization, thus improving the ability of the scaffold to bond to the bone tissue. The scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and the wide angle X-ray diffraction (WAXD) measurements confirmed that SG5 nanoparticles were successfully incorporated into the fibrous gelatin matrix. The composite Gel/SG5/PCL scaffold exhibited more enhanced mechanical properties than individual Gel and Gel/SG5 scaffolds. The presence of SG5 nanoparticles accelerated the nucleation and growth of apatite crystals on the surface of the composite Gel/SG5/PCL scaffold in simulated body fluid (SBF). The osteoblast response in vitro to developed electrospun scaffolds (PCL and Gel/SG5/PCL) was investigated by using normal human primary NHOst cell lines. NHOst cell culture studies showed that higher alkaline phosphatase (ALP) activity and better mineralization were obtained in the case of composite materials than in pure PCL scaffolds. The mechanically strong PCL scaffold served as a skeleton, while the Gel/SG5 fibers facilitated cell spreading and mineralization of the scaffold.

Keywords: Bilayer fibrous scaffold, Ceramic nanoparticles, Electrospinning, Gelatin, Polycaprolactone, Biomechanics, Bone, Calcium phosphate, Cell culture, Electrospinning, Fourier transform infrared spectroscopy, Mechanical properties, Mineralogy, Nanoparticles, Phosphatases, Polycaprolactone, Scanning electron microscopy, X ray diffraction, Polycaprolactone, Alkaline phosphatase activity, Bone tissue engineering, Calcium phosphate nanoparticles, Ceramic nanoparticles, Fibrous scaffolds, Gelatin, Simulated body fluids, Wide-angle x-ray diffraction, Electrospuns, Scaffolds (biology), Electrospinning

Malandrino, A., Noailly, J., Lacroix, D., (2014). Numerical exploration of the combined effect of nutrient supply, tissue condition and deformation in the intervertebral disc Journal of Biomechanics 47, (6), 1520-1525

Novel strategies to heal discogenic low back pain could highly benefit from comprehensive biophysical studies that consider both mechanical and biological factors involved in intervertebral disc degeneration. A decrease in nutrient availability at the bone-disc interface has been indicated as a relevant risk factor and as a possible initiator of cell death processes. Mechanical behaviour of both healthy and degenerated discs could highly interact with cell death in these compromised situations. In the present study, a mechano-transport finite element model was used to investigate the nature of mechanical effects on cell death processes via load-induced metabolic transport variations. Cycles of static sustained compression were chosen to simulate daily human activity. Healthy and degenerated cases were simulated as well as a reduced supply of solutes and an increase in solute exchange area at the bone-disc interface. Results showed that a reduction in metabolite concentrations at the bone-disc boundaries induced cell death, even when the increased exchange area was simulated. Slight local mechanical enhancements of glucose in the disc centre were capable of decelerating cell death but occurred only with healthy mechanical properties. However, mechanical deformations were responsible for a worsening in terms of cell death in the inner annulus, a disadvantaged zone far from the boundary supply with both an increased cell demand and a strain-dependent decrease of diffusivity. Such adverse mechanical effects were more accentuated when degenerative properties were simulated. Overall, this study paves the way for the use of biophysical models for a more integrated understanding of intervertebral disc pathophysiology.

Keywords: Boundary conditions, Cell nutrition, Cell viability, Computational analysis, Intervertebraldisc, Softtissuebiomechanics

Oller-Moreno, S., Pardo, A., Jimenez-Soto, J. M., Samitier, J., Marco, S., (2014). Adaptive Asymmetric Least Squares baseline estimation for analytical instruments SSD 2014 Proceedings 11th International Multi-Conference on Systems, Signals & Devices (SSD) , IEEE (Castelldefels-Barcelona, Spain) , 1569846703

Automated signal processing in analytical instrumentation is today required for the analysis of highly complex biomedical samples. Baseline estimation techniques are often used to correct long term instrument contamination or degradation. They are essential for accurate peak area integration. Some methods approach the baseline estimation iteratively, trying to ignore peaks which do not belong to the baseline. The proposed method in this work consists of a modification of the Asymmetric Least Squares (ALS) baseline removal technique developed by Eilers and Boelens. The ALS technique suffers from bias in the presence of intense peaks (in relation to the noise level). This is typical of diverse instrumental techniques such as Gas Chromatography-Mass Spectrometry (GC-MS) or Gas Chromatography-Ion Mobility Spectrometry (GC-IMS). In this work, we propose a modification (named psalsa) to the asymmetry weights of the original ALS method in order to better reject large peaks above the baseline. Our method will be compared to several versions of the ALS algorithm using synthetic and real GC signals. Results show that our proposal improves previous versions being more robust to parameter variations and providing more accurate peak areas.

Keywords: Gas chromatography, Instruments, Radioactivity measurement, Signal processing, Analytical instrument, Analytical Instrumentation, Asymmetric least squares, Baseline estimation, Baseline removal, Gas chromatography-mass spectrometries (GC-MS), Instrumental techniques, Noise levels, Iterative methods

Lozano-Garcia, M.., Fiz, J., Jané, R., (2014). Análisis de la intensidad de los sonidos respiratorios para el diagnóstico de la parálisis frénica unilateral CASEIB Proceedings XXXII Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2014) , Sociedad Española de Ingeniería Biomédica (Barcelona, Spain) , 1-4

(ISR) es una medida indirecta y no invasiva de la función respiratoria, que permite comparar la actividad en los dos hemitórax de los pacientes con parálisis frénica unilateral. Se registraron los sonidos y el flujo respiratorio en 10 hombres con parálisis frénica unilateral y 10 sujetos sanos (5 hombres/5 mujeres) en posición sentada. Se colocaron 2 micrófonos de contacto en la espalda, uno a cada lado de la columna. La ISR se calculó en el rango frecuencial 70-2000 Hz a partir de la densidad espectral de potencia y para flujos entre 1,2 y 2,4 l/s. Se encontró que las diferencias en la ISR media de los dos hemitórax era significativamente mayor en los pacientes (13.5 dB) que en los sujetos sanos (2.3 dB). Además, se comprobó que esa diferencia era mayor en pacientes con un volumen espiratorio forzado en el primer segundo menor. Por lo tanto, el análisis acústico de la ISR es una técnica no invasiva muy útil para valorar la función respiratoria. Esta técnica puede mejorar la fiabilidad en el diagnóstico de la parálisis frénica unilateral así como la monitorización a largo plazo de estos pacientes.

Giraldo, B., Chaparro, J. A., Caminal, P., Benito, S., (2014). Estudio de la potencia de la inspiración como predictor del proceso de extubación en pacientes CASEIB Proceedings XXXII Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2014) , Sociedad Española de Ingeniería Biomédica (Barcelona, Spain) , 1-4

La extubación de pacientes asistidos mediante ventilación mecánica sigue siendo un proceso fundamental en la práctica clínica, de especial atención en las unidades de cuidados intensivos. En este estudio se propone un nuevo índice de extubación basado en la potencia de la señal de flujo respiratorio (Pi). Se estudiaron un total de 132 pacientes sometidos al proceso de destete: 94 pacientes (GE) con resultado de éxito en la prueba, y 38 pacientes (GF) que fracasaron en el proceso de destete y tuvieron que ser deconectados al ventilador mecánico. La señal de flujo respiratorio fue procesada para obtener la potencia de la fase inspiratoria, considerando las siguientes etapas: a) detección del cruce por cero, b) detección del punto de inflexión, y c) obtención de la potencia de la señal hasta dicho punto. La detección de cruce por cero se realizó utilizando un algoritmo basado en umbrales. Los puntos de inflexión fueron marcados teniendo en cuenta el cero de la segunda derivada. La potencia de la fase inspiratoria se calculó a partir de la energía de la señal desde el cruce por cero hasta el punto de máxima inflexión. El nuevo índice fue evaluado como estimador de éxito en la extubación. Los resultados fueron analizados utilizando clasificadores como regresión logística, análisis discriminante lineal, árboles de decisión, teoría bayesiana, y máquinas de soporte vectorial. Los clasificadores Bayesianos presentaron los mejores resultados con una exactitud del 87%, y sensibilidad y especificidad de 90% y 81%, respectivamente.

Téllez, J., Herrera, S., Benito, S., Giraldo, B., (2014). Estudio del patrón respiratorio en pacientes ancianos CASEIB Proceedings XXXII Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2014) , Sociedad Española de Ingeniería Biomédica (Barcelona, Spain) , 1-4

La clínica relacionada con los pacientes ancianos, refleja una elevada incidencia de enfermedades de origen cardíaco y respiratorio. Alteraciones en el patrón respiratorio como son la respiración periódica (PB) y la respiración Cheyne-Stokes (CSR) pueden estar relacionadas con la insuficiencia cardíaca crónica (ICC). En este estudio se propuso caracterizar estos patrones respiratorios a partir de la envolvente de la señal de flujo respiratorio, aplicando técnicas de análisis frecuencial y de tiempo-frecuencia. Se estudiaron registros de 45 pacientes ancianos (25 pacientes con patrón PB y 20 pacientes con respiración no periódica (nPB)). Se analizaron los resultados considerando todas las posibles combinaciones de tipos de patrones: pacientes con patrones PB (con y sin apnea) vs nPB, y patrones CSR vs PB, CSR vs nPB y PB vs nPB. En el análisis tiempo-frecuencia se obtuvo la mayor exactitud (76.3%) con parámetros correspondientes a la variabilidad frecuencial y la desviación del pico de potencia, al comparar pacientes con patrón respiratorio nPB vs PB. Considerando segmentos de señal de 5 minutos, la potencia de pico de modulación, la variabilidad frecuencial y los rangos intercuartílicos presentaron los mejores resultados, con una exactitud del 72.8% al comparar los tres grupos (nPB, PB y CSR), y del 74.2% al comparar patrones PB vs nPB.

Estrada, L., Torres, A., Jané, R., (2014). Evaluación de la asincronía bilateral y toracoabdominal mediante señales mecanomiográficas CASEIB Proceedings XXXII Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2014) , Sociedad Española de Ingeniería Biomédica (Barcelona, Spain) , 1-4

Este estudio tiene como objetivo evaluar la asincronía en los compartimientos torácico y abdominal, durante la realización de un protocolo respiratorio incremental de presión. La actividad mecanomiográfica fue registrada en el tronco mediante el uso de acelerómetros colocados en la parte izquierda y derecha del tórax y del abdomen. Para extraer la baja frecuencia de las señales mecanomiograficas se utilizó un método basado en la descomposición empírica en modos. Para estudiar la asincronía entre los compartimientos estudiados se utilizaron tres métodos, basados en la figura de Lissajous, la transformada de Hilbert y el algoritmo de Motto. Se observó un aumento de la asincronía toracoabdominal, con el aumento de la carga inspiratoria. Los valores de asincronía encontrados al evaluar el lado izquierdo con el derecho tanto en el diafragma como en el abdomen fueron menores de 40°, mientras que al comparar tanto el lado izquierdo como el derecho entre el tórax y el abdomen estos exhibieron valores menores a 80°. En conclusión, este trabajo demuestra que con un aumento de la carga inspiratoria puede presentarse un aumento de asincronía entre diferentes regiones del tronco. Además, el uso de acelerómetros para el registro de la dinámica respiratoria puede llegar a ser una herramienta complementaria a las actuales como la pletismografía de inductancia respiratoria, debido a su más sencilla manipulación.

Solà, J., Fiz, J.A., Torres, A., Jané, R., (2014). Evaluación de la vía aérea superior en sujetos con SAHS mediante análisis del sonido respiratorio durante vigilia CASEIB Proceedings XXXII Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2014) , Sociedad Española de Ingeniería Biomédica (Barcelona, Spain) , 1-4

El Síndrome de Apnea-Hipopnea del Sueño (SAHS) actualmente se diagnostica mediante la Polisomnografía (PSG), una prueba cara y costosa. Se han propuesto diversas alternativas para ayudar al cribado previo de SAHS. En estudios previos demostramos que los sujetos con SAHS se pueden identificar a partir de las frecuencias de resonancia (formantes) de la respiración nocturna. En este trabajo se extiende el estudio al sonido respiratorio registrado en vigilia. Se seleccionaron diversos ciclos de inspiración y expiración consecutivas en 23 sujetos con diversos grados de SAHS durante el estado de vigilia previo a la PSG. Mediante un modelo autoregresivo (AR) se estimaron los formantes y el área transversal (CSA) de la vía. Se observa que los formantes en determinadas bandas tienen una frecuencia mayor (p<0.04) en sujetos con SAHS levemoderado, con un Índice de Apnea-Hipopnea (AHI) menor que 30, respecto a los sujetos con SAHS severo (AHI≥30). En paralelo, el área promedio de la vía aérea en las zonas con obstrucción muestra una tendencia decreciente (r=-0.498) con la severidad de la patología. Las características de los formantes, combinadas con medidas antropométricas, permiten clasificar a los sujetos con SAHS severo con una sensibilidad (especificidad) de hasta un 84.6% (88.9%). En conclusión, el sonido respiratorio registrado durante vigilia proporciona información valiosa sobre el estado de la vía aérea superior que puede ayudar a identificar un SAHS severo.

Aviles, A. I., Marban, A., Sobrevilla, P., Fernandez, Josep, Casals, A., (2014). A recurrent neural network approach for 3D vision-based force estimation IPTA 2014 4th International Conference on Image Processing Theory, Tools and Applications (IPTA) , IEEE (Paris, France) , 1-6

Robotic-assisted minimally invasive surgery has demonstrated its benefits in comparison with traditional procedures. However, one of the major drawbacks of current robotic system approaches is the lack of force feedback. Apart from space restrictions, the main problems of using force sensors are their high cost and the biocompatibility. In this work a proposal based on Vision Based Force Measurement is presented, in which the deformation mapping of the tissue is obtained using the `2−Regularized Optimization class, and the force is estimated via a recurrent neural network that has as inputs the kinematic variables and the deformation mapping. Moreover, the capability of RNN for predicting time series is used in order to deal with tool occlusions. The highlights of this proposal, according to the results, are: knowledge of material properties are not necessary, there is no need of adding extra sensors and a good trade-off between accuracy and efficiency has been achieved.

Keywords: Force estimation, Regularized optimization, Deformable tracking, Recurrent neural network

Sarlabous, L., Torres, A., Fiz, J.A., Gea, J., Martínez-Llorens, J.M., Jané, R., (2014). Relación entre la presión inspiratoria pico y la activación mecánica de los músculos inspiratorios durante respiración tranquila en pacientes con EPOC CASEIB Proceedings XXXII Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2014) , Sociedad Española de Ingeniería Biomédica (Barcelona, Spain) , 1-4

En la enfermedad pulmonar obstructiva crónica (EPOC) la fuerza muscular inspiratoria (FMI) y la eficiencia mecánica de los músculos inspiratorios (EMMI) podrían verse reducidas como consecuencia de la hiperinsuflación. En este trabajo se registraron la presión inspiratoria en boca (PIpico) y la activación mecánica de los músculos inspiratorios en 10 pacientes EPOC severos y muy severos, durante respiración tranquila. Para determinar la activación mecánica de los músculos inspiratorios se empleó la señal mecanomiográfica diafragmática: MMGdi. La amplitud de la señal MMGdi fue estimada a través de índices lineales (ARV: valor rectificado medio) y no lineales (MLZ: Lempel-Ziv multiestado, y fSampEn: entropía muestral con valores de tolerancia fijos). Nuestra hipótesis es que el ratio entre PIpico, que refleja la FMI, y la amplitud de la señal MMGdi constituye una expresión de la EMMI. Los resultados obtenidos muestran ligeras diferencias entre la PIpico registrada en EPOC severos y muy severos, así como una correlación débil a moderada con los parámetros de función pulmonar y los índices estudiados. Sin embargo, mientras mayor es el grado de severidad (que supone un mayor grado de hiperinsuflación) mayor es el nivel de activación mecánica de los músculos inspiratorios. La activación mecánica de los músculos inspiratorios y la EMMI estimadas mediante MLZ estuvieron mejor correlacionadas con la función pulmonar que ARV y fSampEn. Por consiguiente, la estimación de la actividad mecánica del diafragma mediante el MLZ de la señal MMGdi podría mejorar la estimación no invasiva de la FMI y la EMMI, incluso para niveles muy bajos de esfuerzo inspiratorio.

López Picazo, M., Solà, J., Fiz, J.A., Jané, R., (2014). Sincronización de sistemas de monitorización para el estudio de ronquidos en las distintas fases del sueño en pacientes con SAHS CASEIB Proceedings XXXII Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2014) , Sociedad Española de Ingeniería Biomédica (Barcelona, Spain) , 1-4

El Síndrome de Apnea-Hipopnea del Sueño (SAHS) tiene una incidencia en sujetos de edad media, del 2-4% en mujeres y 4- 6% en hombres, además de múltiples consecuencias asociadas. Sin embargo, a pesar de su prevalencia, menos de un 10% de la población con este síndrome es diagnosticada. Con el objetivo de identificar qué señales debería emplear un futuro método de diagnóstico para pacientes con sospecha de SAHS más eficaz que los actuales, se sugiere un estudio en detalle de los eventos respiratorios que tienen lugar durante la noche. Para ello se parte de los estudios de monitorización del sueño realizados a pacientes con síntomas de SAHS mediante dos plataformas comerciales distintas. En primer lugar, los registros procedentes de dichos estudios se combinan y sincronizan temporalmente de una forma precisa y robusta. Una vez llevada y sincronizada toda la información a una plataforma común, el presente estudio se centra en la relación del SAHS con una nueva información, el roncograma. El concograma permite estudiar la evolución de los ronquidos según la fase de sueño. Aplicando esta medida sobre nuestra base de datos observamos como el tiempo en fase de vigilia, el tiempo en fase REM o la densidad de ronquidos en fases ligeras presentan diferencias estadísticamente significativas para pacientes con distinta severidad de SAHS.

Urra, O., Casals, A., Jané, R., (2014). Study of synergy patterns during the execution of stroke rehabilitation exercises CASEIB Proceedings XXXII Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2014) , Sociedad Española de Ingeniería Biomédica (Barcelona, Spain) , 1-4

Stroke is a leading cause of disability, being motor impairments its major consequence. Despite rehabilitation, more than 60% of the patients report upper-limb motor dysfunction. The design of novel rehabilitation strategies requires objective measures to assess motor impairment and recovery. In a previous study, we proposed to use the synergy components of the unaffected limb as a reference to be targeted by rehabilitation, since they are proven to explain healthy motor control and to be altered after stroke. We demonstrated that healthy subjects have very similar control structures (synergies and activation vectors) in their right and left arms. Here, we investigate the existence of movement-specific control strategies. To do so, we analyze the inter-subject similarity of the healthy control structure in twelve common stroke rehabilitation exercises and we evidence that motor control is movement specific and generalizes across different subjects and their limbs. However, the similarity degree depends on the movement, suggesting that novel training protocols should purposely choose the rehabilitation exercises to ensure maximum control similarity with the reference pattern.

Jané, R., Caminal, P., Giraldo, B., Solà, J., Torres, A., (2014). Libro de Actas del CASEIB 2014 XXXII Congreso Anual de la SEIB , CASEIB-IBEC (Barcelona, Spain) , 20


Keywords: -----

Redondo-Morata, L., Giannotti, M. I., Sanz, F., (2013). AFM-based force-clamp indentation: Force-clamp monitors the lipid bilayer failure kinetics Imaging & Microscopy , 15, (4), 25-27

The lipid bilayer rupture was here explored by means of AFM-based force clamp. For the first time to our knowledge, this technique has been used to evaluate how lipid membranes respond when compressed under an external constant force in the range of nN. We were able to directly quantify the kinetics of the membrane rupture event and the associated energy barriers, in distinction to the classic studies performed at constant velocity.

González-García, C., Cantini, M., Moratal, D., Altankov, G., Salmerón-Sánchez, M., (2013). Vitronectin alters fibronectin organization at the cell-material interface Colloids and Surfaces B: Biointerfaces 111, 618-625

Cells assemble fibronectin (FN) into fibrils in a process mediated by integrins. For this process to occur, it is known that the presence of other serum proteins is necessary. However, the individual effect of these proteins on FN fibrillogenesis has not been addressed so far. In this study, the effect of vitronectin (VN), an ECM adhesion protein, on material-driven FN fibrillogenesis and cell-mediated FN reorganization is investigated. Poly(ethyl acrylate), PEA, which has previously shown the ability to induce the organization of FN into well-developed physiological-like networks upon adsorption, was employed as a material substrate. FN adsorption, cell adhesion and cellular FN reorganization in the presence or absence of VN were studied. Both FN surface density, quantified via western blot, and its distribution on PEA surfaces, determined via atomic force microscopy, were altered when FN was adsorbed competitively with VN at certain compositions. Moreover, the presence of VN on the material surfaces enhanced cell-mediated FN reorganization and secretion, in comparison with the process which took place in the presence of serum proteins.

Palacios-Padrós, A., Caballero-Briones, F., Díez-Pérez, I., Sanz, F., (2013). Tin passivation in alkaline media: Formation of SnO microcrystals as hydroxyl etching product Electrochimica Acta , 111, 837-845

The mechanism of the electrochemical passivation on Tin electrodes in 0.1 M NaOH is studied at low scan rates in a wide potential range. To this aim, tin oxide layers were grown on a polycrystalline tin surface under potentiostatic conditions in both the active and passive electrochemical potential ranges, and characterized by field emission scanning electron microscopy (FESEM), X-ray diffraction (XRD), Raman spectroscopy and electrochemical impedance spectroscopy (EIS). The results show that the first anodic process in the active region corresponds to the formation of a SnO·nH2O prepassive layer that is removed upon increasing the applied potential due to surface etching occurring at the metal/oxide interface. During the etching process, Sn 2+ ions supersaturate at the electrode vicinity thus forming a SnO crystalline phase on top of the electrode surface in the presence of the alkaline medium. At higher anodic potentials, near the passive plateau, the etching process ceases and the current drops due to the formation of a n-type Sn(IV)-based oxide at the metal/SnO interface that provides an efficient electronic passivation of the electrode.

Sachot, N., Castaño, Oscar, Mateos-Timoneda, Miguel A., Engel, Elisabeth, Planell, Josep A., (2013). Hierarchically engineered fibrous scaffolds for bone regeneration Journal of the Royal Society Interface , 10, (88), 20130684

Surface properties of biomaterials play a major role in the governing of cell functionalities. It is well known that mechanical, chemical and nanotopographic cues, for example, influence cell proliferation and differentiation. Here, we present a novel coating protocol to produce hierarchically engineered fibrous scaffolds with tailorable surface characteristics, which mimic bone extracellular matrix. Based on the sol–gel method and a succession of surface treatments, hollow electrospun polylactic acid fibres were coated with a silicon–calcium–phosphate bioactive organic–inorganic glass. Compared with pure polymeric fibres that showed a completely smooth surface, the coated fibres exhibited a nanostructured topography and greater roughness. They also showed improved hydrophilic properties and a Young's modulus sixfold higher than non-coated ones, while remaining fully flexible and easy to handle. Rat mesenchymal stem cells cultured on these fibres showed great cellular spreading and interactions with the material. This protocol can be transferred to other structures and glasses, allowing the fabrication of various materials with well-defined features. This novel approach represents therefore a valuable improvement in the production of artificial matrices able to direct stem cell fate through physical and chemical interactions.

Castangia, I., Manca, M. L., Matricardi, P., Sinico, C., Lampis, S., Fernàndez-Busquets, X., Fadda, A. M., Manconi, M., (2013). Effect of diclofenac and glycol intercalation on structural assembly of phospholipid lamellar vesicles International Journal of Pharmaceutics 456, (1), 1-9

The aim of the current study was to improve the knowledge of drug-glycol-phospholipid-interactions and their effects in lamellar vesicle suitability as drug delivery systems. Liposomes were prepared using hydrogenated soy phosphatidylcholine (P90H, 60. mg/ml) and diclofenac sodium salt at two concentrations (5-10. mg/ml). To obtain innovative vesicles two permeation enhancers with glycol group, diethyleneglycol monoethyl ether and propylene glycol, were added to the water phase at different ratios (5%, 10%, and 20%).Vesicle organization was deeply investigated by physico-chemical characterization, including differential scanning calorimetry and small-angle diffraction signal analysis while macroscopic structure behavior was evaluated by rheological studies. Results evidenced that the presence of the penetration enhancer and diclofenac sodium salt led to structural rearrangements within and among vesicles forming a tridimensional and complex architecture in which vesicles were closely packed and interconnected. This new design allowed a change in the physical state of dispersions that became highly viscous liquid or soft-solid-like, thus forming an ideal system for topical application able of both adhering to the skin and delivering the drug.

Guo, S., Artés, J. M., Díez-Pérez, I., (2013). Electrochemically-gated single-molecule electrical devices Electrochimica Acta 63rd Annual Meeting of the International Society of Electrochemistry , Elsevier (Prague, Czech Republic) 110, 741-753

In the last decade, single-molecule electrical contacts have emerged as a new experimental platform that allows exploring charge transport phenomena in individual molecular blocks. This novel tool has evolved into an essential element within the Molecular Electronics field to understand charge transport processes in hybrid (bio)molecule/electrode interfaces at the nanoscale, and prospect the implementation of active molecular components into functional nanoscale optoelectronic devices. Within this area, three-terminal single-molecule devices have been sought, provided that they are highly desired to achieve full functionality in logic electronic circuits. Despite the latest experimental developments offer consistent methods to bridge a molecule between two electrodes (source and drain in a transistor notation), placing a third electrode (gate) close to the single-molecule electrical contact is still technically challenging. In this vein, electrochemically-gated single-molecule devices have emerged as an experimentally affordable alternative to overcome these technical limitations. In this review, the operating principle of an electrochemically-gated single-molecule device is presented together with the latest experimental methodologies to built them and characterize their charge transport characteristics. Then, an up-to-date comprehensive overview of the most prominent examples will be given, emphasizing on the relationship between the molecular structure and the final device electrical behaviour.

Keywords: Electrochemical gate, Electrochemical switches, NDR, Single-molecule junctions, Unipolar/ambipolar FETs

Almendros, Isaac, Carreras, Alba, Montserrat, Josep M., Gozal, David, Navajas, Daniel, Farre, Ramon, (2012). Potential role of adult stem cells in obstructive sleep apnea Frontiers in Neurology 3, 1-6

Adult stem cells are undifferentiated cells that can be mobilized from the bone marrow or other organs, home into injured tissues and differentiate into different cell phenotypes to serve in a repairing capacity. Furthermore, these cells can respond to inflammation and oxidative stress by exhibiting immunomodulatory properties. The protective and reparative roles of mesenchymal stem cells (MSCs), very small embryonic-like stem cells (VSELs) and endothelial progenitor cells (EPCs) have primarily been examined and characterized in auto-immune and cardiovascular diseases. Obstructive sleep apnea (OSA) is a very prevalent disease (4-5% of adult population and 2-3% of children) characterized by an abnormal increase in upper airway collapsibility. Recurrent airway obstructions elicit arterial oxygen desaturations, increased inspiratory efforts and sleep fragmentation, which have been associated with important long-term neurocognitive, metabolic, and cardiovascular consequences. Since inflammation, oxidative stress and endothelial dysfunction are key factors in the development of the morbid consequences of OSA, bone marrow-derived stem cells could be important modulators of the morbid phenotype by affording a protective role. This mini-review is focused on the recent data available on EPCs, VSELs and MSCs in both animal models and patients with OSA.

Keywords: Mesenchymal Stem Cells, Sleep Apnea, Endothelial progenitor cells, Very Small-like Embryonic Stem Cells, Adult bone-marrow derived stem cells

Esquivel, J. P., Colomer-Farrarons, J., Castellarnau, M., Salleras, M., del Campo, F. J., Samitier, J., Miribel-Catala, P., Sabate, N., (2012). Fuel cell-powered microfluidic platform for lab-on-a-chip applications: Integration into an autonomous amperometric sensing device Lab on a Chip 12, (21), 4232-4235

The present paper reports for the first time the integration of a microfluidic system, electronics modules, amperometric sensor and display, all powered by a single micro direct methanol fuel cell. In addition to activating the electronic circuitry, the integrated power source also acts as a tuneable micropump. The electronics fulfil several functions. First, they regulate the micro fuel cell output power, which off-gas controls the flow rate of different solutions toward an electrochemical sensor through microfluidic channels. Secondly, as the fuel cell powers a three-electrode electrochemical cell, the electronics compare the working electrode output signal with a set reference value. Thirdly, if the concentration measured by the sensor exceeds this threshold value, the electronics switch on an integrated organic display. This integrated approach pushes forward the development of truly autonomous point-of-care devices relying on electrochemical detection.

Gramse, G., Edwards, M. A., Fumagalli, L., Gomila, G., (2012). Dynamic electrostatic force microscopy in liquid media Applied Physics Letters , 101, (21), 213108

We present the implementation of dynamic electrostatic force microscopy in liquid media. This implementation enables the quantitative imaging of local dielectric properties of materials in electrolyte solutions with nanoscale spatial resolution. Local imaging capabilities are obtained by probing the frequency-dependent and ionic concentration-dependent electrostatic forces at high frequency (>1 MHz), while quantification of the interaction forces is obtained with finite-element numerical calculations. The results presented open a wide range of possibilities in a number of fields where the dielectric properties of materials need to be probed at the nanoscale and in a liquid environment.

Solà, J., Fiz, J. A., Morera, J., Jané, R., (2012). Multiclass classification of subjects with sleep apnoea-hypopnoea syndrome through snoring analysis Medical Engineering and Physics , 34, (9), 1213-1220

The gold standard for diagnosing sleep apnoea-hypopnoea syndrome (SAHS) is polysomnography (PSG), an expensive, labour-intensive and time-consuming procedure. Accordingly, it would be very useful to have a screening method to allow early assessment of the severity of a subject, prior to his/her referral for PSG. Several differences have been reported between simple snorers and SAHS patients in the acoustic characteristics of snoring and its variability. In this paper, snores are fully characterised in the time domain, by their sound intensity and pitch, and in the frequency domain, by their formant frequencies and several shape and energy ratio measurements. We show that accurate multiclass classification of snoring subjects, with three levels of SAHS, can be achieved on the basis of acoustic analysis of snoring alone, without any requiring information on the duration or the number of apnoeas. Several classification methods are examined. The best of the approaches assessed is a Bayes model using a kernel density estimation method, although good results can also be obtained by a suitable combination of two binary logistic regression models. Multiclass snore-based classification allows early stratification of subjects according to their severity. This could be the basis of a single channel, snore-based screening procedure for SAHS.

Keywords: Bayes classifier, Kernel density estimation, Sleep apnoea, Snoring

Marco, S., Gutierrez-Galvez, A., (2012). Signal and data processing for machine olfaction and chemical sensing: A review IEEE Sensors Journal , 12, (11), 3189-3214

Signal and data processing are essential elements in electronic noses as well as in most chemical sensing instruments. The multivariate responses obtained by chemical sensor arrays require signal and data processing to carry out the fundamental tasks of odor identification (classification), concentration estimation (regression), and grouping of similar odors (clustering). In the last decade, important advances have shown that proper processing can improve the robustness of the instruments against diverse perturbations, namely, environmental variables, background changes, drift, etc. This article reviews the advances made in recent years in signal and data processing for machine olfaction and chemical sensing.

Keywords: Chemical sensors, Electronic nose, Intelligent sensors, Measurement techniques, Sensor arrays, Sensor systems

Lozano-Garcia, M., Fiz, J.A., Jané, R., (2012). Análisis multicanal de sonidos respiratorios en acústica pulmonar: aplicación clínica en pacientes asmáticos Libro de Actas XXX CASEIB 2012 XXX Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB2012) , Sociedad Española de Ingeniería Biomédica (San Sebastián, Spain) , 1-4

En este trabajo se ha visto que la evaluación de la potencia media de las señales de sonidos respiratorios antes y después de aplicar un fármaco broncodilatador puede reportar información importante sobre el estado y los cambios producidos en el sistema respiratorio. Se ha realizado y puesto a punto un protocolo de registro multicanal de acústica pulmonar mediante la colocación de 5 micrófonos de contacto: uno traqueal y cuatro micrófonos colocados en el tórax posterior. Mediante el análisis de las curvas intensidad-flujo respiratorio se han observado cambios significativos de intensidad a niveles de flujo elevados y en pacientes con una PBD negativa. Es en este grupo de pacientes, no respondedores, donde la técnica propuesta puede aportar información de interés clínico complementaria a la proporcionada por la espirometría clásica.

Urra, O., Fiz, J.A., Abad, J., Jané, R., (2012). Beyond the reach of AHI: identifying key markers for improved systematic diagnosis of SAHS Libro de Actas XXX CASEIB 2012 XXX Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB2012) , Sociedad Española de Ingeniería Biomédica (San Sebastián, Spain) , 1-4

Olivares, A.L., Perrault, C.M., Lacroix, D., (2012). Cell seeding optimization in 3D scaffold under dynamic condition: Computational and experimental methods The Proceedings of the 10th International Symposium on CMBBE 10th International Symposium on Computer Methods in Biomechanics and Biomedical Engineering , ARUP (Berlin, Germany) SS12: In silico modelling of the spinal disc degeneration, 906-911

Proper cell density and spatial distribution in a 3D scaffold are essential to morphogenetic development of an engineered tissue. The aim of this study was to combine computational and experimental techniques to study cell seeding under dynamic conditions. Rapid prototyped poly-caprolactone scaffolds, 5 mm in diameter and 1.5 mm in height, were used in a custom-made microfluidic chamber, thus enabling live visualization of the seeding process. The scaffold morphologies were reconstructed from micro CT images and the fluid volume was created similar to the microfluidic chamber. Computationally cell motion was represented as spherical particles in a fluid medium using a multiphase Lagrangian formulation implemented in Ansys Fluent. Cells were dragged by the fluid flow and adhesion was quantified using wall film theory. Experimentally, fluorescent microspheres, 10 um in diameter, were used, and fluid flow was controlled with a syringe pump. Inlet fluid flow was applied at 0.15 mm/s, identical to the model condition. Live imaging of the seeding process in the microfluidic chamber enables to record particle trajectory and velocity and possible zone of cell adhesion. The computational simulation shows velocities (≈0.6mm/s) in agreement with the particles experiment. Particles distributions was similar and can be highlighted the scaffold design in fluid accessibility.model proposed in a lumbar spine model, given the limited number of parameters involved.

Chaparro, J., Giraldo, B.F., Caminal, P., Benito, S., (2012). Comportamiento de parámetros del patrón respiratorio en clasificadores para la predicción del proceso weaning Libro de Actas XXX CASEIB 2012 XXX Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB2012) , Sociedad Española de Ingeniería Biomédica (San Sebastián, Spain) , 1-4

Toumanidou, T., Fortuny, G., Lacroix, D., Noailly, J., (2012). Constitutive modelling of the lumbar spine musculature The Proceedings of the 10th International Symposium on CMBBE 10th International Symposium on Computer Methods in Biomechanics and Biomedical Engineering , ARUP (Berlin, Germany) SS12: In silico modelling of the spinal disc degeneration, 693-699

Spinal muscles provide stability of the trunk and transmit loading onto the vertebra and intervertebral discs. Current lumbar spine finite element models overlook such muscle contribution or suggest simplifications far from the reality. This study proposes to address this limitation by developing a novel active lumbar spine muscle model. A modified quasi-incompressible fibre-reinforced hyperelastic constitutive model was adopted for the passive and active behavior of the lumbar musculature. The constitutive relation was expressed in terms of muscle fibre, matrix deviatoric and volumetric stresses. A single unidirectional element was used to assess the model under 30% traction and 20% compression strains. For the active fibre stress, a parametric study defined suitable values for a strain-like parameter ζCE that controls muscle activation through deformation thresholds. Stress analysis revealed that ζCE values derived for the different lumbar muscles from literature-based morphometric criteria were unable to induce any active response. Thus, alternative values were proposed keeping the relative activations of the muscles modelled as suggested by the relation of ζCE to the functional geometrical characteristics of these muscles. Stress results for all models were in the plausible range of values reported in literature for the erect posture. The Psoas Major, though, showed an unrealistic high activation for compression strains over 15%. Therefore, a phenomenological calibration of the parameter ζCE would allow further implementation of the constitutive model proposed in a lumbar spine model, given the limited number of parameters involved.

Garde, A., Giraldo, B.F., Jané, R., Latshang, T.D., Turk, A.J., Hess, T., Bosch, M-.M., Barthelmes, D., Hefti, J.P., Maggiorini, M., Hefti, U., Merz, T.M., Schoch, O.D., Bloch, K.E., (2012). Estudio de la respiración periódica en el ascenso a altitudes extremas a partir de la señal de volumen respiratorio Libro de Actas XXX CASEIB 2012 XXX Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB2012) , Sociedad Española de Ingeniería Biomédica (San Sebastián, Spain) , 1-4

La respiración periódica (PB) a gran altitud comparte aspectos fisiopatológicos con la apnea, la respiración Cheyne-Stokes y la PB en pacientes con insuficiencia cardiaca. Cuantificar las inestabilidades del control respiratorio puede proporcionar información relevante de los mecanismos fisiológicos que las producen, y ayudar en las actuaciones terapéuticas. Bajo la hipótesis de que en altitudes extremas la PB puede aparecer incluso durante actividad física, el objetivo es identificar la PB y evaluar el efecto de aclimatación a partir de la caracterización del patrón respiratorio mediante la señal de volumen respiratorio. Se analizaron los datos obtenidos de 34 montañeros sanos ascendiendo al Muztagh Ata, China (7,546m). Sus señales se etiquetaron visualmente como, respiración periódica (PB=40) y no periódica (nPB=371). El patrón respiratorio se caracterizó a partir de parámetros extraídos de la densidad espectral de potencia de la señal de volumen respiratorio. Los mejores resultados clasificando PB y nPB se obtuvieron con Pm (potencia de modulación) y R (ratio entre potencia de modulación y respiración) con una precisión del 80.3% y un área bajo la curva de 84.5%. SaO2 y el número de ciclos periódicos de respiración aumentaron significativamente con la aclimatación (p-valor<0.05). A menor SaO2 se observó una mayor Pm y frecuencia respiratoria, (correlación negativa, p-valor<0.01), y una mayor Pm en periodos etiquetados como PB con > 5 ciclos respiratorios periódicos, (correlación positiva, p-valor<0.01). Estos resultados demuestran que la caracterización espectral de la señal de volumen respiratorio permite identificar los efectos de la hipoxia hipobárica en el control de la respiración.

Torres, A., Sarlabous, L., Fiz, J.A., Jané, R., (2012). Evaluación de diferentes algoritmos adaptativos para la atenuación de la interferencia cardiaca en señales mecanomiográficas simuladas Libro de Actas XXX CASEIB 2012 XXX Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB2012) , Sociedad Española de Ingeniería Biomédica (San Sebastián, Spain) , 1-4

El estudio de la señal mecanomiográfica del músculo diafragma (MMGdi) es una técnica utilizada para evaluar el esfuerzo muscular respiratorio. El estudio de la relación entre los parámetros de amplitud y frecuencia de esta señal con el esfuerzo respiratorio realizado es de gran interés para investigadores y médicos debido a su potencial de diagnóstico sobre la función muscular respiratoria. Las señales MMGdi se ven afectas por una componente interferente correspondiente a la actividad vibratoria cardíaca o interferencia mecanocardiográfica (MCG). Para reducir o atenuar esta actividad se puede utilizar una cancelación adaptativa de interferencias (CAI). En este trabajo se ha evaluado el esquema de CAI propuesto mediante una señal MMGdi sintética generada con amplitud y frecuencia controlada a la que se le ha añadido ruido MCG real adquirido durante apnea. El coeficiente de correlación de Pearson (r) entre la amplitud y la frecuencia teóricas, y la amplitud y la frecuencia evaluadas mediante el RMS y la frecuencia media del espectro, respectivamente, disminuye considerablemente cuando se añade el ruido cardíaco a la señal MMGdi sintética: pasa de 0.95 a 0.87 para la amplitud, y de 0.97 a 0.76 para la frecuencia. Con los algoritmos de CAI propuestos el efecto del ruido MCG sobre la actividad MMGdi se reduce considerablemente (r de 0.93 para la amplitud y 0.97 para la frecuencia media). El método de CAI propuesto en este trabajo es una técnica adecuada para atenuar la interferencia MCG en señales MMGdi.

Ruiz, C., Noailly, J., Lacroix, D., (2012). Material discontinuities create fluid flow instabilities in intervertebral disc poroelastic finite element models The Proceedings of the 10th International Symposium on CMBBE 10th International Symposium on Computer Methods in Biomechanics and Biomedical Engineering , ARUP (Berlin, Germany) SS12: In silico modelling of the spinal disc degeneration, 142-147

Fluid flow predictions are important in intervertebral disc models to explore the mechanobiology and biomechanics of the tissue. Poroelastic models are used in this sense, but the results from applying physiological load rates may present instabilities. Four IVD models including the annulus fibrosus, the nucleus pulposus, and the endplates were used with different mesh sizes under physiological extension and axial rotational loads. Simulations indicated that oscillations were caused by numerical instability of the pore pressure derivation at material discontinuities. Applying local refinement only was not enough to eliminate the instabilities. Indeed, mesh refinements had to be local and material-dependent, and had to be supplemented by the creation of a material transition zone, including exponentially interpolated material properties between the nucleus and the annulus.

Malandrino, A., Noailly, J., Lacroix, D., (2012). Mechanical effect on metabolic transport and cell viability in the intervertebral disc The Proceedings of the 10th International Symposium on CMBBE 10th International Symposium on Computer Methods in Biomechanics and Biomedical Engineering , ARUP (Berlin, Germany) SS12: In silico modelling of the spinal disc degeneration, 248-253

The degeneration process in the intervertebral disc (IVD) is linked to progressive cell death and to mechanical factors. Therefore, the inclusion of cell viability criteria coupled with disc mechanics in a computational model would enable to get a better understanding of the degeneration process in IVD. A recently developed finite element (FE) model of the L4-L5 IVD based on poromechanics and IVD metabolism (Malandrino et al., 2011) was modified to include an exponential decay of cells over time below critical glucose and pH levels. The implementation was verified against in vitro literature data on cell viability. Viability criteria were used in the IVD model where diffusions of glucose, oxygen and lactate accounted for predicted porosity and volume changes. Subtissue-specific mechanical properties and cell concentrations were modelled. Daily compressive phases (standing and resting) were applied. Metabolite boundary concentrations were reduced at the endplates to induce critical conditions within the IVD. Solutions with and without mechanical coupling were compared. Critical glucose rather than pH levels were relevant to cell viability far away from the solute supply. Deformation couplings increased glucose in the disc centre so that cells stopped dying up to 10 hours earlier over two days simulated when mechanical deformations were considered. These results can help in the understanding of coupled mechanical and biological factors. If metabolite supply is disturbed, as it could happen during endplate calcification or circulatory diseases, a local accelerated cell death in the disc centre may occur in absence of tissue compliance. This study highlights the need to restore both nutritional and mechanical factors in order to favour cell viability along regenerative treatments.

Colomer-Farrarons, J., Miribel-Català , P., Juanola-Feliu, E., Samitier, J., (2012). A proof-of-concept of a multi-harvesting power source in a low-voltage CMOS technology IEEE Computer Society 2012 IEEE International Conference on Green Computing and Communications, Conference on Internet of Things, and Conference on Cyber, Physical and Social Computing , IEEE (Besancon, France) , 655-659

This paper presents a view of the state of the art in the field of energy harvesting solutions focused on discrete to integrated solutions in the range of low-power generation, from a few microwatts to several nanowatts. A view of commercial solutions to the new trends in new self-powered smart sensors operating without the use of any kind of battery will be presented. A specific solution developed in our laboratory will be used as an example of application.

Keywords: Electric power generation, Energy scavenging, Low-power electronics, Power conditioning

Sarlabous, L., Torres, A., Fiz, J.A., Jané, R., (2012). Reducción de interferencia cardíaca en señales MMG diafragmáticas registradas durante un protocolo de carga incremental sostenida mediante el algoritmo RLS Libro de Actas XXX CASEIB 2012 XXX Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB2012) , Sociedad Española de Ingeniería Biomédica (San Sebastián, Spain) , 1-4

En este trabajo se aplicó el filtrado adaptativo empleando el algoritmo RLS para reducir la interferencia de origen cardíaco en las señales mecanomiográficas diafragmáticas (MMGdi) registras durante un protocolo de carga incremental sostenida. La señal MMGdi fue dividida en tramos con y sin ruido cardíaco, CRC y SRC, respectivamente. En cada tramo se estudio el comportamiento de la densidad espectral de potencia (DEP), y los parámetros de amplitud RMS y ARV para cada una de las cargas inspiratorias que conforman el test. Los resultados obtenidos, empleando filtro adaptativo de orden =50, con el algoritmo RLS y valores de - = 1, permiten reducir considerablemente la interferencia cardíaca en las señales MMGdi.

Montufar, Edgar B., Traykova, Tania, Planell, Josep A., Ginebra, Maria-Pau, (2011). Comparison of a low molecular weight and a macromolecular surfactant as foaming agents for injectable self setting hydroxyapatite foams: Polysorbate 80 versus gelatine Materials Science and Engineering: C 31, (7), 1498-1504

Hydroxyapatite foams are potential synthetic bone grafting materials or scaffolds for bone tissue engineering. A novel method to obtain injectable hydroxyapatite foams consists in foaming the liquid phase of a calcium phosphate cement. In this process, the cement powder is incorporated into a liquid foam, which acts as a template for macroporosity. After setting, the cement hardens maintaining the macroporous structure of the foam. In this study a low molecular weight surfactant, Polysorbate 80, and a protein, gelatine, were compared as foaming agents of a calcium phosphate cement. The foamability of Polysorbate 80 was greater than that of gelatine, resulting in higher macroporosity in the set hydroxyapatite foam and higher macropore interconnectivity. Gelatine produced less interconnected foams, especially at high concentrations, due to a higher liquid foam stability. However it increased the injectability and cohesion of the foamed paste, and enhanced osteoblastic-like cell adhesion, all of them important properties for bone grafting materials.

Keywords: Hydroxyapatite, Porosity, Calcium phosphate cement, Scaffolds, Foaming, Bone regeneration

Auffarth, Benjamin, Gutierrez-Galvez, Agustín, Marco, Santiago, (2011). Continuous spatial representations in the olfactory bulb may reflect perceptual categories Frontiers in Systems Neuroscience 5, (82), 1-8

In sensory processing of odors, the olfactory bulb is an important relay station, where odor representations are noise-filtered, sharpened, and possibly re-organized. An organization by perceptual qualities has been found previously in the piriform cortex, however several recent studies indicate that the olfactory bulb code reflects behaviorally relevant dimensions spatially as well as at the population level. We apply a statistical analysis on 2-deoxyglucose images, taken over the entire bulb of glomerular layer of the rat, in order to see how the recognition of odors in the nose is translated into a map of odor quality in the brain. We first confirm previous studies that the first principal component could be related to pleasantness, however the next higher principal components are not directly clear. We then find mostly continuous spatial representations for perceptual categories. We compare the space spanned by spatial and population codes to human reports of perceptual similarity between odors and our results suggest that perceptual categories could be already embedded in glomerular activations and that spatial representations give a better match than population codes. This suggests that human and rat perceptual dimensions of odorant coding are related and indicates that perceptual qualities could be represented as continuous spatial codes of the olfactory bulb glomerulus population.

Keywords: Glomeruli, Memory organization, Odor quality, Olfaction, Olfactory bulb, Perceptual categories, Population coding, Spatial coding

Trepat, X., (2011). Forcing tumor arrest Physics , 4, 85


Keywords: -----

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.

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

Auffarth, Benjamin, Gutierrez, Agustin, Marco, Santiago, (2011). Statistical analysis of coding for molecular properties in the olfactory bulb Frontiers in Systems Neuroscience 5, (62), 1-8

The relationship between molecular properties of odorants and neural activities is arguably one of the most important issues in olfaction and the rules governing this relationship are still not clear. In the olfactory bulb (OB), glomeruli relay olfactory information to second-order neurons which in turn project to cortical areas. We investigate relevance of odorant properties, spatial localization of glomerular coding sites, and size of coding zones in a dataset of 2-deoxyglucose images of glomeruli over the entire OB of the rat. We relate molecular properties to activation of glomeruli in the OB using a nonparametric statistical test and a support-vector machine classification study. Our method permits to systematically map the topographic representation of various classes of odorants in the OB. Our results suggest many localized coding sites for particular molecular properties and some molecular properties that could form the basis for a spatial map of olfactory information. We found that alkynes, alkanes, alkenes, and amines affect activation maps very strongly as compared to other properties and that amines, sulfur-containing compounds, and alkynes have small zones and high relevance to activation changes, while aromatics, alkanes, and carboxylics acid recruit very big zones in the dataset. Results suggest a local spatial encoding for molecular properties.

Keywords: Molecular-receptive range, Odor, Olfactory bulb, Olfactory coding, Property-activity relationship, Structure-odor relationship

Tambe, Dhananjay T., Corey Hardin, C., Angelini, Thomas E., Rajendran, Kavitha, Park, Chan Young, Serra-Picamal, Xavier, Zhou, Enhua H., Zaman, Muhammad H., Butler, James P., Weitz, David A., Fredberg, Jeffrey J., Trepat, X., (2011). Collective cell guidance by cooperative intercellular forces Nature Materials 10, (6), 469-475

Cells comprising a tissue migrate as part of a collective. How collective processes are coordinated over large multi-cellular assemblies has remained unclear, however, because mechanical stresses exerted at cell–cell junctions have not been accessible experimentally. We report here maps of these stresses within and between cells comprising a monolayer. Within the cell sheet there arise unanticipated fluctuations of mechanical stress that are severe, emerge spontaneously, and ripple across the monolayer. Within that stress landscape, local cellular migrations follow local orientations of maximal principal stress. Migrations of both endothelial and epithelial monolayers conform to this behaviour, as do breast cancer cell lines before but not after the epithelial–mesenchymal transition. Collective migration in these diverse systems is seen to be governed by a simple but unifying physiological principle: neighbouring cells join forces to transmit appreciable normal stress across the cell–cell junction, but migrate along orientations of minimal intercellular shear stress.

Keywords: Biological materials, Mechanical properties

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

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

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

Simao, C., Mas-Torrent, M., Crivillers, N., Lloveras, V., Artés, Juan Manuel, Gorostiza, Pau, Veciana, Jaume, Rovira, C., (2011). A robust molecular platform for non-volatile memory devices with optical and magnetic responses Nature Chemistry , 3, (5), 359-364

Bistable molecules that behave as switches in solution have long been known. Systems that can be reversibly converted between two stable states that differ in their physical properties are particularly attractive in the development of memory devices when immobilized in substrates. Here, we report a highly robust surface-confined switch based on an electroactive, persistent organic radical immobilized on indium tin oxide substrates that can be electrochemically and reversibly converted to the anion form. This molecular bistable system behaves as an extremely robust redox switch in which an electrical input is transduced into optical as well as magnetic outputs under ambient conditions. The fact that this molecular surface switch, operating at very low voltages, can be patterned and addressed locally, and also has exceptionally high long-term stability and excellent reversibility and reproducibility, makes it a very promising platform for non-volatile memory devices.

Keywords: Self-assembled monolayers, Chromophore-based monolayers, Ultrathin platinum films, Carbon free-radicals, Per-million levels, Polychlorotriphenylmethyl radicals, Electron-transfer, Surface, Logic, Quantification

Trepat, X., Fredberg, J. J., (2011). Plithotaxis and emergent dynamics in collective cellular migration Trends in Cell Biology 21, (11), 638-646

For a monolayer sheet to migrate cohesively, it has long been suspected that each constituent cell must exert physical forces not only upon its extracellular matrix but also upon neighboring cells. The first comprehensive maps of these distinct force components reveal an unexpected physical picture. Rather than showing smooth and systematic variation within the monolayer, the distribution of physical forces is dominated by heterogeneity, both in space and in time, which emerges spontaneously, propagates over great distances, and cooperates over the span of many cell bodies. To explain the severe ruggedness of this force landscape and its role in collective cell guidance, the well known mechanisms of chemotaxis, durotaxis, haptotaxis are clearly insufficient. In a broad range of epithelial and endothelial cell sheets, collective cell migration is governed instead by a newly discovered emergent mechanism of innately collective cell guidance - plithotaxis.

Keywords: Positional information, Drosophila embryo, Sheet migration, Dpp gradient, Cells, Force, Morphogenesis, Transition, Identification, Proliferation

Artés, Juan M., Díez-Pérez, Ismael, Sanz, Fausto, Gorostiza, Pau, (2011). Direct measurement of electron transfer distance decay constants of single redox proteins by electrochemical tunneling spectroscopy ACS Nano 5, (3), 2060-2066

We present a method to measure directly and at the single-molecule level the distance decay constant that characterizes the rate of electron transfer (ET) in redox proteins. Using an electrochemical tunneling microscope under bipotentiostatic control, we obtained current-distance spectroscopic recordings of individual redox proteins confined within a nanometric tunneling gap at a well-defined molecular orientation. The tunneling current decays exponentially, and the corresponding decay constant (β) strongly supports a two-step tunneling ET mechanism. Statistical analysis of decay constant measurements reveals differences between the reduced and oxidized states that may be relevant to the control of ET rates in enzymes and biological electron transport chains.

Keywords: Long-range electron transfer (LRET), Distance decay constant, Single-molecule electrochemistry, Redox enzyme, Metalloprotein, Blue copper protein, Azurin, Electrochemical scanning tunneling microscopy and spectroscopy, Nanoelectrodes, Debye length, Electrochemical charge screening

Angelini, Thomas E., Hannezo, Edouard, Trepat, Xavier, Marquez, Manuel, Fredberg, Jeffrey J., Weitz, David A., (2011). Glass-like dynamics of collective cell migration Proceedings of the National Academy of Sciences of the United States of America 108, (12), 4714-4719

Collective cell migration in tissues occurs throughout embryonic development, during wound healing, and in cancerous tumor invasion, yet most detailed knowledge of cell migration comes from single-cell studies. As single cells migrate, the shape of the cell body fluctuates dramatically through cyclic processes of extension, adhesion, and retraction, accompanied by erratic changes in migration direction. Within confluent cell layers, such subcellular motions must be coupled between neighbors, yet the influence of these subcellular motions on collective migration is not known. Here we study motion within a confluent epithelial cell sheet, simultaneously measuring collective migration and subcellular motions, covering a broad range of length scales, time scales, and cell densities. At large length scales and time scales collective migration slows as cell density rises, yet the fastest cells move in large, multicell groups whose scale grows with increasing cell density. This behavior has an intriguing analogy to dynamic heterogeneities found in particulate systems as they become more crowded and approach a glass transition. In addition we find a diminishing self-diffusivity of short-wavelength motions within the cell layer, and growing peaks in the vibrational density of states associated with cooperative cell-shape fluctuations. Both of these observations are also intriguingly reminiscent of a glass transition. Thus, these results provide a broad and suggestive analogy between cell motion within a confluent layer and the dynamics of supercooled colloidal and molecular fluids approaching a glass transition.

Keywords: Active matter, Cell mechanics, Jamming, Collective cell dynamics, Nonequilibrium

Gauthier, Nils C., Fardin, Marc Antoine, Roca-Cusachs, Pere, Sheetz, Michael P., (2011). Temporary increase in plasma membrane tension coordinates the activation of exocytosis and contraction during cell spreading Proceedings of the National Academy of Sciences of the United States of America 108, (35), 14467-14472

Cell migration and spreading involve the coordination of membrane trafficking, actomyosin contraction, and modifications to plasma membrane tension and area. The biochemical or biophysical basis for this coordination is however unknown. In this study, we show that during cell spreading, lamellipodia protrusion flattens plasma membrane folds and blebs and, once the plasma membrane area is depleted, there is a temporary increase in membrane tension by over twofold that is followed by activation of exocytosis and myosin contraction. Further, an artificial increase in plasma membrane tension stopped lamellipodia protrusion and activated an exocytotic burst. Subsequent decrease in tension restored spreading with activation of contraction. Conversely, blebbistatin inhibition of actomyosin contraction resulted in an even greater increase in plasma membrane tension and exocytosis activation. This spatio-temporal synchronization indicates that membrane tension is the signal that coordinates membrane trafficking, actomyosin contraction, and plasma membrane area change. We suggest that cells use plasma membrane tension as a global physical parameter to control cell motility.

Keywords: Surface-area regulation, Cytoskeleton adhesion, Erythrocyte-membrane, Extensional flow, Elastic tether, Force

Cordeiro, T. N., Schmidt, H., Madrid, C., Juarez, A., Bernado, P., Griesinger, C., Garcia, J., Pons, M., (2011). Indirect DNA readout by an H-NS related protein: Structure of the DNA complex of the C-terminal domain of Ler PLoS Pathogens Plos Pathogens , 7, (11), 12

Ler, a member of the H-NS protein family, is the master regulator of the LEE pathogenicity island in virulent Escherichia coli strains. Here, we determined the structure of a complex between the DNA-binding domain of Ler (CT-Ler) and a 15-mer DNA duplex. CT-Ler recognizes a preexisting structural pattern in the DNA minor groove formed by two consecutive regions which are narrower and wider, respectively, compared with standard B-DNA. The compressed region, associated with an AT-tract, is sensed by the side chain of Arg90, whose mutation abolishes the capacity of Ler to bind DNA. The expanded groove allows the approach of the loop in which Arg90 is located. This is the first report of an experimental structure of a DNA complex that includes a protein belonging to the H-NS family. The indirect readout mechanism not only explains the capacity of H-NS and other H-NS family members to modulate the expression of a large number of genes but also the origin of the specificity displayed by Ler. Our results point to a general mechanism by which horizontally acquired genes may be specifically recognized by members of the H-NS family.

Keywords: Enteropathogenic escherichia-coli, Nucleoid-associated protein, Nmr structure determination, Encoded regulator ler, Controls expression, Binding domain

Valle-Delgado, J. J., Molina-Bolívar, J. A., Galisteo-González, F., Gálvez-Ruiz, M. J., (2011). Evidence of hydration forces between proteins Current Opinion in Colloid and Interface Science , 16, (6), 572-578

Proteins are fundamental molecules in biology that are also involved in a wide range of industrial and biotechnological processes. Consequently, many works in the literature have been devoted to the study of protein-protein and protein-surface interactions in aqueous solutions. The results have been usually interpreted within the frame of the classical Derjaguin-Landau-Verwey-Overbeek (DLVO) theory for colloidal systems. However, against the DLVO predictions, striking evidence of repulsive forces between proteins at high salt concentrations has been observed in different works based on the analysis of the second virial coefficient or on the direct measurement of protein interaction with an atomic force microscope. Hydration forces due to the adsorption of hydrated cations onto the negatively charged protein surfaces have been invoked to rationalize this anomalous repulsion. The hydration forces between proteins provide protein-covered particles with a non-DLVO colloidal stability at high salt concentrations, as different studies in the literature has proven. This review summarizes the most relevant results published so far on the presence of hydration forces between proteins and protein-coated colloidal particles.

Keywords: Colloidal particles, Colloidal stability, Hydrated ions, Hydration forces, Proteins

Woods, N. B., Parker, A. S., Moraghebi, R., Lutz, M. K., Firth, A. L., Brennand, K. J., Berggren, W. T., Raya, A., Belmonte, J. C. I., Gage, F. H., Verma, I. M., (2011). Brief report: Efficient generation of hematopoietic precursors and progenitors from human pluripotent stem cell lines Stem Cells , 29, (7), 1158-1164

By mimicking embryonic development of the hematopoietic system, we have developed an optimized in vitro differentiation protocol for the generation of precursors of hematopoietic lineages and primitive hematopoietic cells from human embryonic stem cells (ESC) and induced pluripotent stem cells (iPSCs). Factors such as cytokines, extra cellular matrix components, and small molecules as well as the temporal association and concentration of these factors were tested on seven different human ESC and iPSC lines. We report the differentiation of up to 84% human CD45+ cells (average 41% +/- 16%, from seven pluripotent lines) from the differentiation culture, including significant numbers of primitive CD45+/CD34+ and CD45+/CD34+/CD38- hematopoietic progenitors. Moreover, the numbers of hematopoietic progenitor cells generated, as measured by colony forming unit assays, were comparable to numbers obtained from fresh umbilical cord blood mononuclear cell isolates on a per CD45+ cell basis. Our approach demonstrates highly efficient generation of multipotent hematopoietic progenitors with among the highest efficiencies reported to date (CD45+/CD34+) using a single standardized differentiation protocol on several human ESC and iPSC lines. Our data add to the cumulating evidence for the existence of an in vitro derived precursor to the hematopoietic stem cell (HSC) with limited engrafting ability in transplanted mice but with multipotent hematopoietic potential. Because this protocol efficiently expands the preblood precursors and hematopoietic progenitors, it is ideal for testing novel factors for the generation and expansion of definitive HSCs with long-term repopulating ability.

Keywords: Differentiation, Hematopoiesis, Hematopoietic progenitors, Pluripotent stem cells

Melchels, Ferry P. W., Tonnarelli, Beatrice, Olivares, Andy L., Martin, Ivan, Lacroix, Damien, Feijen, Jan, Wendt, David J., Grijpma, Dirk W., (2011). The influence of the scaffold design on the distribution of adhering cells after perfusion cell seeding Biomaterials 32, (11), 2878-2884

In natural tissues, the extracellular matrix composition, cell density and physiological properties are often non-homogeneous. Here we describe a model system, in which the distribution of cells throughout tissue engineering scaffolds after perfusion seeding can be influenced by the pore architecture of the scaffold. Two scaffold types, both with gyroid pore architectures, were designed and built by stereolithography: one with isotropic pore size (412 ± 13 [mu]m) and porosity (62 ± 1%), and another with a gradient in pore size (250-500 [mu]m) and porosity (35%-85%). Computational fluid flow modelling showed a uniform distribution of flow velocities and wall shear rates (15-24 s-1) for the isotropic architecture, and a gradient in the distribution of flow velocities and wall shear rates (12-38 s-1) for the other architecture. The distribution of cells throughout perfusion-seeded scaffolds was visualised by confocal microscopy. The highest densities of cells correlated with regions of the scaffolds where the pores were larger, and the fluid velocities and wall shear rates were the highest. Under the applied perfusion conditions, cell deposition is mainly determined by local wall shear stress, which, in turn, is strongly influenced by the architecture of the pore network of the scaffold.

Keywords: Scaffolds, Microstructure, Cell adhesion, Confocal microscopy, Image analysis, Computational fluid dynamics

Urban, Patricia, Estelrich, Joan, Cortés, Alfred, Fernàndez-Busquets, X., (2011). A nanovector with complete discrimination for targeted delivery to Plasmodium falciparum-infected versus non-infected red blood cells in vitro Journal of Controlled Release 151, (2), 202-211

Current administration methods of antimalarial drugs deliver the free compound in the blood stream, where it can be unspecifically taken up by all cells, and not only by Plasmodium-infected red blood cells (pRBCs). Nanosized carriers have been receiving special attention with the aim of minimizing the side effects of malaria therapy by increasing drug bioavailability and selectivity. Liposome encapsulation has been assayed for the delivery of compounds against murine malaria, but there is a lack of cellular studies on the performance of targeted liposomes in specific cell recognition and on the efficacy of cargo delivery, and very little data on liposome-driven antimalarial drug targeting to human-infecting parasites. We have used fluorescence microscopy to assess in vitro the efficiency of liposomal nanocarriers for the targeted delivery of their contents to pRBCs. 200-nm liposomes loaded with quantum dots were covalently functionalized with oriented, specific half-antibodies against P. falciparum late form-infected pRBCs. In less than 90 min, liposomes dock to pRBC plasma membranes and release their cargo to the cell. 100.0% of late form-containing pRBCs and 0.0% of non-infected RBCs in P. falciparum cultures are recognized and permeated by the content of targeted immunoliposomes. Liposomes not functionalized with antibodies are also specifically directed to pRBCs, although with less affinity than immunoliposomes. In preliminary assays, the antimalarial drug chloroquine at a concentration of 2 nM, >= 10 times below its IC50 in solution, cleared 26.7 ± 1.8% of pRBCs when delivered inside targeted immunoliposomes.

Keywords: Antimalarial chemotherapy, Chloroquine, Half-antibodies, Immunoliposomes, Malaria, Nanomedicine

Llorens, Franc, Gil, Vanessa, Antonio del Rio, Jose, (2011). Emerging functions of myelin-associated proteins during development, neuronal plasticity, and neurodegeneration FASEB Journal , 25, (2), 463-475

Adult mammalian central nervous system (CNS) axons have a limited regrowth capacity following injury. Myelin-associated inhibitors (MAIs) limit axonal outgrowth, and their blockage improves the regeneration of damaged fiber tracts. Three of these proteins, Nogo-A, MAG, and OMgp, share two common neuronal receptors: NgR1, together with its coreceptors [p75(NTR), TROY, and Lingo-1]; and the recently described paired immunoglobulin-like receptor B (PirB). These proteins impair neuronal regeneration by limiting axonal sprouting. Some of the elements involved in the myelin inhibitory pathways may still be unknown, but the discovery that blocking both PirB and NgR1 activities leads to near-complete release from myelin inhibition, sheds light on one of the most competitive and intense fields of neuroregeneration study in recent decades. In parallel with the identification and characterization of the roles and functions of these inhibitory molecules in axonal regeneration, data gathered in the field strongly suggest that most of these proteins have roles other than axonal growth inhibition. The discovery of a new group of interacting partners for myelin-associated receptors and ligands, as well as functional studies within or outside the CNS environment, highlights the potential new physiological roles for these proteins in processes, such as development, neuronal homeostasis, plasticity, and neurodegeneration.-Llorens, F., Gil, V., del Rio, J. A. Emerging functions of myelin-associated proteins during development, neuronal plasticity, and neurodegeneration.

Keywords: MAIs, Neural stem cells, Synapse formation

Ivon Rodriguez-Villarreal, Angeles, Tarn, Mark D., Madden, Leigh A., Lutz, Julia B., Greenman, John, Samitier, Josep, Pamme, Nicole, (2011). Flow focussing of particles and cells based on their intrinsic properties using a simple diamagnetic repulsion setup Lab on a Chip 11, (7), 1240-1248

The continuous flow focussing and manipulation of particles and cells are important factors in microfluidic applications for performing accurate and reproducible procedures downstream. Many particle focussing methods require complex setups or channel designs that can limit the process and its applications. Here, we present diamagnetic repulsion as a simple means of focussing objects in continuous flow, based only on their intrinsic properties without the requirement of any label. Diamagnetic polystyrene particles were suspended in a paramagnetic medium and pumped through a capillary between a pair of permanent magnets, whereupon the particles were repelled by each magnet into the central axis of the capillary, thus achieving focussing. By investigating this effect, we found that the focussing was greatly enhanced with (i) increased magnetic susceptibility of the medium, (ii) reduced flow rate of the suspension, (iii) increased particle size, and (iv) increased residence time in the magnetic field. Furthermore, we applied diamagnetic repulsion to the flow focussing of living, label-free HaCaT cells.

Keywords: Feeble magnetic substances, On-chip, Blood-cells, Microfluidic device, Separation, Field, Levitation, Magnetophoresis, Fractionation, Nanoparticles

Giannotti, M. I., Esteban, O., Oliva, M., Garcia-Parajo, M. F., Sanz, F., (2011). pH-Responsive polysaccharide-based polyelectrolyte complexes as nanocarriers for lysosomal delivery of therapeutic proteins Biomacromolecules , American Chemical Society 12, (7), 2524-2533

Nanopharmaceutics composed of a carrier and a protein have the potential to improve the activity of therapeutical proteins. Therapy for lysosomal diseases is limited by the lack of effective protein delivery systems that allow the controlled release of specific proteins to the lysosomes. Here we address this problem by developing functional polyelectrolyte-based nanoparticles able to promote acidic pH-triggered release of the loaded protein. Trimethyl chitosan (TMC) was synthesized and allowed to form polyelectrolyte complexes (PECs) with the lysosomal enzyme α-GAL through self-assembly and ionotropic gelation, with average particle size <200 nm, polydispersity index (PDI) <0.2, ζ potential of 20 mV, and a protein loading efficiency close to 65%. These polyelectrolyte nanoparticles were stable and active under physiological conditions and able to release the enzyme at acidic pH, as demonstrated by in situ atomic force microscopy (AFM). These nanoparticles were further functionalized with Atto 647N for single-particle characterization and tracking their cellular uptake and fate using high-resolution fluorescence microscopy. In contrast with their precursor, TMC, PECs were efficiently internalized by human endothelial cells and mostly accumulated in lysosomal compartments. The superior physicochemical characteristics of the TMC/α-GAL PECs together with their excellent cellular uptake properties indicate their enormous potential as advanced protein delivery systems for the treatment of lysosomal storage diseases.

Keywords: -----

Malandrino, Andrea, Noailly, Jerome, Lacroix, Damien, (2011). The effect of sustained compression on oxygen metabolic transport in the intervertebral disc decreases with degenerative changes PLoS Computational Biology Plos Computational Biology , 7, (8), 1-12

Intervertebral disc metabolic transport is essential to the functional spine and provides the cells with the nutrients necessary to tissue maintenance. Disc degenerative changes alter the tissue mechanics, but interactions between mechanical loading and disc transport are still an open issue. A poromechanical finite element model of the human disc was coupled with oxygen and lactate transport models. Deformations and fluid flow were linked to transport predictions by including strain-dependent diffusion and advection. The two solute transport models were also coupled to account for cell metabolism. With this approach, the relevance of metabolic and mechano-transport couplings were assessed in the healthy disc under loading-recovery daily compression. Disc height, cell density and material degenerative changes were parametrically simulated to study their influence on the calculated solute concentrations. The effects of load frequency and amplitude were also studied in the healthy disc by considering short periods of cyclic compression. Results indicate that external loads influence the oxygen and lactate regional distributions within the disc when large volume changes modify diffusion distances and diffusivities, especially when healthy disc properties are simulated. Advection was negligible under both sustained and cyclic compression. Simulating degeneration, mechanical changes inhibited the mechanical effect on transport while disc height, fluid content, nucleus pressure and overall cell density reductions affected significantly transport predictions. For the healthy disc, nutrient concentration patterns depended mostly on the time of sustained compression and recovery. The relevant effect of cell density on the metabolic transport indicates the disturbance of cell number as a possible onset for disc degeneration via alteration of the metabolic balance. Results also suggest that healthy disc properties have a positive effect of loading on metabolic transport. Such relation, relevant to the maintenance of the tissue functional composition, would therefore link disc function with disc nutrition.

Keywords: Bovine nucleus pulposus, Human anulus fibrosus, Finite-element, Fluid-flow, Hydraulic permeability, Confined compression, Coupled diffusion, Solute transport, Water-content, Lumbar spine

Almendros, Isaac, Farre, Ramon, Planas, Anna M., Torres, Marta, Bonsignore, Maria R., Navajas, Daniel, Montserrat, Josep M., (2011). Tissue oxygenation in brain, muscle, and fat in a rat model of sleep apnea: Differential effect of obstructive apneas and intermittent hypoxia Sleep , 34, (8), 1127-1133

Study Objectives: To test the hypotheses that the dynamic changes in brain oxygen partial pressure (PtO(2)) in response to obstructive apneas or to intermittent hypoxia differ from those in other organs and that the changes in brain PtO(2) in response to obstructive apneas is a source of oxidative stress. Design: Prospective controlled animal study. Setting: University laboratory. Participants: 98 Sprague-Dawley rats. Interventions: Cerebral cortex, skeletal muscle, or visceral fat tissues were exposed in anesthetized animals subjected to either obstructive apneas or intermittent hypoxia (apneic and hypoxic events of 15 s each and 60 events/h) for 1 h. Measurements and Results: Arterial oxygen saturation (spO(2)) presented a stable pattern, with similar desaturations during both stimuli. The PtO(2) was measured by a microelectrode. During obstructive apneas, a fast increase in cerebral PtO(2) was observed (38.2 +/- 3.4 vs. 54.8 +/- 5.9 mm Hg) but not in the rest of tissues. This particular cerebral response was not found during intermittent hypoxia. The cerebral content of reduced glutathione was decreased after obstructive apneas (46.2% +/- 15.2%) compared to controls (100.0% +/- 14.7%), but not after intermittent hypoxia. This antioxidant consumption after obstructive apneas was accompanied by increased cerebral lipid peroxidation under this condition. No changes were observed for these markers in the other tissues. Conclusions: These results suggest the cerebral cortex could be protected in some way from hypoxic periods caused by obstructive apneas. The increased cerebral PtO(2) during obstructive apneas may, however, cause harmful effects (oxidative stress). The obstructive apnea model appears to be more adequate than the intermittent hypoxia model for studying brain changes associated with OSA.

Keywords: Tissue oxygenation, Obstructive apnea, Intermittent hypoxia, Animal model, Oxidative stress

Carulla, Patricia, Bribian, Ana, Rangel, Alejandra, Gavin, Rosalina, Ferrer, Isidro, Caelles, Carme, Antonio del Rio, Jose, Llorens, Franc, (2011). Neuroprotective role of PrP(C) against kainate-induced epileptic seizures and cell death depends on the modulation of JNK3 activation by GluR6/7-PSD-95 binding Molecular Biology of the Cell , 22, (17), 3041-3054

Cellular prion protein (PrP(C)) is a glycosyl-phosphatidylinositol-anchored glycoprotein. When mutated or misfolded, the pathogenic form (PrP(SC)) induces transmissible spongiform encephalopathies. In contrast, PrP(C) has a number of physiological functions in several neural processes. Several lines of evidence implicate PrP(C) in synaptic transmission and neuroprotection since its absence results in an increase in neuronal excitability and enhanced excitotoxicity in vitro and in vivo. Furthermore, PrP(C) has been implicated in the inhibition of N-methyl-D-aspartic acid (NMDA)-mediated neurotransmission, and prion protein gene (Prnp) knockout mice show enhanced neuronal death in response to NMDA and kainate (KA). In this study, we demonstrate that neurotoxicity induced by KA in Prnp knockout mice depends on the c-Jun N-terminal kinase 3 (JNK3) pathway since Prnp(%) Jnk3(%) mice were not affected by KA. Pharmacological blockage of JNK3 activity impaired PrP(C)-dependent neurotoxicity. Furthermore, our results indicate that JNK3 activation depends on the interaction of PrP(C) with postsynaptic density 95 protein (PSD-95) and glutamate receptor 6/7 (GluR6/7). Indeed, GluR6-PSD-95 interaction after KA injections was favored by the absence of PrP(C). Finally, neurotoxicity in Prnp knockout mice was reversed by an AMPA/KA inhibitor (6,7-dinitroquinoxaline-2,3-dione) and the GluR6 antagonist NS-102. We conclude that the protection afforded by PrP(C) against KA is due to its ability to modulate GluR6/7-mediated neurotransmission and hence JNK3 activation.

Keywords: Ischemic brain-injury, Prion protein PrP(C), Stress-inducible protein-1, Synaptic plasticity, Neurite outgrowth, Signaling module, Caspase-3 activation, Organotypic cultures, Cerebral-ischemia

Izquierdo-Useros, Nuria, Esteban, Olga, Rodriguez-Plata, Maria T., Erkizia, Itziar, Prado, Julia G., Blanco, Julia, Garcia-Parajo, Maria F., Martinez-Picado, Javier, (2011). Dynamic imaging of cell-free and cell-associated viral capture in mature dendritic cells Traffic , 12, (12), 1702-1713

Dendritic cells (DCs) capture human immunodeficiency virus (HIV) through a non-fusogenic mechanism that enables viral transmission to CD4(+) T cells, contributing to in vivo viral dissemination. Although previous studies have provided important clues to cell-free viral capture by mature DCs (mDCs), dynamic and kinetic insight on this process is still missing. Here, we used three-dimensional videomicroscopy and single-particle tracking approaches to dynamically dissect both cell-free and cell-associated viral capture by living mDCs. We show that cell-free virus capture by mDCs operates through three sequential phases: virus binding through specific determinants expressed in the viral particle, polarized or directional movements toward concrete regions of the cell membrane and virus accumulation in a sac-like structure where trapped viral particles display a hindered diffusive behavior. Moreover, real-time imaging of cell-associated viral transfer to mDCs showed a similar dynamics to that exhibited by cell-free virus endocytosis leading to viral accumulation in compartments. However, cell-associated HIV type 1 transfer to mDCs was the most effective pathway, boosted throughout enhanced cellular contacts with infected CD4(+) T cells. Our results suggest that in lymphoid tissues, mDC viral uptake could occur either by encountering cell-free or cell-associated virus produced by infected cells generating the perfect scenario to promote HIV pathogenesis and impact disease progression.

Keywords: Dendritic cells, HIV-1, Live cell imaging, Trans-infection

Bohner, M., Loosli, Y., Baroud, G., Lacroix, D., (2011). Commentary: Deciphering the link between architecture and biological response of a bone graft substitute Acta Biomaterialia 7, (2), 478-484

Hundreds of studies have been devoted to the search for the ideal architecture for bone scaffold. Despite these efforts, results are often contradictory, and rules derived from these studies are accordingly vague. In fact, there is enough evidence to postulate that ideal scaffold architecture does not exist. The aim of this document is to explain this statement and review new approaches to decipher the existing but complex link between scaffold architecture and in vivo response.

Keywords: Biomaterial, Bone, Tissue engineering, Resorbable, Graft

Gustavsson, J., Ginebra, M. P., Engel, E., Planell, J., (2011). Ion reactivity of calcium-deficient hydroxyapatite in standard cell culture media Acta Biomaterialia 7, (12), 4242-4252

Solution-mediated surface reactions occur for most calcium phosphate-based biomaterials and may influence cellular response. A reasonable extrapolation of such processes observed in vitro to in vivo performance requires a deep understanding of the underlying mechanisms. We therefore systematically investigated the nature of ion reactivity of calcium-deficient hydroxyapatite (CDHA) by exposing it for different periods of time to standard cell culture media of different chemical composition (DMEM and McCoy medium, with and without osteogenic supplements and serum proteins). Kinetic ion interaction studies of principal extracellular ions revealed non-linear sorption of Ca2+ (∼50% sorption) and K+ (∼8%) as well as acidification of all media during initial contact with CDHA (48 h). Interestingly, inorganic phosphorus (Pi) was sorbed from McCoy medium (∼50%) or when using osteogenic media containing β-glycerophosphate, but not from DMEM medium. Non-linear sorption data could be perfectly described by pseudo-first-order and pseudo-second-order sorption models. At longer contact time (21 days), and with frequent renewal of culture medium, sorption of Ca2+ remained constant throughout the experiment, while sorption of Pi gradually decreased in McCoy medium. In great contrast, CDHA began to release Pi slowly with time when using DMEM medium. Infrared spectra showed that CDHA exposed to culture media had a carbonated surface chemistry, suggesting that carbonate plays a key role in the ion reactivity of CDHA. Our data show that different compositions of the aqueous environment may provoke opposite ion reactivity of CDHA, and this must be carefully considered when evaluating the osteoinductive potential of the material.

Keywords: Hydroxyapatite, Bioactive materials, Cell culture medium, Ion exchange, Sorption models

Perut, F., Montufar, E. B., Ciapetti, G., Santin, M., Salvage, J., Traykova, T., Planell, J. A., Ginebra, M. P., Baldini, N., (2011). Novel soybean/gelatine-based bioactive and injectable hydroxyapatite foam: Material properties and cell response Acta Biomaterialia 7, (4), 1780-1787

Despite their known osteoconductivity, clinical use of calcium phosphate cements is limited both by their relatively slow rate of resorption and by rheological properties incompatible with injectability. Bone in-growth and material resorption have been improved by the development of porous calcium phosphate cements. However, injectable formulations have so far only been obtained through the addition of relatively toxic surfactants. The present work describes the response of osteoblasts to a novel injectable foamed bone cement based on a composite formulation including the bioactive foaming agents soybean and gelatine. The foaming properties of both defatted soybean and gelatine gels were exploited to develop a self-hardening soy/gelatine/hydroxyapatite composite foam able to retain porosity upon injection. After setting, the foamed paste produced a calcium-deficient hydroxyapatite scaffold, showing good injectability and cohesion as well as interconnected porosity after injection. The intrinsic bioactivity of soybean and gelatine was shown to favour osteoblast adhesion and growth. These findings suggest that injectable, porous and bioactive calcium phosphate cements can be produced for bone regeneration through minimally invasive surgery.

Keywords: Calcium phosphate cement, Composite, Bone tissue engineering, Cell viability, Bioactivity

Crona, Mikael, Torrents, Eduard, Rohr, Asmund K., Hofer, Anders, Furrer, Ernst, Tomter, Ane B., Andersson, K. Kristoffer, Sahlin, Margareta, Sjoberg, Britt-Marie, (2011). NrdH-redoxin protein mediates high enzyme activity in manganese-reconstituted ribonucleotide reductase from bacillus anthracis Journal of Biological Chemistry , 286, (38), 33053-33060

Bacillus anthracis is a severe mammalian pathogen encoding a class Ib ribonucleotide reductase (RNR). RNR is a universal enzyme that provides the four essential deoxyribonucleotides needed for DNA replication and repair. Almost all Bacillus spp. encode both class Ib and class III RNR operons, but the B. anthracis class III operon was reported to encode a pseudogene, and conceivably class Ib RNR is necessary for spore germination and proliferation of B. anthracis upon infection. The class Ib RNR operon in B. anthracis encodes genes for the catalytic NrdE protein, the tyrosyl radical metalloprotein NrdF, and the flavodoxin protein NrdI. The tyrosyl radical in NrdF is stabilized by an adjacent Mn(2)(III) site (Mn-NrdF) formed by the action of the NrdI protein or by a Fe(2)(III) site (Fe-NrdF) formed spontaneously from Fe(2+) and O(2). In this study, we show that the properties of B. anthracis Mn-NrdF and Fe-NrdF are in general similar for interaction with NrdE and NrdI. Intriguingly, the enzyme activity of Mn-NrdF was approximately an order of magnitude higher than that of Fe-NrdF in the presence of the class Ib-specific physiological reductant NrdH, strongly suggesting that the Mn-NrdF form is important in the life cycle of B. anthracis. Whether the Fe-NrdF form only exists in vitro or whether the NrdF protein in B. anthracis is a true cambialistic enzyme that can work with either manganese or iron remains to be established.

Keywords: Escherichia-coli, Corynebacterium-ammoniagenes, Crystal-structure, Cofactor, Cubunit, Growth, Genes

Calvo, Daniel, Tort, Nuria, Pablo Salvador, J., Marco, M. Pilar, Centi, Fabiana, Marco, Santiago, (2011). Preliminary study for simultaneous detection and quantification of androgenic anabolic steroids using ELISA and pattern recognition techniques Analyst , 136, (-----), 4045-4052

A first step towards the multidetection, identification and quantification of anabolic androgenic steroids by enzyme-linked immunosorbent assay (ELISA) has been performed in this study. This proposal combines multiple competitive ELISA assays with different cross-reactivity profiles and multivariate data analysis techniques. Data have been analyzed by principal component analysis in conjunction with a novel K-nearest line classifier. This proposal allows simultaneous detection of up to four different steroids in the range of concentration from 0.1 to 316.2 nM with a total rate of 90.6% of correct detection, even in the presence of cross-reactivities. A methodology for concentration prediction is also presented with satisfactory results.

Keywords: -----

Dols-Perez, Aurora, Fumagalli, Laura, Cohen Simonsen, Adam, Gomila, Gabriel, (2011). Ultrathin spin-coated dioleoylphosphatidylcholine lipid layers in dry conditions: A combined atomic force microscopy and nanomechanical study Langmuir , 27, (21), 13165-13172

Atomic force microscopy (AFM) has been used to study the structural and mechanical properties of low concentrated spin-coated dioleoylphosphatidylcholine (DOPC) layers in dry environment (RH approximate to 0%) at the nanoscale. It is shown that for concentrations in the 0.1-1 mM range the structure of the DOPC spin-coated samples consists of an homogeneous lipid monolayer similar to 1.3 nm thick covering the whole substrate on top of which lipid bilayer (or multilayer) micro- and nanometric patches and rims are formed. The thickness of the bilayer structures is found to be similar to 4.5 nm (or multiples of this value for multilayer structures), while the lateral dimensions range from micrometers to tens of nanometer depending on the lipid concentration. The force required to break a bilayer (breakthrough force) is found to be similar to 0.24 nN. No dependence of the mechanical values on the lateral dimensions of the bilayer structures is evidenced. Remarkably, the thickness and breakthrough force values of the bilayers measured in dry environment are very similar to values reported in the literature for supported DOPC bilayers in pure water.

Sjoberg, B. M., Torrents, E., (2011). Shift in ribonucleotide reductase gene expression in pseudomonas aeruginosa during infection Infection and Immunity , 79, (7), 2663-2669

The roles of different ribonucleotide reductases (RNRs) in bacterial pathogenesis have not been studied systematically. In this work we analyzed the importance of the different Pseudomonas aeruginosa RNRs in pathogenesis using the Drosophila melanogaster host-pathogen interaction model. P. aeruginosa codes for three different RNRs with different environmental requirements. Class II and III RNR chromosomal mutants exhibited reduced virulence in this model. Translational reporter fusions of RNR gene nrdA, nrdJ, or nrdD to the green fluorescent protein were constructed to measure the expression of each class during the infection process. Analysis of the P. aeruginosa infection by flow cytometry revealed increased expression of nrdJ and nrdD and decreased nrdA expression during the infection process. Expression of each RNR class fits with the pathogenicities of the chromosomal deletion mutants. An extended understanding of the pathogenicity and physiology of P. aeruginosa will be important for the development of novel drugs against infections in cystic fibrosis patients.

Keywords: Broad-host-range, Anaerobic growth, Drosophila-melanogaster, Bacterial biofilms, Escherichia-coli, Cystic-fibrosis, Model host, Virulence, Promoter, Vectors

Pedro, L., Banos, R. C., Aznar, S., Madrid, C., Balsalobre, C., Juarez, A., (2011). Antibiotics shaping bacterial genome: Deletion of an IS91 flanked virulence determinant upon exposure to subinhibitory antibiotic concentrations PLoS ONE 6, (11), 11

The nucleoid-associated proteins Hha and YdgT repress the expression of the toxin a-hemolysin. An Escherichia coli mutant lacking these proteins overexpresses the toxin a-hemolysin encoded in the multicopy recombinant plasmid pANN202-312R. Unexpectedly, we could observe that this mutant generated clones that no further produced hemolysin (Hly(-)). Generation of Hly(-) clones was dependent upon the presence in the culture medium of the antibiotic kanamycin (km), a marker of the hha allele (hha::Tn5). Detailed analysis of different Hly(-) clones evidenced that recombination between partial IS91 sequences that flank the hly operon had occurred. A fluctuation test evidenced that the presence of km in the culture medium was underlying the generation of these clones. A decrease of the km concentration from 25 mg/l to 12.5 mg/l abolished the appearance of Hly(-) derivatives. We considered as a working hypothesis that, when producing high levels of the toxin (combination of the hha ydgT mutations with the presence of the multicopy hemolytic plasmid pANN202-312R), the concentration of km of 25 mg/l resulted subinhibitory and stimulated the recombination between adjacent IS91 flanking sequences. To further test this hypothesis, we analyzed the effect of subinhibitory km concentrations in the wild type E. coli strain MG1655 harboring the parental low copy number plasmid pHly152. At a km concentration of 5 mg/l, subinhibitory for strain MG1655 (pHly152), generation of Hly(-) clones could be readily detected. Similar results were also obtained when, instead of km, ampicillin was used. IS91 is flanking several virulence determinants in different enteric bacterial pathogenic strains from E. coli and Shigella. The results presented here evidence that stress generated by exposure to subinhibitory antibiotic concentrations may result in rearrangements of the bacterial genome. Whereas some of these rearrangements may be deleterious, others may generate genotypes with increased virulence, which may resume infection.

Keywords: Promotes horizontal dissemination, Enterica serovar typhimurium, Escherichia-coli strains, Insertion-sequence IS91, H-NS, Adaptive amplification, Pathogenicity islands, Hemolysin

Llorens, Franc, Hummel, Manuela, Pastor, Xavier, Ferrer, Anna, Pluvinet, Raquel, Vivancos, Ana, Castillo, Ester, Iraola, Susana, Mosquera, Ana M., Gonzalez, Eva, Lozano, Juanjo, Ingham, Matthew, Dohm, Juliane C., Noguera, Marc, Kofler, Robert, Antonio del Rio, Jose, Bayes, Monica, Himmelbauer, Heinz, Sumoy, Lauro, (2011). Multiple platform assessment of the EGF dependent transcriptome by microarray and deep tag sequencing analysis BMC Genomics , 12, 326

Background: Epidermal Growth Factor (EGF) is a key regulatory growth factor activating many processes relevant to normal development and disease, affecting cell proliferation and survival. Here we use a combined approach to study the EGF dependent transcriptome of HeLa cells by using multiple long oligonucleotide based microarray platforms (from Agilent, Operon, and Illumina) in combination with digital gene expression profiling (DGE) with the Illumina Genome Analyzer. Results: By applying a procedure for cross-platform data meta-analysis based on RankProd and GlobalAncova tests, we establish a well validated gene set with transcript levels altered after EGF treatment. We use this robust gene list to build higher order networks of gene interaction by interconnecting associated networks, supporting and extending the important role of the EGF signaling pathway in cancer. In addition, we find an entirely new set of genes previously unrelated to the currently accepted EGF associated cellular functions. Conclusions: We propose that the use of global genomic cross-validation derived from high content technologies (microarrays or deep sequencing) can be used to generate more reliable datasets. This approach should help to improve the confidence of downstream in silico functional inference analyses based on high content data.

Keywords: Gene-expression measurements, Quality-control maqc, Cancer-cell-lines, Real-time pcr, Oligonucleotide microarrays, Phosphorylation dynamics, In-vivo, Networks, Signal, Technologies

Miranda Coelho, Nuno, Gonzalez-Garcia, Cristina, Salmeron-Sanchez, Manuel, Altankov, George, (2011). Arrangement of type IV collagen and laminin on substrates with controlled density of -OH groups Tissue Engineering Part A , 17, (17-18), 2245-2257

Collagen IV (Col IV) and laminin (Lam) are the main structural components of the basement membrane where they form two overlapping polymeric networks. We studied the adsorption pattern of these proteins on five model surfaces with tailored density of -OH groups obtained by copolymerization of different ratios ethyl acrylate (EA) and hydroxyl EA (HEA): X(OH) = 0, X(OH) = 0.3, X(OH) = 0.5, X(OH) = 0.7, and X(OH) = 1 (where X refers the ratio of HEA). Atomic force microscopy revealed substratum-specific adsorption patterns of Col IV and Lam, ranging from single molecules deposition on more hydrophilic substrata to the formation of complex networks on hydrophobic ones. Human umbilical endothelial cells were used to study the biological performance of adsorbed proteins, following the overall cell morphology, the quantities for cell adhesion and spreading, and the development of focal adhesion complexes and actin cytoskeleton. Surprisingly, two optima in the cellular interaction were observed-one on the most hydrophilic X(OH) = 1 and other on the relatively hydrophobic X(OH) = 0.3 substrate-valid for both Col IV and Lam. When the proteins were adsorbed consecutively, a hydrophobic shift to X(OH) = 0 substratum was obtained. Collectively, these data suggest that varying with the density of -OH groups one can tailor the conformation and the functional activity of adsorbed basement membrane proteins.

Keywords: Atomic-force microscopy, Fibronectin adsorption, Basement-membranes, Polymer surfaces, Cell-adhesion, Biomaterials, Wettability, Fibrinogen

Miranda Coelho, Nuno, Gonzalez-Garcia, Cristina, Salmeron-Sanchez, Manuel, Altankov, George, (2011). Arrangement of type IV collagen on NH(2) and COOH functionalized surfaces Biotechnology and Bioengineering , 108, (12), 3009-3018

Apart from the paradigm that cell-biomaterials interaction depends on the adsorption of soluble adhesive proteins we anticipate that upon distinct conditions also other, less soluble ECM proteins such as collagens, associate with the biomaterials interface with consequences for cellular response that might be of significant bioengineering interest. Using atomic force microscopy (AFM) we seek to follow the nanoscale behavior of adsorbed type IV collagen (Col IV)-a unique multifunctional matrix protein involved in the organization of basement membranes (BMs) including vascular ones. We have previously shown that substratum wettability significantly affects Col IV adsorption pattern, and in turn alters endothelial cells interaction. Here we introduce two new model surfaces based on self-assembled monolayers (SAMs), a positively charged - NH(2), and negatively charged -COOH surface, to learn more about their particular effect on Col IV behavior. AFM studies revealed distinct pattern of Col IV assembly onto the two SAMs resembling different aspects of network-like structure or aggregates (suggesting altered protein conformation). Moreover, the amount of adsorbed FITC-labeled Col IV was quantified and showed about twice more protein on NH(2) substrata. Human umbilical vein endothelial cells attached less efficiently to Col IV adsorbed on negatively charged COOH surface judged by altered cell spreading, focal adhesions formation, and actin cytoskeleton development. Immunofluorescence studies also revealed better Col IV recognition by both alpha(1) and alpha(2) integrins on positively charged NH(2) substrata resulting in higher phosphorylated focal adhesion kinase recruitment in the focal adhesion complexes. On COOH surface, no integrin clustering was observed. Taken altogether these results, point to the possibility that combined NH(2) and Col IV functionalization may support endothelization of cardiovascular implants.

Keywords: Collagen type IV, SAMs, AFM, Surface-induced protein assembly, Endothelial cells, Vascular grafts

Caballero-Briones, F., Palacios-Padrós, A., Sanz, Fausto, (2011). CuInSe2 films prepared by three step pulsed electrodeposition. Deposition mechanisms, optical and photoelectrochemical studies Electrochimica Acta , 56, (26), 9556-9567

p-Type semiconducting copper indium diselenide thin films have been prepared onto In2O3:Sn substrates by a recently developed pulse electrodeposition method that consists in repeated cycles of three potential application steps. The Cu–In–Se electrochemical system and the related single component electrolytes were studied by cyclic voltammetry to identify the electrode processes and study the deposition processes. In situ atomic force microscopy measurements during the first 100 deposition cycles denote a continuous nucleation and growth mechanism. Particles removed by film sonication from some of the films were characterized by transmission electron microscopy and determined to consist in nanoscopic and crystalline CuInSe2. The remaining film is still crystalline CuInSe2, as assessed by X-ray diffraction. The chemical characterization by combined X-ray photoelectron spectroscopy, X-ray fluorescence and inductively coupled plasma optical emission spectroscopy, showed that films were Cu-poor and Se-poor. Raman characterization of the as-grown films showed that film composition varies with film thickness; thinner films are Se-rich, while thicker ones have an increased Cu–Se content. Different optical absorption bands were identified by the analysis of the UV–NIR transmittance spectra that were related with the presence of CuInSe2, ordered vacancy compounds, Se, Cu2−xSe and In2Se3. The photoelectrochemical activity confirmed the p-type character and showed a better response for the films prepared with the pulse method.

Keywords: CuInSe2, Solar cells, Electrodeposition, Optical properties, As-deposited films, ITO substrate

Garrido-Delgado, R., Arce, L., Guaman, A. V., Pardo, A., Marco, S., Valcárcel, M., (2011). Direct coupling of a gas-liquid separator to an Ion Mobility Spectrometer for the classification of different white wines using chemometrics tools Talanta , 84, (2), 471-479

The potential of a vanguard technique as is the Ion Mobility Spectrometry with Ultraviolet ionization (UV-IMS) coupled to a Continuous Flow System (CFS) have been demonstrated in this work by using a Gas Phase Separator (GPS). This vanguard system (CFS-GPS-UV-IMS) has been used for the analysis of different types of white wines to obtain a characteristic profile for each type of wine and their posterior classification using different chemometric tools. Precision of the method was 3.1% expressed as relative standard deviation. A deep chemometric study was carried out for the classification of the four types of wines selected. The best classification performance was obtained by first reducing the data dimensionality by Principal Component Analysis (PCA) followed by Linear Discriminant Analysis (LDA) and finally using a K-Nearest Neighbour (kNN) classifier. The classification rate in an independent validation set were 92.0% classification rate value with confidence interval [89.0%, 95.0%] at P = 0.05 confidence level. The same white wines analyzed by using CFS-GPS-UV-IMS were analyzed by using Gas Chromatography with a Flame Detector (GC-FID) as conventional technique. The chromatographic method used for the determination of superior alcohols in wine samples shown in the Regulation CEE 1238/1992 was selected to carry out the analysis of the same samples set and later the classification using appropriate chemometric tools. In this case, strategies PCA-LDA and kNN classifier were also used for the correct classification of the wine samples. This combination showed similar results to the ones obtained with the proposed method.

Keywords: Classification, White wines, Ultraviolet-Ion Mobility Spectrometry, Gas Phase Separate, Vanguard method, Continuous Flow System, Chemometric analysis.

Manzo, C., van Zanten, T. S., Garcia-Parajo, M. F., (2011). Nanoscale fluorescence correlation spectroscopy on intact living cell membranes with NSOM probes Biophysical Journal , 100, (2), L8-L10

Characterization of molecular dynamics on living cell membranes at the nanoscale is fundamental to unravel the mechanisms of membrane organization and compartmentalization. Here we demonstrate the feasibility of fluorescence correlation spectroscopy (FCS) based on the nanometric illumination of near-field scanning optical microscopy (NSOM) probes on intact living cells. NSOM-FCS applied to fluorescent lipid analogs allowed us to reveal details of the diffusion hidden by larger illumination areas. Moreover, the technique offers the unique, advantages of evanescent axial illumination and straightforward implementation of multiple color excitation. As such, NSOM-FCS represents a powerful tool to study a variety of dynamic processes occurring at the nanometer scale on cell membranes.

Keywords: Mode wave-guides, Lipid rafts, Difussion, Organization, Aperture

Perán, M., Sánchez-Ferrero, A., Tosh, D., Marchal, J. A., Lopez, E., Alvarez, P., Boulaiz, H., Rodríguez-Serrano, F., Aranega, A., (2011). Ultrastructural and molecular analyzes of insulin-producing cells induced from human hepatoma cells Cytotherapy , 13, (2), 193-200

Background aims. Diabetes type I is an autoimmune disease characterized by the destruction of pancreatic insulin-producing (beta-) cells and resulting in external insulin dependence for life. Islet transplantation represents a potential treatment for diabetes but there is currently a shortage of suitable organs donors. To augment the supply of donors, different strategies are required to provide a potential source of beta-cells. These sources include embryonic and adult stem cells as well as differentiated cell types. The main goal of this study was to induce the transdifferentiation (or conversion of one type cell to another) of human hepatoma cells (HepG2 cells) to insulin-expressing cells based on the exposure of HepG2 cells to an extract of rat insulinoma cells (RIN). Methods. HepG2 cells were first transiently permeabilized with Streptolysin O and then exposed to a cell extract obtained from RIN cells. Following transient exposure to the RIN extract, the HepG2 cells were cultured for 3 weeks. Results. Acquisition of the insulin-producing cell phenotype was determined on the basis of (i) morphologic and (ii) ultrastructural observations, (iii) immunologic detection and (iv) reverse transcription (RT)-polymerase chain reaction (PCR) analysis. Conclusions. This study supports the use of cell extract as a feasible method for achieve transdifferentiation of hepatic cells to insulin-producing cells.

Keywords: Beta-cells, Diabetes, Insulin-producing cells, Transdifferentiation

de Alba, C. F., Solorzano, C., Paytubi, S., Madrid, C., Juarez, A., Garcia, J., Pons, M., (2011). Essential residues in the H-NS binding site of Hha, a co-regulator of horizontally acquired genes in Enterobacteria FEBS Letters , 585, (12), 1765-1770

Proteins of the Hha/YmoA family co-regulate with H-NS the expression of horizontally acquired genes in Enterobacteria. Systematic mutations of conserved acidic residues in Hha have allowed the identification of D48 as an essential residue for H-NS binding and the involvement of E25. Mutations of these residues resulted in deregulation of sensitive genes in vivo. D48 is only partially solvent accessible, yet it defines the functional binding interface between Hha and H-NS confirming that Hha has to undergo a conformational change to bind H-NS. Exposed acidic residues, such as E25, may electrostatically facilitate and direct the approach of Hha to the positively charged region of H-NS enabling the formation of the final complex when D48 becomes accessible by a conformational change of Hha. Structured summary of protein interactions: YdgT and H-NS bind by nuclear magnetic resonance (View interaction) Hha and H-NS bind by nuclear magnetic resonance (View Interaction 1, 2, 3) Hha physically interacts with H-NS by pull down (View Interaction 1, 2).

Keywords: Nucleoid associated protein, H-NS, Hha, Transcription repression

Krishnan, Ramaswamy, Klumpers, Darinka D., Park, Chan Y., Rajendran, Kavitha, Trepat, Xavier, van Bezu, Jan, van Hinsbergh, Victor W. M., Carman, Christopher V., Brain, Joseph D., Fredberg, Jeffrey J., Butler, James P., van Nieuw Amerongen, Geerten P., (2011). Substrate stiffening promotes endothelial monolayer disruption through enhanced physical forces American Journal of Physiology - Cell Physiology , 300, (1), C146-C154

A hallmark of many, sometimes life-threatening, inflammatory diseases and disorders is vascular leakage. The extent and severity of vascular leakage is broadly mediated by the integrity of the endothelial cell (EC) monolayer, which is in turn governed by three major interactions: cell-cell and cell-substrate contacts, soluble mediators, and biomechanical forces. A potentially critical but essentially uninvestigated component mediating these interactions is the stiffness of the substrate to which the endothelial monolayer is adherent. Accordingly, we investigated the extent to which substrate stiffening influences endothelial monolayer disruption and the role of cell-cell and cell-substrate contacts, soluble mediators, and physical forces in that process. Traction force microscopy showed that forces between cell and cell and between cell and substrate were greater on stiffer substrates. On stiffer substrates, these forces were substantially enhanced by a hyperpermeability stimulus (thrombin, 1 U/ml), and gaps formed between cells. On softer substrates, by contrast, these forces were increased far less by thrombin, and gaps did not form between cells. This stiffness-dependent force enhancement was associated with increased Rho kinase activity, whereas inhibition of Rho kinase attenuated baseline forces and lessened thrombin-induced inter-EC gap formation. Our findings demonstrate a central role of physical forces in EC gap formation and highlight a novel physiological mechanism. Integrity of the endothelial monolayer is governed by its physical microenvironment, which in normal circumstances is compliant but during pathology becomes stiffer.

Keywords: Contraction, Human umbilical vein endothelial cells, Permeability, Traction force, Cell-cell contact, Cell-substrate contact, Substrate stiffness, Rho kinase, Vascular endothelial cadherin, Thrombin

Sánchez-Martín, M. J., Urbán, P., Pujol, M., Haro, I., Alsina, M. A., Busquets, M. A., (2011). Biophysical investigations of GBV-C E1 peptides as potential inhibitors of HIV-1 fusion peptide ChemPhysChem , 12, (15), 2816-2822

Five peptide sequences corresponding to the E1 protein of GBV-C [NCCAPEDIGFCLEGGCLV (P7), APEDIGFCLEGGCLVALG (P8), FCLEGGCLVALGCTICTD (P10), QAGLAVRPGKSAAQLVGE (P18), and AQLVGELGSLYGPLSVSA (P22)] were synthesized because they were capable of interfering with the HIV-1 fusion peptide (HIV-1 FP)-vesicle interaction. In this work the interaction of these peptides with the HIV-1 FP, as well as with membrane models, was analyzed to corroborate their inhibition ability and to understand if the interaction with the fusion peptide takes place in solution or at the membrane level. Several studies were carried out on aggregation and membrane fusion, surface Plasmon resonance, and conformational analysis by circular dichroism. Moreover, in vitro toxicity assays, including cytotoxicity studies in 3T3 fibroblasts and hemolysis assays in human red blood cells, were performed to evaluate if these peptides could be potentially used in anti-HIV-1 therapy. Results show that P10 is not capable of inhibiting membrane fusion caused by HIV-1 and it aggregates liposomes and fuses membranes, thus we decided to discard it for futures studies. P18 and P22 do not inhibit membrane fusion, but they inhibit the ability of HIV-1 FP to form pores in bilayers, thus we have not discarded them yet. P7 and P8 were selected as the best candidates for future studies because they are capable of inhibiting membrane fusion and the interaction of HIV-1 FP with bilayers. Therefore, these peptides could be potentially used in future anti-HIV-1 research. Part of the gang: Liposomes are deposited on a surface plasmon resonance chip (see AFM image of the chip) to observe the interaction of peptides corresponding to the E1 envelop protein of the hepatitis G virus with membranes to show how they reduce the interaction of the HIV-1 fusion peptide.

Keywords: HIV-1 fusion protein, Liposomes, Membranes, Peptides, Viruses

Almendros, I., Farré, R., Torres, M., Bonsignore, M. R., Dalmases, M., Ramírez, J., Navajas, D., Montserrat, J. M., (2011). Early and mid-term effects of obstructive apneas in myocardial injury and inflammation Sleep Medicine , 12, (10), 1037-1040

Background: Obstructive sleep apnea (OSA) is associated with cardiovascular disorders, but the different comorbidities in OSA patients make it difficult to know their specific effects on the development of cardiovascular injury. The aim of the present study was to investigate whether recurrent obstructive apneas could lead to myocardial injury. Methods: Thirty-six male Sprague-Dawley rats (300-350. g) were either acutely (3. h) or sustainably (5. h/day, for 10. days) subjected to obstructive apneas with a pattern of 15. s each, 60. apneas/h. Corresponding control groups were formed for the acute and sustained models. To assess the induction of systemic inflammation, IL1-β was measured in plasma. Ventricular tissue injury was evaluated by histological techniques (presence of inflammatory cell infiltration, eosin autofluorescence, and detection of apoptosis). Results: After 3. h of obstructive apneas, a significant increase in IL1-β (64.9. ±. 29.6. ng/μl) were observed with respect to the controls (7.3. ±. 1.0. ng/μl), but no myocardial injury was present. Conversely to the acute model, the systemic inflammation triggered by obstructive apneas for 10. days was reduced. However, the percentage of area with enhanced eosin autofluorescence and of apoptotic cells (1.83. ±. 0.35% and 24.4. ±. 1.5%, respectively) was increased when compared to the control group (0.72. ±. 0.20% and 5.0. ±. 2.8%, respectively). Conclusions: This study suggests that obstructive apneas are a potential source of early systemic and ventricular inflammation and myocardial cell injury after sustained apneas application, which could represent an initial phase in the progression of heart disease associated with OSA.

Keywords: Animal models, Inflammation, Myocardial injury, Obstructive sleep apnea

Dellaca, Raffaele, Montserrat, Josep M., Govoni, Leonardo, Pedotti, Antonio, Navajas, Daniel, Farre, Ramon, (2011). Telemetric CPAP titration at home in patients with sleep apnea-hypopnea syndrome Sleep Medicine , 12, (2), 153-157

Background: Home continuous positive airway pressure (CPAP) titration with automatic devices is not possible in a non-negligible percentage of patients with sleep apnea-hypopnea syndrome (SAHS). Objectives: To test the feasibility of a novel telemetric system for home CPAP titration. Methods: One-night home CPAP titration was carried out on 20 SAHS patients (56 +/- 3 years; BMI = 35 +/- 2 kg/m(2)). A telemetric unit, based on the conventional GPRS mobile phone network and connected to a commercial CPAP device, allowed the hospital technician to monitor flow, pressure and air leaks by remote control and titrate CPAP (elimination of apneas, hypopneas, flow limitation and snoring) in real time. After 1 week, a full hospital polysomnography was performed while the patient was subjected to the value of CPAP that was previously titrated at home via telemetry. Results: The home-titrated CPAP systematically improved patients' breathing: the apnea-hypopnea index and percentage of sleep time with arterial oxygen saturation below 90% were reduced from 58.1 +/- 5.1 to 3.8 +/- 0.6 events/h and from 19.8 +/- 1.1% to 4.4 +/- 0.7%, respectively. This CPAP value (9.15 +/- 0.47 cmH(2)O) was virtually the same as the pressure that optimized breathing during hospital polysomnography (9.20 +/- 0.41 cmH(2)O; mean difference: 0.02 cmH(2)O, limits of agreement: +/- 1.00 cmH(2)O). Conclusions: This pilot study shows that a simple telemetric system, requiring neither a special telemedicine network nor any infrastructure in the patient's home, made it possible to perform effective remote CPAP titration on SAHS patients.

Keywords: Home CPAP titration by telemetry, Telecare, Telemedicine, E-health, Obstructive sleep apnea, Point of care

Castillo-Fernandez, Oscar, Salieb-Beugelaar, Georgette B., van Nieuwkasteele, Jan W., Bomer, Johan G., Arundell, Martin, Samitier, Josep, van den Berg, Albert, Eijkel, Jan C. T., (2011). Electrokinetic DNA transport in 20 nm-high nanoslits: Evidence for movement through a wall-adsorbed polymer nanogel Electrophoresis , 32, (18), 2402-2409

The electrokinetic transport behavior of lambda-DNA (48 kbp) in 20 nm-high fused-silica nanoslits in the presence of short-chain PVP is investigated. Mobility and video data show a number of phenomena that are typical of DNA transport through gels or polymer solutions, thus indicative of rigid migration obstacles in the DNA pathway. Calculations show that a several nanometer thin layer of wall-adsorbed PVP ('nano-gel') can provide such a rigid obstacle matrix to the DNA. Such ultrathin wall-adsorbed polymer layers represent a new type of matrix for electrokinetic DNA separation.

Keywords: λ-DNA, Biased reptation, Caterpillar movement, Nanoslits, Pathways, PVP

Mir, Monica, Martinez-Rodriguez, Sergio, Castillo-Fernandez, Oscar, Homs-Corbera, Antoni, Samitier, Josep, (2011). Electrokinetic techniques applied to electrochemical DNA biosensors Electrophoresis , 32, (8), 811-821

Electrokinetic techniques are contact-free methods currently used in many applications, where precise handling of biological entities, such as cells, bacteria or nucleic acids, is needed. These techniques are based on the effect of electric fields on molecules suspended in a fluid, and the corresponding induced motion, which can be tuned according to some known physical laws and observed behaviours. Increasing interest on the application of such strategies in order to improve the detection of DNA strands has appeared during the recent decades. Classical electrode-based DNA electrochemical biosensors with combined electrokinetic techniques present the advantage of being able to improve the working electrode's bioactive part during their fabrication and also the hybridization yield during the sensor detection phase. This can be achieved by selectively manipulating, driving and directing the molecules towards the electrodes increasing the speed and yield of the floating DNA strands attached to them. On the other hand, this technique can be also used in order to make biosensors reusable, or reconfigurable, by simply inverting its working principle and pulling DNA strands away from the electrodes. Finally, the combination of these techniques with nanostructures, such as nanopores or nanochannels, has recently boosted the appearance of new types of electrochemical sensors that exploit the time-varying position of DNA strands in order to continuously scan these molecules and to detect their properties. This review gives an insight into the main forces involved in DNA electrokinetics and discusses the state of the art and uses of these techniques in recent years.

Keywords: Electrochemical DNA biosensors, Lab-on-a-chip (LOC), Micro-total analysis systems (mu TAS), Nanopore

Sandino, Clara, Lacroix, Damien, (2011). A dynamical study of the mechanical stimuli and tissue differentiation within a CaP scaffold based on micro-CT finite element models Biomechanics and Modeling in Mechanobiology 10, (4), 565-576

The control of the mechanical stimuli transmitted to the cells is critical for the design of functional scaffolds for tissue engineering. The objective of this study was to investigate the dynamics of the mechanical stimuli transmitted to the cells during tissue differentiation in an irregular morphology scaffold under compressive load and perfusion flow. A calcium phosphate-based glass porous scaffold was used. The solid phase and the fluid flow within the pores were modeled as linear elastic solid material and Newtonian fluid, respectively. In the fluid model, different levels of viscosity were used to simulate tissue differentiation. Compressive strain of 0.5% and fluid flow with constant inlet velocity of 10 μm/s or constant inlet pressure of 3 Pa were applied. Octahedral shear strain and fluid shear stress were used as mechano-regulatory stimuli. For constant inlet velocity, stimuli equivalent to bone were predicted in 80% of pore volume for the case of low tissue viscosity. For the cases of high viscosity, fluctuations between stimuli equivalent to tissue formation and cell death were predicted due to the increase in the fluid shear stress when tissue started to fill pores. When constant pressure was applied, stimuli equivalent to bone were predicted in 62% of pore volume when low tissue viscosity was used and 42% when high tissue viscosity was used. This study predicted critical variations of fluid shear stress when cells differentiated. If these variations are not controlled in vitro, they can impede the formation of new matured tissue.

Keywords: Engineering

Noailly, Jérôme, Planell, Josep, Lacroix, Damien, (2011). On the collagen criss-cross angles in the annuli fibrosi of lumbar spine finite element models Biomechanics and Modeling in Mechanobiology 10, (2), 203-219

In the human lumbar spine, annulus fibrosus fibres largely contribute to intervertebral disc stability. Detailed annulus models are therefore necessary to obtain reliable predictions of lumbar spine mechanics by finite element modelling. However, different definitions of collagen orientations coexist in the literature for healthy human lumbar annuli. Therefore, four annulus fibre-induced anisotropy models were built from reported anatomical descriptions, and inserted in a L3–L5 lumbar bi-segment finite element model. Annulus models were, respectively, characterized by radial, tangential, radial and tangential, and no fibre orientation gradients. The effect of rotational and axial compressive loadings was simulated and first, predictions were compared to experimental data. Then, intervertebral disc local biomechanics was studied under axial rotation and axial compression. A new parameter, i.e. the fibre contribution quality parameter, was computed in the anterior, lateral, postero-lateral, and posterior annuli of each model, in function of fibre stresses, radial load distributions, and matrix shear strains. Locally, each annulus model behaved differently, affecting intervertebral disc biomechanics and segmental motions. The fibre contribution quality parameter allowed establishing direct links between local annulus fibre organization and local annulus loadings, while other kinematical and biomechanical data did not. It was concluded that functional relations should exist between local annulus fibre orientations and overall segment morphology. The proposed fibre contribution quality parameter could be used to examine such relations and calibrate lumbar spine finite element models by locally adjusting the annulus bundle criss-cross angles. Conclusions of this study are particularly relevant to patient-specific models or artificial disc designs.

Keywords: Physics and Astronomy

Miguel Munoz, Luis, Casals, Alicia, Frigola, Manel, Amat, Josep, (2011). Motor-model-based dynamic scaling in human-computer interfaces IEEE Transactions on Systems Man and Cybernetics Part B-Cybernetics , 41, (2), 435-447

This paper presents a study on how the application of scaling techniques to an interface affects its performance. A progressive scaling factor based on the position and velocity of the cursor and the targets improves the efficiency of an interface, thereby reducing the user's workload. The study uses several human-motor models to interpret human intention and thus contribute to defining and adapting the scaling parameters to the execution of the task. Two techniques addressed to vary the control-display ratio are compared, and a new method for aiding in the task of steering is proposed.

Keywords: Performance, Movements

Queiroz, Mário H., Madrid, Cristina, Paytubi, Sònia, Balsalobre, Carlos, Juárez, Antonio, (2011). Integration Host Factor alleviates H-NS silencing of the Salmonella enterica serovar Typhimurium master regulator of SPI1, hilA Microbiology-Sgm , 157, (9), 2504-2514

Coordination of the expression of Salmonella enterica invasion genes on pathogenicity island 1 (SPI1) depends on a complex circuit involving several regulators that converge on expression of the hilA gene, which encodes a transcriptional activator (HilA), that modulates expression of the SPI1 virulence genes. Two of the global regulators influencing hilA expression are the nucleoid associated proteins Hha and H-NS. They interact and form a complex that modulates gene expression. A chromosomal transcriptional fusion was constructed to assess the effect of these modulators on hilA transcription under several environmental conditions as well as at different stages of the growth curve. The results obtained showed that these proteins play a relevant role in silencing hilA expression both at low temperature and low osmolarity, irrespective of the growth phase. H-NS accounts for the main repressory activity. At high temperature and osmolarity H-NS-mediated silencing completely ceases when cells enter the stationary phase, and hilA expression is induced. Mutants lacking IHF did not induce hilA in cells entering the stationary phase, and this lack of induction was dependent on the presence of H-NS. Band shift assays and in vitro transcription data evidence that for hilA induction under certain growth conditions, IHF is required to alleviate H-NS-mediated silencing.

Keywords: -----

Gugutkov, Dencho, Gonzalez-Garcia, Cristina, Altankov, George, Salmeron-Sanchez, Manuel, (2011). Fibrinogen organization at the cell-material interface directs endothelial cell behavior Journal of Bioactive and Compatible Polymers , 26, (4), 375-387

Fibrinogen (FG) adsorption on surfaces with controlled fraction of -OH groups was investigated with AFM and correlated to the initial interaction of primary endothelial cells (HUVEC). The -OH content was tailored making use of a family of copolymers consisting of ethyl acrylate (EA) and hydroxyl ethyl acrylate (HEA) in different ratios. The supramolecular distribution of FG changed from an organized network-like structure on the most hydrophobic surface (-OH(0)) to dispersed molecular aggregate one as the fraction of -OH groups increases, indicating a different conformation by the adsorbed protein. The best cellular interaction was observed on the most hydrophobic (-OH(0)) surface where FG assembled in a fibrin-like appearance in the absence of any thrombin. Likewise, focal adhesion formation and actin cytoskeleton development was poorer as the fraction of hydroxy groups on the surface was increased. The biological activity of the surface-induced FG network to provide 3D cues in a potential tissue engineered scaffold, making use of electrospun PEA fibers (-OH(0)), seeded with human umbilical vein endothelial cells was investigated. The FG assembled on the polymer fibers gave rise to a biologically active network able to direct cell orientation along the fibers (random or aligned), promote cytoskeleton organization and focal adhesion formation.

Keywords: Fibrinogen, Cell-material interactions, HUVEC, Electrospun fibers, Fibrinogen organization, Cell-material interface, Endothelial cell behavior, Ethyl acrylate, Hydroxyl ethyl acrylate

Galbusera, F., Schmidt, H., Noailly, J., Malandrino, A., Lacroix, D., Wilke, H.J, Shirazi-Adl, A., (2011). Comparison of four methods to simulate swelling in poroelastic finite element models of intervertebral discs Journal of the Mechanical Behavior of Biomedical Materials , 4, (7), 1234-1241

Osmotic phenomena influence the intervertebral disc biomechanics. Their simulation is challenging and can be undertaken at different levels of complexity. Four distinct approaches to simulate the osmotic behaviour of the intervertebral disc (a fixed boundary pore pressure model, a fixed osmotic pressure gradient model in the whole disc or only in the nucleus pulposus, and a swelling model with strain-dependent osmotic pressure) were analysed. Predictions were compared using a 3D poroelastic finite element model of a L4–L5 spinal unit under three different loading conditions: free swelling for 8 h and two daily loading cycles: (i) 200 N compression for 8 h followed by 500 N compression for 16 h; (ii) 500 N for 8 h followed by 1000 N for 16 h. Overall, all swelling models calculated comparable results, with differences decreasing under greater loads. Results predicted with the fixed boundary pore pressure and the fixed osmotic pressure in the whole disc models were nearly identical. The boundary pore pressure model, however, cannot simulate differential osmotic pressures in disc regions. The swelling model offered the best potential to provide more accurate results, conditional upon availability of reliable values for the required coefficients and material properties. Possible fields of application include mechanobiology investigations and crack opening and propagation. However, the other approaches are a good compromise between the ease of implementation and the reliability of results, especially when considering higher loads or when the focus is on global results such as spinal kinematics.

Keywords: Intervertebral disc, Boundary pore pressure, Osmotic pressure, Swelling, Finite element, Poroelasticity

Byrne, Damien P., Lacroix, Damien, Prendergast, Patrick J., (2011). Simulation of fracture healing in the tibia: Mechanoregulation of cell activity using a lattice modeling approach Journal of Orthopaedic Research , 29, (10), 1496-1503

In this study, a three-dimensional (3D) computational simulation of bone regeneration was performed in a human tibia under realistic muscle loading. The simulation was achieved using a discrete lattice modeling approach combined with a mechanoregulation algorithm to describe the cellular processes involved in the healing process namely proliferation, migration, apoptosis, and differentiation of cells. The main phases of fracture healing were predicted by the simulation, including the bone resorption phase, and there was a qualitative agreement between the temporal changes in interfragmentary strain and bending stiffness by comparison to experimental data and clinical results. Bone healing was simulated beyond the reparative phase by modeling the transition of woven bone into lamellar bone. Because the simulation has been shown to work with realistic anatomical 3D geometry and muscle loading, it demonstrates the potential of simulation tools for patient-specific pre-operative treatment planning.

Keywords: Tissue differentiation, Computational analysis, Mechanical conditions, Bone regeneration, Weight-bearing, Proliferation, Osteoblast, Stiffness, Ingrowth, Scaffold

Banos, R. C., Aznar, S., Madrid, C., Juarez, A., (2011). Differential functional properties of chromosomal- and plasmid-encoded H-NS proteins Research in Microbiology , 162, (4), 382-385

The nucleoid-associated protein H-NS can be either chromosomal- or plasmid-encoded. We provide in this report evidence indicating that chromosomal- and plasmid-encoded H-NS proteins may differ in their functional properties. The modulatory function of chromosomal H-NS is antagonized by the H-NSTEPEC protein. We show that the H-NS protein encoded by the IncHI plasmid R27 (H-NSR27) is less sensitive to H-NSTEPEC antagonism than its chromosomal counterpart. H-NSR27 plays a relevant role by modulating R27 conjugation in response to temperature. Hence, we suggest that this modulator has evolved to avoid the deregulation of R27 conjugation by H-NSTEPEC-like proteins.

Keywords: H-NS, Conjugation, R27, H-NS antagonism, H-NSTEPEC

Urban, Patricia, Estelrich, Joan, Adeva, Alberto, Cortes, Alfred, Fernàndez-Busquets, X., (2011). Study of the efficacy of antimalarial drugs delivered inside targeted immunoliposomal nanovectors Nanoscale Research Letters 6, (1), 620

Paul Ehrlich's dream of a 'magic bullet' that would specifically destroy invading microbes is now a major aspect of clinical medicine. However, a century later, the implementation of this medical holy grail continues being a challenge in three main fronts: identifying the right molecular or cellular targets for a particular disease, having a drug that is effective against it, and finding a strategy for the efficient delivery of sufficient amounts of the drug in an active state exclusively to the selected targets. In a previous work, we engineered an immunoliposomal nanovector for the targeted delivery of its contents exclusively to Plasmodium falciparum-infected red blood cells [pRBCs]. In preliminary assays, the antimalarial drug chloroquine showed improved efficacy when delivered inside immunoliposomes targeted with the pRBC-specific monoclonal antibody BM1234. Because difficulties in determining the exact concentration of the drug due to its low amounts prevented an accurate estimation of the nanovector performance, here, we have developed an HPLC-based method for the precise determination of the concentrations in the liposomal preparations of chloroquine and of a second antimalarial drug, fosmidomycin. The results obtained indicate that immunoliposome encapsulation of chloroquine and fosmidomycin improves by tenfold the efficacy of antimalarial drugs. The targeting antibody used binds preferentially to pRBCs containing late maturation stages of the parasite. In accordance with this observation, the best performing immunoliposomes are those added to Plasmodium cultures having a larger number of late form-containing pRBCs. An average of five antibody molecules per liposome significantly improves in cell cultures the performance of immunoliposomes over non-functionalized liposomes as drug delivery vessels. Increasing the number of antibodies on the liposome surface correspondingly increases performance, with a reduction of 50% parasitemia achieved with immunoliposomes encapsulating 4 nM chloroquine and bearing an estimated 250 BM1234 units. The nanovector prototype described here can be a valuable platform amenable to modification and improvement with the objective of designing a nanostructure adequate to enter the preclinical pipeline as a new antimalarial therapy.

Keywords: Plasmodium falciparum, Antimalarial drug, Nanovector, Immuno-liposomes

Barthelmebs, L., Jonca, J., Hayat, A., Prieto-Simon, B., Marty, J. L., (2011). Enzyme-Linked Aptamer Assays (ELAAs), based on a competition format for a rapid and sensitive detection of Ochratoxin A in wine Food Control , 22, (5), 737-743

Ochratoxin A (OTA) is one of the most important mycotoxins because of its high toxicity to both humans and animals and its occurrence in a number of basic foods and agro-products. The need to develop high-performing methods for OTA analysis able to improve the traditional ones is evident. In this work, through in vitro SELEX (Systematic Evolution of Ligands by EXponential enrichment) two aptamers, designated H8 and H12 were produced that bind with nanomolar affinity with Ochratoxin A (OTA). Two strategies were investigated by using an indirect and a direct competitive Enzyme-Linked Aptamer Assay (ELAA) and were compared to the classical competitive Enzyme-Linked Immunosorbent Assay (ELISA) for the determination of OTA in spiked red wine samples. The limit of detection attained (1 ng/mL), the midpoint value obtained (5 ng/mL) and the analysis time needed (125 min) for the real sample analysis validate the direct competitive ELAA as useful screening tool for routine use in the control of OTA level in wine.

Keywords: Competitive Enzyme-Linked Aptamer Assay (ELAA), DNA aptamer, Ochratoxin A, SELEX, Wine analysis

Rodriguez-Segui, Santiago A., Pons Ximenez, Jose Ignacio, Sevilla, Lidia, Ruiz, Ana, Colpo, Pascal, Rossi, Francois, Martinez, Elena, Samitier, Josep, (2011). Quantification of protein immobilization on substrates for cellular microarray applications Journal of Biomedical Materials Research - Part A , 98A, (2), 245-256

Cellular microarray developments and its applications are the next step after DNA and protein microarrays. The choice of the surface chemistry of the substrates used for the implementation of this technique, that must favor proper protein immobilization while avoiding cell adhesion on the nonspotted areas, presents a complex challenge. This is a key issue since usually the best nonfouling surfaces are also the ones that retain immobilized the smallest amounts of printed protein. To quantitatively assess the amount of protein immobilization, in this study several combinations of fluorescently labeled fibronectin (Fn*) and streptavidin (SA*) were microspotted, with and without glycerol addition in the printing buffer, on several substrates suitable for cellular microarrays. The substrates assayed included chemically activated surfaces as well as Poly ethylene oxide (PEO) films that are nonfouling in solution but accept adhesion of proteins in dry conditions. The results showed that the spotted Fn* was retained by all the surfaces, although the PEO surface did show smaller amounts of immobilization. The SA*, on the other hand, was only retained by the chemically activated surfaces. The inclusion of glycerol in the printing buffer significantly reduced the immobilization of both proteins. The results presented in this article provide quantitative evidence of the convenience of using a chemically activated surface to immobilize proteins relevant for cellular microarray applications, particularly when ECM proteins are cospotted with smaller factors which are more difficult to be retained by the surfaces.

Keywords: Protein immobilization, Quantification, Microarray, Substrate, Surface chemistry

Fernandez, Javier G., Samitier, Josep, Mills, Christopher A., (2011). Simultaneous biochemical and topographical patterning on curved surfaces using biocompatible sacrificial molds Journal of Biomedical Materials Research - Part A , 98A, (2), 229-234

A method for the simultaneous (bio)chemical and topographical patterning of enclosed structures in poly(dimethyl siloxane) (PDMS) is presented. The simultaneous chemical and topography transference uses a water-soluble chitosan sacrificial mold to impart a predefined pattern with micrometric accuracy to a PDMS replica. The method is compared to conventional soft-lithography techniques on planar surfaces. Its functionality is demonstrated by the transference of streptavidin directly to the surface of the three-dimensional PDMS structures as well as indirectly using streptavidin-loaded latex nanoparticles. The streptavidin immobilized on the PDMS is tested for bioactivity by coupling with fluorescently labeled biotin. This proves that the streptavidin is immobilized on the PDMS surface, not in the bulk of the polymer, and is therefore accessible for use as signaling/binding element in micro and bioengineering. The use of a biocompatible polymer and processes enables the technique to be used for the chemical patterning of tissue constructions.

Keywords: Biotechnology, Chitosan, Microfabrication, MEMs, Soft lithography

Lacroix, Damien, Ramirez Patino, Juan Fernando, (2011). Finite Element Analysis of Donning Procedure of a Prosthetic Transfemoral Socket Annals of Biomedical Engineering , 39, (12), 2972-2983

Lower limb amputation is a severe psychological and physical event in a patient. A prosthetic solution can be provided but should respond to a patient-specific need to accommodate for the geometrical and biomechanical specificities. A new approach to calculate the stress-strain state at the interaction between the socket and the stump of five transfemoral amputees is presented. In this study the socket donning procedure is modeled using an explicit finite element method based on the patient-specific geometry obtained from CT and laser scan data. Over stumps the mean maximum pressure is 4 kPa (SD 1.7) and the mean maximum shear stresses are 1.4 kPa (SD 0.6) and 0.6 kPa (SD 0.3) in longitudinal and circumferential directions, respectively. Locations of the maximum values are according to pressure zones at the sockets. The stress-strain states obtained in this study can be considered more reliable than others, since there are normal and tangential stresses associated to the socket donning procedure.

Keywords: Trans-tibial prosthesis, Knee residual limb, Pressure distribution, Transtibial amputees, Stump/socket interface, Mechanical conditions, Load-transfer, Soft-tissues, Stresses, Contact

Roa, J. J., Oncins, G., Diaz, J., Capdevila, X. G., Sanz, F., Segarra, M., (2011). Study of the friction, adhesion and mechanical properties of single crystals, ceramics and ceramic coatings by AFM Journal of the European Ceramic Society 31, (4), 429-449

This paper reviews commonly used methods of analyzing and interpreting friction, adhesion and nanoindentation with an AFM tip test data, with a particular emphasis of the testing of single crystals, metals, ceramics and ceramic coatings. Experimental results are reported on the friction, mechanical and adhesion properties of these materials. The popularity of AFM testing is evidenced by the large quantity of papers that report such measurements in the last decade. Unfortunately, a lot of information about these topics is scare in the literature. The present paper is aimed to present the basic physical modelling employed and also some examples using each technique.

Keywords: Mechanical properties, Plasticity, Biomedical applications, Engine components

Zalvidea, D., Claverol-Tinturé, E., (2011). Second Harmonic Generation for time-resolved monitoring of membrane pore dynamics subserving electroporation of neurons Biomedical Optics Express , 2, (2), 305-314

Electroporation of neurons, i.e. electric-field induced generation of membrane nanopores to facilitate internalization of molecules, is a classic technique used in basic neuroscience research and recently has been proposed as a promising therapeutic strategy in the area of neuro-oncology. To optimize electroporation parameters, optical techniques capable of delivering time and spatially-resolved information on electroporation pore formation at the nanometer scale would be advantageous. For this purpose we describe here a novel optical method based on second harmonic generation (SHG) microscopy. Due to the nonlinear and coherent nature of SHG, the 3D radiation lobes from stained neuronal membranes are sensitive to the spatial distribution of scatterers in the illuminated patch, and in particular to nanopore formation.We used phase-array analysis to computationally study the SHG signal as a function of nanopore size and nanopore population density and confirmed experimentally, in accordance with previous work, the dependence of nanopore properties on membrane location with respect to the electroporation electric field; higher nanopore densities, lasting < 5 milliseconds, are observed at membrane patches perpendicular to the field whereas lower density is observed at partly tangent locations. Differences between near-anode and near-cathode cell poles are also measured, showing higher pore densities at the anodic pole compared to cathodic pole. This technique is promising for the study of nanopore dynamics in neurons and for the optimization of novel electroporation-based therapeutic approaches.

Pegueroles, M., Aguirre, A., Engel, E., Pavon, G., Gil, F. J., Planell, J. A., Migonney, V., Aparicio, C., (2011). Effect of blasting treatment and Fn coating on MG63 adhesion and differentiation on titanium: a gene expression study using real-time RT-PCR Journal of Materials Science: Materials in Medicine , 22, (3), 617-627

Biomaterial surface properties, via alterations in the adsorbed protein layer, and the presence of specific functional groups can influence integrin binding specificity, thereby modulating cell adhesion and differentiation processes. The adsorption of fibronectin, a protein directly involved in osteoblast adhesion to the extracellular matrix, has been related to different physical and chemical properties of biomaterial surfaces. This study used blasting particles of different sizes and chemical compositions to evaluate the response of MG63 osteoblast-like cells on smooth and blasted titanium surfaces, with and without fibronectin coatings, by means of real-time reverse transcription-polymerase chain reaction (qRT-PCR) assays. This response included (a) expression of the alpha(5), alpha(v) and alpha(3) integrin subunits, which can bind to fibronectin through the RGD binding site, and (b) expression of alkaline phosphatase (ALP) and osteocalcin (OC) as cell-differentiation markers. ALP activity and synthesis of OC were also tested. Cells on SiC-blasted Ti surfaces expressed higher amounts of the alpha(5) mRNA gene than cells on Al2O3-blasted Ti surfaces. This may be related to the fact that SiC-blasted surfaces adsorbed higher amounts of fibronectin due to their higher surface free energy and therefore provided a higher number of specific cell-binding sites. Fn-coated Ti surfaces decreased alpha(5) mRNA gene expression, by favoring the formation of other integrins involved in adhesion over alpha(5)beta(1). The changes in alpha(5) mRNA expression induced by the presence of fibronectin coatings may moreover influence the osteoblast differentiation pathway, as fibronectin coatings on Ti surfaces also decreased both ALP mRNA expression and ALP activity after 14 and 21 days of cell culture.

Keywords: -----

Aydin, E., Planell, J. A., Hasirci, V., (2011). Hydroxyapatite nanorod-reinforced biodegradable poly(l-lactic acid) composites for bone plate applications Journal of Materials Science: Materials in Medicine , 22, (11), 2413-2427

Novel PLLA composite fibers containing hydroxyapatite (HAp) nanorods with or without surface lactic acid grafting were produced by extrusion for use as reinforcements in PLLA-based bone plates. Fibers containing 0-50% (w/w) HAp nanorods, aligned parallel to fiber axis, were extruded. Lactic acid surface grafting of HAp nanorods (lacHAp) improved the tensile properties of composites fibers better than the non-grafted ones (nHAp). Best tensile modulus values of 2.59, 2.49, and 4.12 GPa were obtained for loadings (w/w) with 30% lacHAp, 10% nHAp, and 50% amorphous HAp nanoparticles, respectively. Bone plates reinforced with parallel rows of these composite fibers were molded by melt pressing. The best compressive properties for plates were obtained with nHAp reinforcement (1.31 GPa Young's Modulus, 110.3 MPa compressive strength). In vitro testing with osteoblasts showed good cellular attachment and spreading on composite fibers. In situ degradation tests revealed faster degradation rates with increasing HAp content. To our knowledge, this is the first study containing calcium phosphate-polymer nanocomposite fibers for reinforcement of a biodegradable bone plate or other such implants and this biomimetic design was concluded to have potential for production of polymer-based biodegradable bone plates even for load bearing applications.

Hristova, K., Pecheva, E., Pramatarova, L., Altankov, G., (2011). Improved interaction of osteoblast-like cells with apatite-nanodiamond coatings depends on fibronectin Journal of Materials Science: Materials in Medicine , 22, (8), 1891-1900

New apatite (AP)/nanodiamond (ND) coating has been developed to improve physical and biological properties of stainless steel (SS) versus single AP coating. Homogeneously electrodeposited AP-ND layer demonstrates increased mechanical strength, interlayer cohesion and ductility. In the absence of serum, osteoblast-like MG63 cells attach well but poorly spread on both AP and AP-ND substrata. Pre-adsorption with serum or fibronectin (FN) improves the cellular interaction-an effect that is better pronounced on the AP-ND coating. In single protein adsorption study fluorescein isothiocyanate-labeled FN (FITC-FN) shows enhanced deposition on the AP-ND layer consistent with the significantly improved cell adhesion, spreading and focal adhesions formation (in comparison to SS and AP), particularly at low FN adsorption concentrations (1 mu g/ml). Higher FN concentrations (20 mu g/ml) abolish this difference suggesting that the promoted cellular interaction of serum (where FN is low) is caused by the greater affinity for FN. Moreover, it is found that MG63 cells tend to rearrange both adsorbed and secreted FN on the AP-ND layer suggesting facilitated FN matrix formation.

Keywords: Extracellular-matrix, Protein adsorption, Integrins, Adhesion, Biomaterials, Surfaces, Polymerization, Composite, Implants, Titanium

Rodríguez-Hernández, Ana, Juárez, A., Engel, E., Gil, F., (2011). Streptococcus sanguinis adhesion on titanium rough surfaces: effect of shot-blasting particles Journal of Materials Science: Materials in Medicine , Springer Netherlands 22, (8), 1-10

Dental implant failure is commonly associated to dental plaque formation. This problem starts with bacterial colonization on implant surface upon implantation. Early colonizers (such as Streptococcus sanguinis) play a key role on that process, because they attach directly to the surface and facilitate adhesion of later colonizers. Surface treatments have been focused to improve osseointegration, where shot-blasting is one of the most used. However the effects on bacterial adhesion on that sort of surfaces have not been elucidated at all. A methodological procedure to test bacterial adherence to titanium shot-blasted surfaces (alumina and silicon carbide) by quantifying bacterial detached cells per area unit, was performed. In parallel, the surface properties of samples (i.e., roughness and surface energy), were analyzed in order to assess the relationship between surface treatment and bacterial adhesion. Rather than roughness, surface energy correlated to physicochemical properties of shot-blasted particles appears as critical factors for S. sanguinis adherence to titanium surfaces.

Keywords: Engineering

Cagido, Viviane Ramos, Zin, Walter Araujo, Ramirez, Jose, Navajas, Daniel, Farre, Ramon, (2011). Alternating ventilation in a rat model of increased abdominal pressure Respiratory Physiology & Neurobiology , 175, (3), 310-315

During alternating ventilation (AV) one lung is inflating while the other is deflating. Considering the possible respiratory and hemodynamic advantages of AV, we investigated its effects during increased intra-abdominal pressure (IAP = 10 mmHg). In Sprague-Dawley rats (n = 6, 270–375 g) the main bronchi were independently cannulated, and respiratory mechanics determined while animals underwent different ventilatory patterns: synchronic ventilation without increased IAP (SV-0), elevated IAP during SV (SV-10), and AV with elevated IAP (AV-10). Thirty-three other animals (SV-0, n = 10; SV-10, n = 11 and AV-10, n = 12) were ventilated during 3 h. Mean arterial pressure (MAP), and lung histology were assessed. Increased IAP resulted in significantly higher elastances (p < 0.001), being AV-10 lower than SV-10 (p < 0.020). SV-10 showed higher central venous pressure (p < 0.003) than S-0; no change was observed in AV-10. Wet/dry lung weight ratio was lower in AV-10 than SV-10 (p = 0.009). Application of AV reduced hemodynamic and lung impairments induced by increased IAP during SV.

Keywords: Alternating ventilation, Respiratory mechanics, Intra-abdominal pressure, Hemodynamic, Mechanical ventilation, Animal model

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.

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

Perez, R. A., Del Valle, S., Altankov, G., Ginebra, M. P., (2011). Porous hydroxyapatite and gelatin/hydroxyapatite microspheres obtained by calcium phosphate cement emulsion Journal of Biomedical Materials Research - Part B: Applied Biomaterials , 97B, (1), 156-166

Hydroxyapatite and hybrid gelatine/hydroxyapatite microspheres were obtained through a water in oil emulsion of a calcium phosphate cement (CPC). The setting reaction of the CPC, in this case the hydrolysis of alpha-tricalcium phosphate, was responsible for the consolidation of the microspheres. After the setting reaction, the microspheres consisted of an entangled network of hydroxyapatite crystals, with a high porosity and pore sizes ranging between 0.5 and 5 mu m. The size of the microspheres was tailored by controlling the viscosity of the hydrophobic phase, the rotation speed, and the initial powder size of the CPC. The incorporation of gelatin increased the sphericity of the microspheres, as well as their size and size dispersion. To assess the feasibility of using the microspheres as cell microcarriers, Saos-2 cells were cultured on the microspheres. Fluorescent staining, SEM studies, and LDH quantification showed that the microspheres were able to sustain cell growth. Cell adhesion and proliferation was significantly improved in the hybrid gelatin/hydroxyapatite microspheres as compared to the hydroxyapatite ones.

Keywords: Calcium phosphate(s), Bone graft, Microspheres, Composite/hard tissue, Hydroxy(1)lapatite

Banos, R. C., Martinez, J., Polo, C., Madrid, C., Prenafeta, A., Juarez, A., (2011). The yfeR gene of Salmonella enterica serovar Typhimurium encodes an osmoregulated LysR-type transcriptional regulator Fems Microbiology Letters , 315, (1), 63-71

A genetic screening for osmoregulated genes allowed us to identify the yfeR gene of Salmonella enterica serovar Typhimurium. The yfeR gene product encodes a novel LysR-type transcriptional regulator (LTTR), the expression of which decreases when external osmolarity increases. Out of the adjacent gene yfeH, YfeR modulates expression of several genes that may be required for optimal growth under low osmolarity conditions.

Keywords: YfeR, Salmonella, LysR, Osmoregulation, LTTR

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.

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

Morgenstern, R., Morgenstern, C., Jané, R., Lee, S. H., (2011). Usefulness of an expandable interbody spacer for the treatment of foraminal stenosis in extremely collapsed disks preliminary clinical experience with endoscopic posterolateral transforaminal approach Journal of Spinal Disorders & Techniques , 24, (8), 485-491

Study Design: Clinical series of patients with degenerative disk disease undergoing an endoscopic posterolateral transforaminal procedure that used a reaming foraminoplasty technique to enlarge the foramen coupled with insertion of the B-Twin expandable spacer. Objectives: This retrospective analysis of 107 consecutive patients sought to assess the outcome of this surgical procedure. Summary of Background Data: Reamed endoscopic foraminoplasty under direct endoscopic vision has been shown to be suitable for extremely collapsed disks (> 50% total disk height) despite the difficult access, especially at L5-S1. The authors tried to investigate the efficacy of an expandable spacer being inserted by the endoscopic transforaminal approach to solve foraminal stenosis without bone fusion techniques. Methods: The procedure consists of bone reaming under direct endoscopic control to wide the foramen followed by insertion of the B-Twin expandable device as a disk spacer to restore partially or to maintain the height of the collapsed disk. Outcome measures included visual analog scale (VAS) for pain, the Oswestry Disability Index (ODI) for functional disability, and radioimaging studies. Results: Mean follow-up was 27.2 months. Clinical outcome was considered excellent in 64 patients, good in 25, fair in 10, and poor in 8. Results were similar in single and double B-Twin spacer insertions. Postoperative mean values for VAS and ODI scores improved significantly as compared with preoperative data. Mean VAS and ODI scores were significantly higher in patients with fair or poor results than in those with excellent or good outcome. In 2 cases, clear signs of end plate bone resorption in the control computed tomographic scans at 6 months and 12 months leading to a substantial loss of disk height were documented. Conclusions: This preliminary study has shown the efficacy of an endoscopic surgical technique for the treatment of foraminal stenosis in extremely collapsed disks.

Keywords: Foraminal stenosis, B-twin expandable spacer, Endoscopic foraminoplasty, Minimally invasive surgery, Surgical technique, Spinal spacer, Lumbar, Diskectomy, Fusion, Discectomy

Fiz, José Antonio, Solà, J., Jané, Raimon, (2011). Métodos de análisis del ronquido Medicina Clínica , 137, (1), 36-42

El ronquido es un sonido respiratorio que se produce durante el sueño, ya sea nocturno o diurno. El ronquido puede ser inspiratorio, espiratorio o puede ocupar todo el ciclo respiratorio. Tiene su origen en la vibración de los diferentes tejidos de la vía aérea superior. Se han descrito numerosos métodos para analizarlo, desde el simple interrogatorio, pasando por cuestionarios estándares, hasta llegar a los métodos acústicos más sofisticados, que se han desarrollado gracias al gran avance de las técnicas biomédicas en los últimos años. El presente trabajo describe el estado del arte actual en los procedimientos de análisis del ronquido.

Keywords: Ronquido, Apnea del sueño, Síndrome de apnea-hipoapnea del sueño, Snoring, Sleep apnea, Sleep Apnea and Hipoapnea Syndrome

A. Mathur, P. Roca-Cusachs, O. M. Rossier, S. J. Wind, M. P. Sheetz, J. Hone, (2011). New approach for measuring protrusive forces in cells Journal of Vacuum Science & Technology B: Microelectronics and Nanometer Structures , 29, (6), 06FA02

Roa, J. J., Oncins, G., Diaz, J., Sanz, F., Segarra, M., (2011). Calculation of young's modulus value by means of AFM Recent Patents on Nanotechnology , 5, (1), 27-36

In the last years, Atomic Force Microscopy (AFM) has become a powerful tool not only to study the surface morphology but also the nanomechanics of all kind of samples. In this paper, the applicability of this technique is reviewed and its basic aspects of operation, advantages and drawbacks of using the AFM probe as a picoindenter (Force Spectroscopy mode, FS-AFM) are discussed. The patents concerning picoindentation measurements are discussed in the text and special attention is paid to measurements performed on hard materials as ceramics, as they have not been as thoroughly reviewed in the literature as in the case of soft matter. The possibilities of AFM in the nanomechanics field include the quantitative determination of the Young's modulus (E) and the transition force from elastic to plastic deformation regimes, the measurement of adhesion forces and deformation mechanisms while applying vertical forces in the range from tens of pN to mu N.

Keywords: Hard materials, Young's modulus, AFM-FS, Picoindentation technique

Paytubi, S., Garcia, J., Juarez, A., (2011). Bacterial Hha-like proteins facilitate incorporation of horizontally transferred DNA Central European Journal of Biology , 6, (6), 879-886

Horizontal gene transfer (HGT), non-hereditary transfer of genetic material between organisms, accounts for a significant proportion of the genetic variability in bacteria. In Gram negative bacteria, the nucleoid-associated protein H-NS silences unwanted expression of recently acquired foreign DNA. This, in turn, facilitates integration of the incoming genes into the regulatory networks of the recipient cell. Bacteria belonging to the family Enterobacteriaceae express an additional protein, the Hha protein that, by binding to H-NS, potentiates silencing of HGT DNA. We provide here an overview of Hha-like proteins, including their structure and function, as well as their evolutionary relationship. We finally present available information suggesting that, by expressing Hha-like proteins, bacteria such as Escherichia coli facilitate HGT incorporation and hence, the impact of HGT in their genetic diversity.

Keywords: Hha, H-NS, HGT DNA, Enterobacteria, Nucleoid-associated proteins, Enterica serovar typhimurium, Histone-like protein, h-ns, Escherichia-coli, Yersinia-enterocolitica, Salmonella-enterica

Rodríguez, J. E., Cruz, I., Vergés, E., Ayala, D., (2011). A connected-component-labeling-based approach to virtual porosimetry Graphical Models , 73, (5), 296-310

Analyzing the pore-size distribution of porous materials, made up of an aggregation of interconnected pores, is a demanding task. Mercury intrusion porosimetry (MIP) is a physical method that intrudes mercury into a sample at increasing pressures to obtain a pore-size histogram. This method has been simulated in-silice with several approaches requiring prior computation of a skeleton. We present a new approach to simulate MIP that does not require skeleton computation. Our method is an iterative process that considers the diameters corresponding to pressures. At each iteration, geometric tests detect throats for the corresponding diameter and a CCL process collects the region invaded by the mercury. Additionally, a new decomposition model called CUDB, is used. This is suitable for computing the throats and performs better with the CCL algorithm than a voxel model. Our approach obtains the pore-size distribution of the porous medium, and the corresponding pore graph.

Keywords: Micro CT, Pore map, Porous media, Skeleton, Virtual MIP

Tahirbegi, I. B., Mir, M., (2011). Slit-wave model for band structures in solid state physics Modern Physics Letters B , 25, (3), 151-161

The reason behind the entire development in silicon technology was band models in solid state physics. However, the theories postulated in order to give response to this phenomenon do not explain all kinds of materials. In a bid to overcome this limitation, we approach the problem from another point of view. In this work, the wave properties of the electrons from the external orbitals of the atoms and its diffraction patterns through the lattice structure of the material have been used to explain the band structure of metals, semiconductor and insulators. In order to probe this hypothesis, a simulation has been used and according to the relation between the lattice constant and the atomic diameter, the splitting of the bands have been observed for different kind of materials, showing a strong correlation between the simulation and the experimental results.

Keywords: Electrical band structure, Band gap, Fraunhofer diffraction, Semiconductor, Insulator

Garde, A., Giraldo, B.F., Sornmo, L., Jané, R., (2011). Analysis of the respiratory flow cycle morphology in chronic heart failure patients applying principal components analysis Engineering in Medicine and Biology Society 33rd Annual International Conference of the IEEE EMBS , IEEE (Boston, USA) Engineering in Medicine and Biology Society, 1725-1728

The study of flow cycle morphology provides new information about the breathing pattern. This study proposes the characterization of cycle morphology in chronic heart failure patients (CHF) patients, with periodic (PB) and non-periodic breathing (nPB) patterns, and healthy subjects. Principal component analysis is applied to extract a respiratory cycle model for each time segment defined by a 30-s moving window. To characterize morphology of the model waveform, a number of parameters are extracted whose significance is evaluated in terms of the following three classification problems: CHF patients with either PB or nPB, CHF patients versus healthy subjects, and nPB patients versus healthy subjects. 26 CHF patients (8 with PB and 18 with non-periodic breathing pattern (nPB)) and 35 healthy subjects are studied. The results show that a respiratory cycle compressed in time characterizes PB patients, i.e., shorter inspiratory and expiratory periods, and higher dispersion of the maximum inspiratory and expiratory flow value (accuracy of 87%). The maximal expiratory flow instant occurs earlier in CHF patients than in healthy subjects (accuracy of 87%), with a steeper slope between inspiration and expiration. It is also found that the standard deviation of the expiratory period, evaluated for each subject, is much lower in CHF patients than in healthy subjects. The maximal expiratory flow instant occurs earlier (accuracy of 84%) in nPB patients, when comparing subjects with similar respiratory pattern like nPB patients and healthy subjects.

Keywords: -----

Chaparro, J.A., Giraldo, B.F. , Caminal, P., Benito, S., (2011). Analysis of the respiratory pattern variability of patients in weaning process using autoregressive modeling techniques Engineering in Medicine and Biology Society 33rd Annual International Conference of the IEEE EMBS , IEEE (Boston, USA) Engineering in Medicine and Biology Society, 5690-5693

One of the most challenging problems in intensive care is the process of discontinuing mechanical ventilation, called weaning process. An unnecessary delay in the discontinuation process and an early weaning trial are undesirable. This paper proposes to analysis the respiratory pattern variability of these patients using autoregressive modeling techniques: autoregressive models (AR), autoregressive moving average models (ARMA), and autoregressive models with exogenous input (ARX). A total of 153 patients on weaning trials from mechanical ventilation were analyzed: 94 patients with successful weaning (group S); 38 patients that failed to maintain spontaneous breathing (group F), and 21 patients who had successful weaning trials, but required reintubation in less than 48 h (group R). The respiratory pattern was characterized by their time series. The results show that significant differences were obtained with parameters as model order and first coefficient of AR model, and final prediction error by ARMA model. An accuracy of 86% (84% sensitivity and 86% specificity) has been obtained when using order model and first coefficient of AR model, and mean of breathing duration.

Keywords: -----

Solà, J., Fiz, J.A., Morera, J., Jané, R., (2011). Bayes classification of snoring subjects with and without Sleep Apnea Hypopnea Syndrome, using a Kernel method Engineering in Medicine and Biology Society 33rd Annual International Conference of the IEEE EMBS , IEEE (Boston, USA) Engineering in Medicine and Biology Society, 6071-6074

The gold standard for diagnosing Sleep Apnea Hypopnea Syndrome (SAHS) is the Polysomnography (PSG), an expensive, labor-intensive and time-consuming procedure. It would be helpful to have a simple screening method that allowed to early determining the severity of a subject prior to his/her enrolment for a PSG. Several differences have been reported in the acoustic snoring characteristics between simple snorers and SAHS patients. Previous studies usually classify snoring subjects into two groups given a threshold of Apnea-Hypoapnea Index (AHI). Recently, Bayes multi-group classification with Gaussian Probability Density Function (PDF) has been proposed, using snore features in combination with apnea-related information. In this work we show that the Bayes classifier with Kernel PDF estimation outperforms the Gaussian approach and allows the classification of SAHS subjects according to their severity, using only the information obtained from snores. This could be the base of a single

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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.

Keywords: Biomedical equipment, Diseases, Nanotechnology

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

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

Keywords: Sensors, Inference mechanisms, Probability, Simulation

del Moral Zamora, B., Colomer, J., Mir, M., Homs, A., Miribel, P., Samitier, J., (2011). Combined impedance and dielectrophoresis portable device for point-of-care analysis Proceedings SPIE Bioelectronics, Biomedical, and Bioinspired Systems V; and Nanotechnology V , SPIE (Prague, Czech Republic) 8068, 80680T (19)

In the 90s, efforts arise in the scientific world to automate and integrate one or several laboratory applications in tinny devices by using microfluidic principles and fabrication technologies used mainly in the microelectronics field. It showed to be a valid method to obtain better reactions efficiency, shorter analysis times, and lower reagents consumption over existing analytical techniques. Traditionally, these fluidic microsystems able to realize laboratory essays are known as Lab-On-a-Chip (LOC) devices. The capability to transport cells, bacteria or biomolecules in an aqueous medium has significant potential for these microdevices, also known as micro-Total-Analysis Systems (uTAS) when their application is of analytical nature. In particular, the technique of dielectrophoresis (DEP) opened the possibility to manipulate, actuate or transport such biological particles being of great potential in medical diagnostics, environmental control or food processing. This technique consists on applying amplitude and frequency controlled AC signal to a given microsystem in order to manipulate or sort cells. Furthermore, the combination of this technique with electrical impedance measurements, at a single or multiple frequencies, is of great importance to achieve novel reliable diagnostic devices. This is because the sorting and manipulating mechanism can be easily combined with a fully characterizing method able to discriminate cells. The paper is focused in the electronics design of the quadrature DEP generator and the four-electrode impedance measurement modules. These together with the lab-on-a-chip device define a full conception of an envisaged Point-of-Care (POC) device.

Morgenstern, C., Schwaibold, M., Randerath, W., Bolz, A., Jané, R., (2011). Comparison of upper airway respiratory resistance measurements with the esophageal pressure/airflow relationship during sleep Engineering in Medicine and Biology Society 33rd Annual International Conference of the IEEE EMBS , IEEE (Boston, USA) Engineering in Medicine and Biology Society, 3205-3208

Measurement of upper airway resistance is of interest in sleep disordered breathing to estimate upper airway patency. Resistance is calculated with the airflow and respiratory effort signals. However, there is no consensus on a standard for upper airway resistance measurement. This study proposes a new benchmarking method to objectively compare different upper airway resistance measurement methods by objectively differentiating between breaths with inspiratory flow limitation (high resistance) and non-limited breaths (low resistance). Resistance was measured at peak-Pes, at peak-flow, at the linear portion of a polynomial equation, as an area comparative and as average resistance for an inspiration. A total of 20 patients with systematic, gold-standard esophageal pressure and nasal airflow acquisition were analyzed and 109,955 breaths were automatically extracted and evaluated. Relative resistance values in relationship to a reference resistance value obtained during wakefulness were also analyzed. The peak-Pes measurement method obtained the highest separation index with significant (p < 0.001) differences to the other methods, followed by the area comparative and the peak-flow methods. As expected, average resistances were significantly (p < 0.001) lower for the non-IFL than for the IFL group. Hence, we recommend employing the peak-Pes for accurate upper airway resistance estimation.

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Amigo, L. E., Casals, A., Amat, J., (2011). Design of a 3-DoF joint system with dynamic servo-adaptation in orthotic applications Proceedings 2011 IEEE International Conference on Robotics and Automation (ICRA) , IEEE (Shanghai, China) , 3700-3705

Most exoskeleton designs rely on structures and mechanical joints that do not guarantee the right match between the orthosis and the user. This paper proposes a virtual joint model based on three active degrees of freedom aimed to emulate a human joint. This joint is capable of performing a dynamic servo-adaptation in real-time to avoid misalignments and to provide a flexible adjustment to different users' sizes in order to avoid undesirable interaction forces.

Keywords: Actuators, Elbow, Exoskeletons, Joints, Knee, Medical treatment

Punter-Villagrasa, J., Colomer-Farrarons, J., Miribel-Catala, P., Puig-Vidal, M., Samitier, J., (2011). Discrete to full custom ASIC solutions for bioelectronic applications Proceedings of the SPIE - The International Society for Optical Engineering VLSI Circuits and Systems V , SPIE - The International Society for Optical Engineering (Prague, Czech Republic) 8067, 80670Q

This paper presents a first approach on multi-pathogen detection system for portable point-of-care applications on discrete electronics field. The main interest is focused on the development of custom built electronic solutions for bioelectronics applications, from discrete devices to ASICS solutions.

Keywords: Application specific integrated circuits, Biomedical electronics, Biosensors

Sarlabous, L., Torres, A., Fiz, J.A., Gea, J., Martinez-Llorens, J.M., Morera, J., Jané, R. , (2011). Evaluation of the respiratory muscles efficiency during an incremental flow respiratory test Engineering in Medicine and Biology Society 33rd Annual International Conference of the IEEE EMBS , IEEE (Boston, USA) Engineering in Medicine and Biology Society, 3820-3823

The aim of this study was to evaluate the respiratory muscles efficiency during a progressive incremental flow (IF) respiratory test in healthy and Chronic Obstructive Pulmonary Disease (COPD) subjects. To achieve this, the relationship between mouth Inspiratory Pressure (IP) increment, which is a measure of the force produced by respiratory muscles, and respiratory muscular activity increment, evaluated by means of Mechanomyografic (MMG) signals of the diaphragm muscle, was analyzed. Moreover, the correlation between the respiratory efficiency measure and the obstruction severity of the subjects was also examined. Data from two groups of subjects were analyzed. One group consisted of four female subjects (two healthy subjects and two moderate COPD patients) and the other consisted of ten male subjects (six severe and four very severe COPD patients). All subjects performed an easy IF respiratory test, in which small IP values were reached. We have found that there is an increase of amplitude and a displacement towards low frequencies in the MMG signals when the IP increases. Furthermore, it has also been found that respiratory muscles efficiency is lower when greater the obstructive severity of the patients is, and it is lower in women than in men. These results suggest that the information provided by MMG signals could be used to evaluate the muscular efficiency in healthy and COPD subjects.

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Ziyatdinov, Andrey, Fernandez-Diaz, Eduard, Chaudry, A., Marco, Santiago, Persaud, Krishna, Perera, Alexandre, (2011). A large scale virtual gas sensor array Olfaction and Electronic Nose: Proceedings of the 14th International Symposium on Olfaction and Electronic Nose AIP Conference Proceedings (ed. Perena Gouma, SUNY Stony Brook), AIP (New York City, USA) 1362, (1), 151-152

This paper depicts a virtual sensor array that allows the user to generate gas sensor synthetic data while controlling a wide variety of the characteristics of the sensor array response: arbitrary number of sensors, support for multi-component gas mixtures and full control of the noise in the system such as sensor drift or sensor aging. The artificial sensor array response is inspired on the response of 17 polymeric sensors for three analytes during 7 month. The main trends in the synthetic gas sensor array, such as sensitivity, diversity, drift and sensor noise, are user controlled. Sensor sensitivity is modeled by an optionally linear or nonlinear method (spline based). The toolbox on data generation is implemented in open source R language for statistical computing and can be freely accessed as an educational resource or benchmarking reference. The software package permits the design of scenarios with a very large number of sensors (over 10000 sensels), which are employed in the test and benchmarking of neuromorphic models in the Bio-ICT European project NEUROCHEM.

Keywords: Data analysis, Circuit noise, Data acquisition, Signal processing

Colomer-Farrarons, Jordi , Miribel-Català, Pedro Luís, Samitier, Josep , (2011). Low-voltage µpower CMOS subcutaneous biomedical implantable device for true/false applications Biomedical Engineering IASTED International Conference Biomedical Engineering (Biomed 2011) (ed. Baumgartner, C.), ACTA Press (Innsbruck, Austria) Biomedical Engineering, 424-428

A ±1.2V / 350μW integrated front-end architecture for a true/false in-vivo subcutaneous detection device is presented. The detection is focused on using three electrodes amperometric sensors. The powering and AM transcutaneous communication are based on an inductively coupled link working at 13.56 MHz. A prototype device (5.5 mm x 29.5 mm) has been implemented and fully validated.

Keywords: Implantable Device, Front-End architecture, Bioelectronics, Microelectronics Design, Biosensors

Pairo, Erola, Maynou, Joan, Vallverdu, Montserrat, Caminal, Pere, Marco, Santiago, Perera, Alexandre, (2011). MEET: Motif elements estimation toolkit Engineering in Medicine and Biology Society (EMBC) 33rd Annual International Conference of the IEEE , IEEE (Boston, USA) , 6483-6486

MEET is an R package that integrates a set of algorithms for the detection of transcription factor binding sites (TFBS). The MEET R package includes five motif searching algorithms: MEME/MAST(Multiple Expectation-Maximization for Motif Elicitation), Q-residuals, MDscan (Motif Discovery scan), ITEME (Information Theory Elements for Motif Estimation) and MATCH. In addition MEET allows the user to work with different alignment algorithms: MUSCLE (Multiple Sequence Comparison by Log-Expectation), ClustalW and MEME. The package can work in two modes, training and detection. The training mode allows the user to choose the best parameters of a detector. Once the parameters are chosen, the detection mode allows to analyze a genome looking for binding sites. Both modes can combine the different alignment and detection methods, offering multiple possibilities. Combining the alignments and the detection algorithms makes possible the comparison between detection models at the same level, without having to care about the differences produced during the alignment process. The MEET R package can be downloaded from tar.gz

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Mesquita, J., Fiz, J.A., Solà, J., Morera, J., Jané, R., (2011). Normal non-regular snores as a tool for screening SAHS severity Engineering in Medicine and Biology Society 33rd Annual International Conference of the IEEE EMBS , IEEE (Boston, USA) Engineering in Medicine and Biology Society, 3197-3200

Snoring is one of the earliest and most consistent sign of upper airway obstruction leading to Sleep Apnea-Hypopnea Syndrome (SAHS). Several studies on post-apneic snores, snores that are emitted immediately after an apnea, have already proven that this type of snoring is most distinct from that of normal snoring. However, post-apneic snores are more unlikely and sometimes even inexistent in simple snorers and mild SAHS subjects. In this work we address that issue by proposing the study of normal non-regular snores. They correspond to successive snores that are separated by normal breathing cycles. The results obtained establish the feasibility of acoustic parameters of normal non-regular snores as a promising tool for a prompt screening of SAHS severity.

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Ziyatdinov, Andrey, Calvo, Jose Maria Blanco, Lechon, Miguel, Bermudez i Badia, Sergi, Verschure, Paul F. M. J., Marco, Santiago, Perera, Alexandre, (2011). Odour mapping under strong backgrounds with a metal oxide sensor array Olfaction and Electronic Nose: Proceedings of the 14th International Symposium on Olfaction and Electronic Nose AIP Conference Proceedings (ed. Perena Gouma, SUNY Stony Brook), AIP (New York City, USA) 1362, (1), 232-233

This work describes the data from navigation experiments with the mobile robot, equipped with the sensor array of three MOX gas sensors. Performed four series of measurements aim to explore the capabilities of sensor array to build the odour map with one or two odour sources in the wind tunnel space. It was demonstrated that the method based on Independent Component Analysis (ICA) is able to discriminate two odour sources, that in future can be used in the surge-and-cast robot navigation algorithm.

Keywords: Mobile robots, Data acquisition, MIS devices, Chemioception

Arcentales, A., Giraldo, B.F., Caminal, P., Benito, S., Voss, A., (2011). Recurrence quantification analysis of heart rate variability and respiratory flow series in patients on weaning trials Engineering in Medicine and Biology Society 33rd Annual International Conference of the IEEE EMBS , IEEE (Boston, USA) Engineering in Medicine and Biology Society, 2724-2727

Autonomic nervous system regulates the behavior of cardiac and respiratory systems. Its assessment during the ventilator weaning can provide information about physio-pathological imbalances. This work proposes a non linear analysis of the complexity of the heart rate variability (HRV) and breathing duration (TTot) applying recurrence plot (RP) and their interaction joint recurrence plot (JRP). A total of 131 patients on weaning trials from mechanical ventilation were analyzed: 92 patients with successful weaning (group S) and 39 patients that failed to maintain spontaneous breathing (group F). The results show that parameters as determinism (DET), average diagonal line length (L), and entropy (ENTR), are statistically significant with RP for TTot series, but not with HRV. When comparing the groups with JRP, all parameters have been relevant. In all cases, mean values of recurrence quantification analysis are higher in the group S than in the group F. The main differences between groups were found on the diagonal and vertical structures of the joint recurrence plot.

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Marco, Santiago, (2011). Signal processing for chemical sensing: Statistics or biological inspiration Olfaction and Electronic Nose: Proceedings of the 14th International Symposium on Olfaction and Electronic Nose AIP Conference Proceedings (ed. Perena Gouma, SUNY Stony Brook), AIP (New York City, USA) 1362, (1), 145-146

Current analytical instrumentation and continuous sensing can provide huge amounts of data. Automatic signal processing and information evaluation is needed to overcome drowning in data. Today, statistical techniques are typically used to analyse and extract information from continuous signals. However, it is very interesting to note that biology (insects and vertebrates) has found alternative solutions for chemical sensing and information processing. This is a brief introduction to the developments in the European Project: Bio-ICT NEUROCHEM: Biologically Inspired Computation for Chemical Sensing (grant no. 216916) Fp7 project devoted to biomimetic olfactory systems.

Keywords: Signal processing, Chemioception, Neural nets, Computational complexity

Jané, R., Fiz, J.A., Solà, J., Mesquita, J., Morera, J., (2011). Snoring analysis for the screening of sleep apnea hypopnea syndrome with a single-channel device developed using polysomnographic and snoring databases Engineering in Medicine and Biology Society 33rd Annual International Conference of the IEEE EMBS , IEEE (Boston, USA) Engineering in Medicine and Biology Society, 8331-8333

Several studies have shown differences in acoustic snoring characteristics between patients with Sleep Apnea-Hypopnea Syndrome (SAHS) and simple snorers. Usually a few manually isolated snores are analyzed, with an emphasis on postapneic snores in SAHS patients. Automatic analysis of snores can provide objective information over a longer period of sleep. Although some snore detection methods have recently been proposed, they have not yet been applied to full-night analysis devices for screening purposes. We used a new automatic snoring detection and analysis system to monitor snoring during full-night studies to assess whether the acoustic characteristics of snores differ in relation to the Apnea-Hypopnea Index (AHI) and to classify snoring subjects according to their AHI. A complete procedure for device development was designed, using databases with polysomnography (PSG) and snoring signals. This included annotation of many types of episodes by an expert physician: snores, inspiration and exhalation breath sounds, speech and noise artifacts, The AHI of each subject was estimated with classical PSG analysis, as a gold standard. The system was able to correctly classify 77% of subjects in 4 severity levels, based on snoring analysis and sound-based apnea detection. The sensitivity and specificity of the system, to identify healthy subjects from pathologic patients (mild to severe SAHS), were 83% and 100%, respectively. Besides, the Apnea Index (AI) obtained with the system correlated with the obtained by PSG or Respiratory Polygraphy (RP) (r=0.87, p<0.05).

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Gutierrez-Galvez, Agustin, Fernandez, Luis, Marco, Santiago, (2011). Study of sensory diversity and redundancy to encode for chemical mixtures Olfaction and Electronic Nose: Proceedings of the 14th International Symposium on Olfaction and Electronic Nose AIP Conference Proceedings (ed. Perena Gouma, SUNY Stony Brook), AIP (New York City, USA) 1362, (1), 147-148

Inspired by sensory diversity and redundancy at the olfactory epithelium, we have built a large chemical sensor array based on commercial MOX sensors. Different sensor families along with temperature modulation accounts for sensory diversity, whereas sensors of the same family combined with different load resistors provide redundancy to the system. To study the encoding of odor mixtures, a data collection consisting on the response of the array to 3 binary mixtures of ethanol, acetone, and butanone with 18 different concentration ratios is obtained.

Keywords: Chemioception, Sensors, Data acquisition, Temperature measurement

Vaca, R., Aranda, J., Amat, J., Casals, A., (2011). Safe human-robot co-manipulation in assisted robotic surgery International Journal of Computer Assisted Radiology and Surgery Computer Assisted Radiology and Surgery (CARS) , Springer (Berlin, Germany) 6, S281

Mir, M., (2011). Aptamers: The new biorecognition element for proteomic biosensing Biochemistry Research Updates (ed. Baginski, Simon J.), Nova Science Publishers, Inc (Hauppauge, USA) , -----

Aptamers are single stranded artificial nucleic acid ligands that can be generated against almost any kind of target, such as ions, metabolites aminoacids, drugs, toxins, proteins or whole cells. They are isolated from combinatorial libraries of synthetic nucleic acids by an iterative process of adsorption, recovery and amplification, know as SELEX (Systematic Evolution of Ligands by EXponential enrichment) process. Aptamers, the nucleic acid equivalent to antibodies, are easy to synthesise, is not required the use of animals for its synthesis, for this reason it can be developed again toxins and small molecules that do not produce immune response in animals and can be tuned for affinity in closer to assay conditions permitting recognition out of the physiological state. So, aptamers posses numerous advantages that make them preferred candidates as biorecognition elements. In view of the advantages and simple structure of aptamers, they have been used in a wide range of applications such as therapeutics, diagnosis, chromatography, environmental detection, among other.

Keywords: Aptamers, Biosensors, Protein recognition

Serra, T., Navarro, M., Planell, J., (2011). Fabrication and characterization of biodegradable composite scaffolds for tissue engineering Innovative developments in virtual and physical prototyping: Proceedings of the 5th international conference on advanced research in virtual and rapid prototyping (ed. Bartolo, P.J.), CRC Press (Leira, Portugal) Biomanufacturing, 67

Innovative Developments in Virtual and Physical Prototyping presents essential research in the area of Virtual and Rapid Prototyping. The volume contains reviewed papers presented at the 5th International Conference on Advanced Research in Virtual and Rapid Prototyping, hosted by the Centre for Rapid and Sustainable Product Development of the Polytechnic Institute of Leiria, Portugal, from September 28 to October 1, 2011. A wide range of topics is covered, such as CAD and 3D Data Acquisition Technologies, Additive and Nano Manufacturing Technologies, Rapid Tooling & Manufacturing, Biomanufacturing, Materials for Advanced Manufacturing Processes, Virtual Environments and Simulation, Applications of Virtual and Physical Prototyping Technologies. Innovative Developments in Virtual and Physical Prototyping is intended for engineers, designers and manufacturers who are active in the areas of mechanical, industrial and biomedical engineering.

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Mateos-Timoneda, M. A., Planell, J. A., Engel, E., (2011). Modifying biomaterial surfaces for the repair and regeneration of nerve cells Surface Modification of Biomaterials: Methods Analysis and Applications (ed. Williams, R.), Woodhead Publishing (Cambridge, UK) , 325-343

This chapter discusses the use of chemical and topographical modification of biomaterials in the field of repair and regeneration of nerve tissue. The chapter first reviews briefly the methods developed to chemically and topographically modify the surface of biomaterials. The chapter then discusses how these modified surfaces interact with nerve cells and guide cellular activities.

Keywords: Chemical modification, Nerve repair, Topographical modification

van Zanten, Thomas S., Garcia-Parajo, Maria F., (2011). Near-field scanning optical microscopy of biological membranes Life at the Nanoscale: Atomic Force Microscopy of Live Cells (ed. Dufrene, Y.), Pan Stanford Publishing Pte Ltd. (Singapore) , 185-207

The nanoscale analysis of living cells using atomic force microscopy (AFM)-based techniques is an exciting, rapidly evolving research field. During the past years, there has been tremendous progress in using AFM to observe cell surfaces at high resolution, to study cellular mechanics, to localize cell surface receptors, and to measure the forces involved in cellular interactions. This timely book provides a comprehensive overview of the use of AFM and related scanning probe microscopies for cell surface analysis, from the basics to the applications. The book will appeal to anyone involved in cell biology, microbiology, biophysics, biochemistry, or nanobiosciences. It covers all cell types, from viruses and protoplasts to bacteria and animal cells, and discusses a range of advanced AFM modalities, including high-resolution imaging, nanoindentation measurements, recognition imaging, as well as single-molecule and single-cell force spectroscopy. The different chapters are authored by cutting-edge experts, each representing his or her specialized areas. Each chapter covers methodologies for sample preparation and analysis, and highlights recent examples to illustrate the power of AFM techniques in life sciences and nanomedicine.

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Gorostiza, P., Isacoff, E.Y., (2011). Photoswitchable ligand-gated ion channels Photosensitive molecules for controlling biological function (ed. Chambers, J. J. , Kramer, R. H.), Springer (Saskatoon, Canada) 55, 267-285

Ligand-activated proteins can be controlled with light by means of synthetic photoisomerizable tethered ligands (PTLs). The application of PTLs to ligand-gated ion channels, including the nicotinic acetylcholine receptor and ionotropic glutamate receptors, is reviewed with emphasis on rational photoswitch design and the mechanisms of optical switching. Recently reported molecular dynamic methods allow simulation with high reliability of novel PTLs for any ligand-activated protein whose structure is known.

Keywords: Nicotinic acetylcholine receptor, Kainate receptor, Glutamate receptor, Photoisomerizable tether ligand (PTL), Optical switch, Nanotoggle, Azobenzene, Neurobiology,, Nanoengineering, Nanomedicine

Colomer-Farrarons, Jordi, Miribel-Català, Pere LI., Rodríguez-Villarreal, A. Ivón, Samitier, Josep, (2011). Portable bio-devices: Design of electrochemical instruments from miniaturized to implantable devices New perspectives in biosensors technology and applications (ed. Andrea Serra, Pier), InTech (Rijeka, Croatia) Biomedical Engineering, 373-400

A biosensor is a detecting device that combines a transducer with a biologically sensitive and selective component. Biosensors can measure compounds present in the environment, chemical processes, food and human body at low cost if compared with traditional analytical techniques. This book covers a wide range of aspects and issues related to biosensor technology, bringing together researchers from 12 different countries. The book consists of 20 chapters written by 69 authors and divided in three sections: Biosensors Technology and Materials, Biosensors for Health and Biosensors for Environment and Biosecurity.

Keywords: Bio-Devices, Electrochemical Instruments, Miniaturized Devices, Nanobiosensor

Martinez, Elena, Samitier, Josep, (2011). Soft lithography and variants Generating micro- and nanopatterns on polymeric materials (ed. del Campo, Aranzazu , Arzt, Eduard), Wiley-VCH Verlag GmbH&Co (Weinheim) , 57-66

Martí, E., Pantano, L., Bañez-Coronel, M., Llorens, F., Miñones-Moyano, E., Porta, S., Sumoy, L., Ferrer, Isidro, Estivill, X., (2010). A myriad of miRNA variants in control and Huntington's disease brain regions detected by massively parallel sequencing Nucleic Acids Research , 38, (20), 7219-7235

Huntington disease (HD) is a neurodegenerative disorder that predominantly affects neurons of the forebrain. We have applied the Illumina massively parallel sequencing to deeply analyze the small RNA populations of two different forebrain areas, the frontal cortex (FC) and the striatum (ST) of healthy individuals and individuals with HD. More than 80% of the small-RNAs were annotated as microRNAs (miRNAs) in all samples. Deep sequencing revealed length and sequence heterogeneity (IsomiRs) for the vast majority of miRNAs. Around 80–90% of the miRNAs presented modifications in the 3′-terminus mainly in the form of trimming and/or as nucleotide addition variants, while the 5′-terminus of the miRNAs was specially protected from changes. Expression profiling showed strong miRNA and isomiR expression deregulation in HD, most being common to both FC and ST. The analysis of the upstream regulatory regions in co-regulated miRNAs suggests a role for RE1-Silencing Transcription Factor (REST) and P53 in miRNAs downregulation in HD. The putative targets of deregulated miRNAs and seed-region IsomiRs strongly suggest that their altered expression contributes to the aberrant gene expression in HD. Our results show that miRNA variability is a ubiquitous phenomenon in the adult human brain, which may influence gene expression in physiological and pathological conditions.

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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.

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

Sisquella, X., de Pourcq, K., Alguacil, J., Robles, J., Sanz, F., Anselmetti, D., Imperial, S., Fernàndez-Busquets, X., (2010). A single-molecule force spectroscopy nanosensor for the identification of new antibiotics and antimalarials FASEB Journal , 24, (11), 4203-4217

An important goal of nanotechnology is the application of individual molecule handling techniques to the discovery of potential new therapeutic agents. Of particular interest is the search for new inhibitors of metabolic routes exclusive of human pathogens, such as the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway essential for the viability of most human pathogenic bacteria and of the malaria parasite. Using atomic force microscopy single-molecule force spectroscopy (SMFS), we have probed at the single-molecule level the interaction of 1-deoxy-D-xylulose 5-phosphate synthase (DXS), which catalyzes the first step of the MEP pathway, with its two substrates, pyruvate and glyceraldehyde-3-phosphate. The data obtained in this pioneering SMFS analysis of a bisubstrate enzymatic reaction illustrate the substrate sequentiality in DXS activity and allow for the calculation of catalytic parameters with single-molecule resolution. The DXS inhibitor fluoropyruvate has been detected in our SMFS competition experiments at a concentration of 10 mu M, improving by 2 orders of magnitude the sensitivity of conventional enzyme activity assays. The binding of DXS to pyruvate is a 2-step process with dissociation constants of k(off) = 6.1 x 10(-4) +/- 7.5 x 10(-3) and 1.3 x 10(-2) +/- 1.0 x 10(-2) s(-1), and reaction lengths of x(beta) = 3.98 +/- 0.33 and 0.52 +/- 0.23 angstrom. These results constitute the first quantitative report on the use of nanotechnology for the biodiscovery of new antimalarial enzyme inhibitors and open the field for the identification of compounds represented only by a few dozens of molecules in the sensor chamber.

Keywords: Malaria, 2-C-methyl-D-erythritol-4-phosphate pathway, 1-deoxy-D-xylulose 5-phosphate synthase, Pyruvate, Glyceraldehyde-3-phosphate, Drug discovery

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

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

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

Sabaté, R., Espargaró, A., de Groot, N. S., Valle-Delgado, J. J., Fernàndez-Busquets, X., Ventura, S., (2010). The role of protein sequence and amino acid composition in amyloid formation: Scrambling and backward reading of IAPP amyloid fibrils Journal of Molecular Biology , 404, (2), 337-352

The specific functional structure of natural proteins is determined by the way in which amino acids are sequentially connected in the polypeptide. The tight sequence/structure relationship governing protein folding does not seem to apply to amyloid fibril formation because many proteins without any sequence relationship have been shown to assemble into very similar β-sheet-enriched structures. Here, we have characterized the aggregation kinetics, seeding ability, morphology, conformation, stability, and toxicity of amyloid fibrils formed by a 20-residue domain of the islet amyloid polypeptide (IAPP), as well as of a backward and scrambled version of this peptide. The three IAPP peptides readily aggregate into ordered, β-sheet-enriched, amyloid-like fibrils. However, the mechanism of formation and the structural and functional properties of aggregates formed from these three peptides are different in such a way that they do not cross-seed each other despite sharing a common amino acid composition. The results confirm that, as for globular proteins, highly specific polypeptide sequential traits govern the assembly pathway, final fine structure, and cytotoxic properties of amyloid conformations.

Keywords: Amyloid formation, Islet amyloid polypeptide, Protein aggregation, Protein sequence, Retro proteins

Salleras, M., Carmona, M., Marco, S., (2010). Issues in the use of thermal transients to achieve accurate time-constant spectrums and differential structure functions IEEE Transactions on Advanced Packaging , 33, (4), 918-923

An analysis of accuracy of time-constant spectrum extraction from thermal transients has been performed. Numerical calculations based on analytical models and finite element method simulations have been used in order to obtain the thermal transients. Simple geometries have been used such that analytical expressions for their time-constant spectrums are known. Results show that a large error in the time-constant spectrum is obtained for very small rms error ( 1 mK) in the thermal transient. The estimation problem is ill-conditioned. Moreover, the differential structure function shows a low accuracy identifying stacked structures. The initial part of the differential structure function shows numerical oscillations and the final part has an asymptotic behavior to infinity that has been identified as an artifact related to errors in the time-constant spectrum estimation. Peak identification from the differential structure function heavily depends on an accurate determination of the time-constant spectrum. The limited spectral resolution and dynamic range of the differential structure function are a direct consequence of the time-constant spectrum imprecision.

Keywords: Finite element analysis, Spectral analysis

Mateos-Timoneda, M. A., Engel, Elisabeth, (2010). Modifying biomaterial surfaces for the repair and regeneration of nerve cells Surface modification of biomaterials: Methods analysis and applications (ed. Williams, R.), Woodhead Publishing Ltd (Cambridge, UK) Part 2: Analytica Techniques and Applications, 325-343

The surface modification of biomaterials plays a significant role in determining the outcome of biological-material interactions. With the appropriate modification a material's surface can be tailored to improve biocompatibility, adhesion and cell interactions. Consequently surface modification is vital in the development and design of new biomaterials and medical devices. Surface modification of biomaterials reviews both established surface modifications and those still in the early stages of research and discusses how they can be used to optimise biological interactions and enhance clinical performance. Part one begins with chapters looking at various types and techniques of surface modification including plasma polymerisation, covalent binding of poly (ethylene glycol) (PEG), heparinisation, peptide functionalisation and calcium phosphate deposition before going on to examine metal surface oxidation and biomaterial surface topography to control cellular response with particular reference to technologies, cell behaviour and biomedical applications. Part two studies the analytical techniques and applications of surface modification with chapters on analysing biomaterial surface chemistry, surface structure, morphology and topography before moving onto discuss modifying biomaterial surfaces to optimise interactions with blood, control infection, optimise interactions with soft tissues, repair and regenerate nerve cells, control stem cell growth and differentiation and to optimise interactions with bone. The distinguished editor and international team of contributors to Surface modification of biomaterials have produced a unique overview and detailed chapters on a range of surface modification techniques which will provide an excellent resource for biomaterials researchers and scientists and engineers concerned with improving the properties of biomaterials. It will also be beneficial for academics researching surface modification.

Keywords: -----

Fernàndez-Busquets, X., Körnig, A., Bucior, I., Burger, M. M., Anselmetti, D., (2009). Self-recognition and Ca2+-dependent carbohydrate-carbohydrate cell adhesion provide clues to the cambrian explosion Molecular Biology and Evolution , 26, (11), 2551-2561

The Cambrian explosion of life was a relatively short period approximately 540 Ma that marked a generalized acceleration in the evolution of most animal phyla, but the trigger of this key biological event remains elusive. Sponges are the oldest extant Precambrian metazoan phylum and thus a valid model to study factors that could have unleashed the rise of multicellular animals. One such factor is the advent of self-/non-self-recognition systems, which would be evolutionarily beneficial to organisms to prevent germ-cell parasitism or the introduction of deleterious mutations resulting from fusion with genetically different individuals. However, the molecules responsible for allorecognition probably evolved gradually before the Cambrian period, and some other (external) factor remains to be identified as the missing triggering event. Sponge cells associate through calcium-dependent, multivalent carbohydrate-carbohydrate interactions of the g200 glycan found on extracellular proteoglycans. Single molecule force spectroscopy analysis of g200-g200 binding indicates that calcium affects the lifetime (+Ca/-Ca: 680 s/3 s) and bond reaction length (+Ca/-Ca: 3.47 /2.27). Calculation of mean g200 dissociation times in low and high calcium within the theoretical framework of a cooperative binding model indicates the nonlinear and divergent characteristics leading to either disaggregated cells or stable multicellular assemblies, respectively. This fundamental phenomenon can explain a switch from weak to strong adhesion between primitive metazoan cells caused by the well-documented rise in ocean calcium levels at the end of Precambrian time. We propose that stronger cell adhesion allowed the integrity of genetically uniform animals composed only of "self" cells, facilitating genetic constitutions to remain within the metazoan individual and be passed down inheritance lines. The Cambrian explosion might have been triggered by the coincidence in time of primitive animals endowed with self-/non-self-recognition and of a surge in seawater calcium that increased the binding forces between their calcium-dependent cell adhesion molecules.

Keywords: Calcium, Cambrian explosion, Carbohydrates, Cell adhesion, Origin of Metazoa, Sponges

van Zanten, T. S., Cambi, A., Koopman, M., Joosten, B., Figdor, Carl G., Garcia-Parajo, M. F., (2009). Hotspots of GPI-anchored proteins and integrin nanoclusters function as nucleation sites for cell adhesion Proceedings of the National Academy of Sciences of the United States of America 106, (44), 18557-18562

Recruitment of receptor proteins to lipid rafts has been proposed as an important mechanism to regulate their cellular function. In particular, rafts have been implicated in regulation of integrin-mediated cell adhesion, although the underlying mechanism remains elusive. We used single-molecule near-field optical microscopy (NSOM) with localization accuracy of approximately 3 nm, to capture the spatio-functional relationship between the integrin LFA-1 and raft components (GPI-APs) on immune cells. Dual color nanoscale imaging revealed the existence of a nanodomain GPI-AP subpopulation that further concentrated in regions smaller than 250 nm, suggesting a hierarchical prearrangement of GPI-APs on resting monocytes. We previously demonstrated that in quiescent monocytes, LFA-1 preorganizes in nanoclusters. We now show that integrin nanoclusters are spatially different but reside proximal to GPI-AP nanodomains, forming hotspots on the cell surface. Ligand-mediated integrin activation resulted in an interconversion from monomers to nanodomains of GPI-APs and the generation of nascent adhesion sites where integrin and GPI-APs colocalized at the nanoscale. Cholesterol depletion significantly affected the reciprocal distribution pattern of LFA-1 and GPI-APs in the resting state, and LFA-1 adhesion to its ligand. As such, our data demonstrate the existence of nanoplatforms as essential intermediates in nascent cell adhesion. Since raft association with a variety of membrane proteins other than LFA-1 has been documented, we propose that hotspots regions enriched with raft components and functional receptors may constitute a prototype of nanoscale inter-receptor assembly and correspond to a generic mechanism to offer cells with privileged areas for rapid cellular function and responses to the outside world.

Keywords: Integrin LFA-1, Membrane nanocompartments, Near-field scanning optical microscopy (NSOM), Single molecule detection

Arteaga, O., Escudero, C., Oncins, G., El-Hachemic, Z., Llorens, J., Crusats, J., Canillas, A., Ribo, J. M., (2009). Reversible mechanical induction of optical activity in solutions of soft-matter nanophases Chemistry - An Asian Journal , 4, (11), 1687-1696

Nanophases of J-aggregates of several achiral amphiphilic porphyrins, which have thin long acicular shapes (nanoribbons), show the immediate and reversible formation of a stationary mechano-chiral state in the solution by vortex stirring, as detected by their circular dichroic signals measured by 2-modulator generallized ellipsometry. The results suggest that when a macroscopic chiral force creates supramolecular chirality, it also creates an enantiomeric excess of screw distortions, which may be detected by their excitonic absorption. An explanation on the effect of the shear flow gradients is proposed on the basis of the orientation of the rotating particles in the vortex and the size, shape, and mechanical properties of the nanoparticles.

Keywords: Chirality, Circular dichroism, Nanoparticles, Selfassembly, Supramolecular chemistry

Malandrino, A., Planell, J. A., Lacroix, D., (2009). Statistical factorial analysis on the poroelastic material properties sensitivity of the lumbar intervertebral disc under compression, flexion and axial rotation Journal of Biomechanics 42, (16), 2780-2788

A statistical factorial analysis approach was conducted on a poroelastic finite element model of a lumbar intervertebral disc to analyse the influence of six material parameters (permeabilities of annulus, nucleus, trabecular vertebral bone, cartilage endplate and Young's moduli of annulus and nucleus) on the displacement, fluid pore pressure and velocity fields. Three different loading modes were investigated: compression, flexion and axial rotation. Parameters were varied considering low and high levels in agreement with values found in the literature for both healthy and degenerated lumbar discs. Results indicated that annulus stiffness and cartilage endplate permeability have a strong effect on the overall fluid- and solid-phase responses in all loading conditions studied. Nucleus stiffness showed its main relevance in compression while annulus permeability influenced mainly the annular pressure field. This study confirms the permeability's central role in biphasic modelling and highlights for the lumbar disc which experiments of material property characterization should be performed. Moreover, such sensitivity study gives important guidelines in poroelastic material modelling and finite element disc validation.

Keywords: Intervertebral disc, Permeability, Fractional factorial design, Design of experiments, Finite element analysis

Caballero, D., Samitier, J., Errachid, A., (2009). Submerged nanocontact printing (SnCP) of thiols Journal of Nanoscience and Nanotechnology , 9, (11), 6478-6482

Biological patterned surfaces having sub-micron scale resolution are of great importance in many fields of life science and biomedicine. Different techniques have been proposed for surface patterning at the nanoscale. However, most of them present some limitations regarding the patterned area size or are time-consuming. Micro/nanocontact printing is the most representative soft lithography-based technique for surface patterning at the nanoscale. Unfortunately, conventional micro/nanocontact printing also suffers from problems such as diffusion and stamp collapsing that limit pattern resolution. To overcome these problems, a simple way of patterning thiols under liquid media using submerged nanocontact printing (SnCP) over large areas (similar to cm(2)) achieving nanosize resolution is presented. The technique is also low cost and any special equipment neither laboratory conditions are required. Nanostructured poly(dimethyl siloxane) stamps are replicated from commercially available digital video disks. SnCP is used to stamp patterns of 200 nm 1-octadecanethiol lines in liquid media, avoiding ink diffusion and stamp collapsing, over large areas on gold substrates compared with conventional procedures. Atomic force microscopy measurements reveal that the patterns have been successfully transferred with high fidelity. This is an easy, direct, effective and low cost methodology for molecule patterning immobilization which is of interest in those areas that require nanoscale structures over large areas, such as tissue engineering or biosensor applications.

Keywords: Submerged Nanocontact Printing, Replica Molding, Nanopatterning, Large Area, Dip-pen nanolithography, High-aspect-ratio, Soft lithography, Submicronscale, Nanoimprint lithography, Thin-film, Surfaces, Fabrication, Proteins, Nanofabrication

Colomer-Farrarons, J., Miribel-Catala , P., Saiz-Vela, A., Samitier, J., (2009). A 60 uW low-power low-voltage power management unit for a self-powered system based on low-cost piezoelectric powering generators Proceedings of the 35th European Solid-State Circuits Conference. ESSCIRC 2009 35th European Solid-State Circuits Conference. ESSCIRC 2009 (ed. Tsoukalas, D., Papananos, Y.), IEEE (Athens, Greece) , 280-283

This paper presents the architecture of a novel implementation of an integrated self-powered system based on piezoelectric vibrations in a 0.13Îum technology. The electromechanical transduction is performed by using a low-cost commercial piezoelectric, working at low frequencies, with voltages up to 2.5V. The system is conceived as a System In a Package (SiP). The full integrated system is adapted to work with low-voltage and low-power conditions. The full custom power management circuit is used to charge a storage capacitor (super capacitor), from which the stored energy will be used to power, by controlled cycles of discharge operation of a very low power wireless sensor node that could be used in heavy machinery monitoring. Each circuitry block of the power management circuitry is presented and discussed. The simulated studies are fully validated by experimental tests. The experimental consumption of the power management unit is 67μW, approach to the theoretical expected value of 60ÎuW.

Keywords: -----

Correa, R., Laciar, E., Arini, P., Jané, R., (2009). Analysis of QRS loop changes in the beat-to-beat vectocardiogram of ischemic patients undergoing PTCA Engineering in Medicine and Biology Society (EMBC) 31st Annual International Conference of the IEEE , IEEE (Minneapolis, USA) , 1750-1753

In the present work, we have studied dynamic changes of QRS loop in the Vectocardiogram (VCG) of 80 patients that underwent Percutaneous Transluminal Coronary Angioplasty (PTCA). The VCG was obtained for each patient using the XYZ orthogonal leads of their electrocardiographic (ECG) records acquired before, during and after PTCA procedure. In order to analyze the variations of VCG, it has been proposed in this study the following parameters a) Maximum module of the cardiac depolarization vector, b) Volume, c) and Area of vectocardiographic loop corresponding to the QRS complex of each beat, d) Maximum distance between Centroid and the Loop, e) Angle between the XY plane and the Optimum Plane, f) Relation between the Area and Perimeter. The results obtained indicate that the parameters proposed show significant statistics differences (p-value<0.05) before, during (with some exceptions at the first minute of balloon inflation) and after PTCA. We conclude that the variations observed in the proposed parameters correctly represent not only the morphological changes in the depolarization VCG but also they reflect the modifications in the levels of cardiac ischemia induced by PTCA.

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Diez, P. F., Mut, V., Laciar, E., Torres, A., Avila, E., (2009). Application of the empirical mode decomposition to the extraction of features from EEG signals for mental task classification Engineering in Medicine and Biology Society (EMBC) 31st Annual International Conference of the IEEE , IEEE (Minneapolis, USA) , 2579-2582

In this work, it is proposed a technique for the feature extraction of electroencephalographic (EEG) signals for classification of mental tasks which is an important part in the development of Brain Computer Interfaces (BCI). The Empirical Mode Decomposition (EMD) is a method capable to process nonstationary and nonlinear signals as the EEG. This technique was applied in EEG signals of 7 subjects performing 5 mental tasks. For each mode obtained from the EMD and each EEG channel were computed six features: Root Mean Square (RMS), Variance, Shannon Entropy, Lempel-Ziv Complexity Value, and Central and Maximum Frequencies, obtaining a feature vector of 180 components. The Wilks' lambda parameter was applied for the selection of the most important variables reducing the dimensionality of the feature vector. The classification of mental tasks was performed using Linear Discriminate Analysis (LD) and Neural Networks (NN). With this method, the average classification over all subjects in database was 91±5% and 87±5% using LD and NN, respectively. It was concluded that the EMD allows getting better performances in the classification of mental tasks than the obtained with other traditional methods, like spectral analysis.

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Morgenstern, C., Schwaibold, M., Randerath, W., Bolz, A., Jané, R., (2009). Automatic differentiation of obstructive and central hypopneas with esophageal pressure measurement during sleep Engineering in Medicine and Biology Society (EMBC) 31st Annual International Conference of the IEEE , IEEE (Minneapolis, USA) 2009, 7102-7105

The differentiation between obstructive and central respiratory events is one of the most recurrent tasks in the diagnosis of sleep disordered breathing. Esophageal pressure measurement is the gold-standard method to assess respiratory effort and identify these events. But as its invasiveness discourages its use in clinical routine, non-invasisve systems have been proposed for differentiation. However, their adoption has been slow due to their limited clinical validation, as the creation of manual, gold-standard validation sets by human experts is a cumbersome procedure. In this study, a new system is proposed for an objective automatic, gold-standard differentiation between obstructive and central hypopneas with the esophageal pressure signal. First, an overall of 356 hypopneas of 16 patients were manually scored by a human expert to create a gold-standard validation set. Then, features were extracted from each hypopnea to train and test classifiers (Discriminant Analysis, Support Vector Machines and adaboost classifiers) to differentiate between central and obstructive hypopneas with the gold-standard esophageal pressure signal. The automatic differentiation system achieved promising results, with a sensitivity of 0.88, a specificity of 0.93 and an accuracy of 0.90. Hence, this system seems promising for an automatic, gold-standard differentiation between obstructive and central hypopneas.

Keywords: -----

Colomer-Farrarons, J., Miribel-Catala , P., Rodriguez, I., Samitier, J., (2009). CMOS front-end architecture for in-vivo biomedical implantable devices 35th Annual Conference of IEEE Industrial Electronics (IECON 2009) 35th Annual Conference of IEEE Industrial Electronics (IECON 2009) , IEEE (Porto, Portugal) , 4401-4408

An integrated front-end architecture for In-Vivo detection is presented. The system is conceived to be implanted under the human skin. The powering and communication between this device and an external primary transmitter are based on an inductive link. The presented architecture is oriented to two different approaches, defining a True/False alarm system, based on amperometric or impedance biosensors. The particular case of the amperometric sensor is used to validate the architecture in terms of different integrated modules fabricated in a 0.13μm technology. A potentiostat amplifier has been integrated to control an amperometric biosensor as well as a current sensing method based on a transimpedance amplifier is used to measure the current. It is also introduced the electronics designed for the bio-impedance case.

Keywords: -----

Garde, A., Sornmo, L., Jané, R., Giraldo, B. F., (2009). Correntropy-based analysis of respiratory patterns in patients with chronic heart failure Engineering in Medicine and Biology Society (EMBC) 31st Annual International Conference of the IEEE , IEEE (Minneapolis, USA) , 4687-4690

A correntropy-based technique is proposed for the analysis and characterization of respiratory flow signals in chronic heart failure (CHF) patients with both periodic and nonperiodic breathing (PB and nPB), and healthy subjects. Correntropy is a novel similarity measure which provides information on temporal structure and statistical distribution simultaneously. Its properties lend itself to the definition of the correntropy spectral density (CSD). An interesting result from CSD-based spectral analysis is that both the respiratory frequency and modulation frequency can be detected at their original positions in the spectrum without prior demodulation of the flow signal. The respiratory pattern is characterized by a number of spectral parameters extracted from the respiratory and modulation frequency bands. The results show that the power of the modulation frequency band offers excellent performance when classifying CHF patients versus healthy subjects, with an accuracy of 95.3%, and nPB patients versus healthy subjects with 90.7%. The ratio between the power in the modulation and respiration frequency bands provides the best results classifying CHF patients into PB and nPB, with an accuracy of 88.9%.

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Arizmendi, C., Romero, E., Alquezar, R., Caminal, P., Díaz, I., Benito, S., Giraldo, B. F., (2009). Data mining of patients on weaning trials from mechanical ventilation using cluster analysis and neural networks Engineering in Medicine and Biology Society (EMBC) 31st Annual International Conference of the IEEE , IEEE (Minneapolis, USA) , 4343-4346

The process of weaning from mechanical ventilation is one of the challenges in intensive care. 149 patients under extubation process (T-tube test) were studied: 88 patients with successful trials (group S), 38 patients who failed to maintain spontaneous breathing and were reconnected (group F), and 23 patients with successful test but that had to be reintubated before 48 hours (group R). Each patient was characterized using 8 time series and 6 statistics extracted from respiratory and cardiac signals. A moving window statistical analysis was applied obtaining for each patient a sequence of patterns of 48 features. Applying a cluster analysis two groups with the majority dataset were obtained. Neural networks were applied to discriminate between patients from groups S, F and R. The best performance obtained was 84.0% of well classified patients using a linear perceptron trained with a feature selection procedure (that selected 19 of the 48 features) and taking as input the main cluster centroid. However, the classification baseline 69.8% could not be improved when using the original set of patterns instead of the centroids to classify the patients.

Orosco, L., Laciar, E., Correa, A. G., Torres, A., Graffigna, J. P., (2009). An epileptic seizures detection algorithm based on the empirical mode decomposition of EEG Engineering in Medicine and Biology Society (EMBC) 31st Annual International Conference of the IEEE , IEEE (Minneapolis, USA) , 2651-2654

Epilepsy is a neurological disorder that affects around 50 million people worldwide. The seizure detection is an important component in the diagnosis of epilepsy. In this study, the Empirical Mode Decomposition (EMD) method was proposed on the development of an automatic epileptic seizure detection algorithm. The algorithm first computes the Intrinsic Mode Functions (IMFs) of EEG records, then calculates the energy of each IMF and performs the detection based on an energy threshold and a minimum duration decision. The algorithm was tested in 9 invasive EEG records provided and validated by the Epilepsy Center of the University Hospital of Freiburg. In 90 segments analyzed (39 with epileptic seizures) the sensitivity and specificity obtained with the method were of 56.41% and 75.86% respectively. It could be concluded that EMD is a promissory method for epileptic seizure detection in EEG records.

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Sarlabous, L., Torres, A., Fiz, J. A., Gea, J., Martinez-Llorens, J. M., Jané, R., (2009). Evaluation of the respiratory muscular function by means of diaphragmatic mechanomyographic signals in COPD patients Engineering in Medicine and Biology Society (EMBC) 31st Annual International Conference of the IEEE , IEEE (Minneapolis, USA) , 3925-3928

The study of mechanomyographic (MMG) signals of respiratory muscles is a promising technique in order to evaluate the respiratory muscular effort. In this work MMG signals from left and right hemidiaphragm (MMGl and MMGr, respectively) acquired during a respiratory protocol have been analyzed. The acquisition of both MMG signals was carried out by means of two capacitive accelerometers placed on both left and right sides of the costal wall. The signals were recorded in a group of six patients with Chronic Obstructive Pulmonary Disease (COPD). It has been observed that with the increase of inspiratory pressure it takes place an increase of the amplitude and a displacement toward low frequencies in both left and right MMG signals. Furthermore, it has been seen that the increase of amplitude and the decrease of frequency in MMG signals are more pronounced in severe COPD patients. This behaviour is similar for both MMGl and MMGr signals. Results suggest that the use of MMG signals could be potentially useful for the evaluation of the respiratory muscular function in COPD patients.

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Otero, J., Puig-Vidal, M., Frigola, M., Casals, A., (2009). Micro-to-nano optical resolution in a multirobot nanobiocharacterization station 2009 IEEE/RSJ International Conference on Intelligent Robots and Systems, IROS 2009 IEEE RSJ International Conference on Intelligent Robots and Systems , IEEE (St. Louis, USA) , 5357-5362

A multi-robot cooperation station for nano-bio characterization of biological specimens is presented. The station is composed of two long travel range and high resolution robots equipped with self-sensing nanoprobes that are able to cooperate with each other and with standard AFM systems, over a common sample. The robots are guided by the use of an upright high-depth-of-field optical microscope to perform complex nano-bio characterization experiments. To achieve the required precision between the two robots reference frames, specific image processing techniques are needed. One of the tips is dedicated to acquire the topography of the sample at nano scale while the second probe performs the biocharacterization experiments. The obtained results show that the two robots can cooperate within the required resolution in bacterial nanomechanical characterization while high resolution topographic images are acquired.

Keywords: AFM

Sarlabous, L., Torres, A., Fiz, J. A., Gea, J., Galdiz, J. B., Jané, R., (2009). Multistate Lempel-Ziv (MLZ) index interpretation as a measure of amplitude and complexity changes Engineering in Medicine and Biology Society (EMBC) 31st Annual International Conference of the IEEE , IEEE (Minneapolis, USA) , 4375-4378

The Lempel-Ziv complexity (LZ) has been widely used to evaluate the randomness of finite sequences. In general, the LZ complexity has been used to determine the complexity grade present in biomedical signals. The LZ complexity is not able to discern between signals with different amplitude variations and similar random components. On the other hand, amplitude parameters, as the root mean square (RMS), are not able to discern between signals with similar power distributions and different random components. In this work, we present a novel method to quantify amplitude and complexity variations in biomedical signals by means of the computation of the LZ coefficient using more than two quantification states, and with thresholds fixed and independent of the dynamic range or standard deviation of the analyzed signal: the Multistate Lempel-Ziv (MLZ) index. Our results indicate that MLZ index with few quantification levels only evaluate the complexity changes of the signal, with high number of levels, the amplitude variations, and with an intermediate number of levels informs about both amplitude and complexity variations. The study performed in diaphragmatic mechanomyographic signals shows that the amplitude variations of this signal are more correlated with the respiratory effort than the complexity variations. Furthermore, it has been observed that the MLZ index with high number of levels practically is not affected by the existence of impulsive, sinusoidal, constant and Gaussian noises compared with the RMS amplitude parameter.

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Correa, L. S., Laciar, E., Mut, V., Torres, A., Jané, R., (2009). Sleep apnea detection based on spectral analysis of three ECG - Derived respiratory signals Engineering in Medicine and Biology Society (EMBC) 31st Annual International Conference of the IEEE , IEEE (Minneapolis, USA) , 4723-4726

An apnea detection method based on spectral analysis was used to assess the performance of three ECG derived respiratory (EDR) signals. They were obtained on R wave area (EDR1), heart rate variability (EDR2) and R peak amplitude (EDR3) of ECG record in 8 patients with sleep apnea syndrome. The mean, central, peak and first quartile frequencies were computed from the spectrum every 1 min for each EDR. For each frequency parameter a threshold-based decision was carried out on every 1 min segment of the three EDR, classifying it as 'apnea' when its frequency value was below a determined threshold or as 'not apnea' in other cases. Results indicated that EDR1, based on R wave area has better performance in detecting apnea episodes with values of specificity (Sp) and sensitivity (Se) near 90%; EDR2 showed similar Sp but lower Se (78%); whereas EDR3 based on R peak amplitude did not detect appropriately the apneas episodes reaching Sp and Se values near 60%.

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Garde, A., Giraldo, B. F., Jané, R., Sornmo, L., (2009). Time-varying respiratory pattern characterization in chronic heart failure patients and healthy subjects Engineering in Medicine and Biology Society (EMBC) 31st Annual International Conference of the IEEE , IEEE (Minneapolis, USA) , 4007-4010

Patients with chronic heart failure (CHF) with periodic breathing (PB) and Cheyne-Stokes respiration (CSR) tend to exhibit higher mortality and poor prognosis. This study proposes the characterization of respiratory patterns in CHF patients and healthy subjects using the envelope of the respiratory flow signal, and autoregressive (AR) time-frequency analysis. In time-varying respiratory patterns, the statistical distribution of the AR coefficients, pole locations, and the spectral parameters that characterize the discriminant band are evaluated to identify typical breathing patterns. In order to evaluate the accuracy of this characterization, a feature selection process followed by linear discriminant analysis is applied. 26 CHF patients (8 patients with PB pattern and 18 with non-periodic breathing pattern (nPB)) are studied. The results show an accuracy of 83.9% with the mean of the main pole magnitude and the mean of the total power, when classifying CHF patients versus healthy subjects, and 83.3% for nPB versus healthy subjects. The best result when classifying CHF patients into PB and nPB was an accuracy of 88.9%, using the coefficient of variation of the first AR coefficient and the mean of the total power.

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Gorostiza, P., Isacoff, E. Y., (2008). Optical switches for remote and noninvasive control of cell signaling Science 322, (5900), 395-399

Although the identity and interactions of signaling proteins have been studied in great detail, the complexity of signaling networks cannot be fully understood without elucidating the timing and location of activity of individual proteins. To do this, one needs a means for detecting and controlling specific signaling events. An attractive approach is to use light, both to report on and control signaling proteins in cells, because light can probe cells in real time with minimal damage. Although optical detection of signaling events has been successful for some time, the development of the means for optical control has accelerated only recently. Of particular interest is the development of chemically engineered proteins that are directly sensitive to light.

Keywords: Ion channels, Acetylcholine receptor, Glutamate-receptor, Potassium channel, K+ channel, Light, Neurons, Channelrhodopsin-2, Manipulation, Activation

Morales, R., Riss, M., Wang, L., Gavin, R., Del Rio, J. A., Alcubilla, R., Claverol-Tinture, E., (2008). Integrating multi-unit electrophysiology and plastic culture dishes for network neuroscience Lab on a Chip 8, (11), 1896-1905

The electrophysiological characterisation of cultured neurons is of paramount importance for drug discovery, safety pharmacology and basic research in the neurosciences. Technologies offering low cost, low technical complexity and potential for scalability towards high-throughput electrophysiology on in vitro neurons would be advantageous, in particular for screening purposes. Here we describe a plastic culture substrate supporting low-complexity multi-unit loose-patch recording and stimulation of developing networks while retaining manufacturability compatible with low-cost and large-scale production. Our hybrid polydimethylsilane (PDMS)-on-polystyrene structures include chambers (6 mm in diameter) and microchannels (25 mu m x 3.7 mu m 1 mm) serving as substrate-embedded recording pipettes. Somas are plated and retained in the chambers due to geometrical constraints and their processes grow along the microchannels, effectively establishing a loose-patch configuration without human intervention. We demonstrate that off-the-shelf voltage-clamp, current-clamp and extracellular amplifiers can be used to record and stimulate multi-unit activity with the aid of our dishes. Spikes up to 50 pA in voltage-clamp and 300 mu V in current-clamp modes are recorded in sparse and bursting activity patterns characteristic of 1 week-old hippocampal cultures. Moreover, spike sorting employing principal component analysis (PCA) confirms that single microchannels support the recording of multiple neurons. Overall, this work suggests a strategy to endow conventional culture plasticware with added functionality to enable cost-efficient network electrophysiology.

Keywords: Electrophysiological characterisation, Cultured neurons, Polydimethylsilane (PDMS)-on-polystyrene structures

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.

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

Caballero-Briones, F., Palacios-Padros, A., Pena, J. L., Sanz, F., (2008). Phase tailored, potentiodynamically grown P-Cu2-xTe/Cu layers Electrochemistry Communications , 10, (11), 1684-1687

In this work we successfully prepared p-type semiconducting Cu2-xTe layers on Cu substrates by applying a potential multistep signal. Spontaneously deposited tellurium layers were reduced in a single cathodic sweep. The X-ray diffraction characterization showed the presence of single-phased, crystalline Cu2-xTe in the weissite form. A further anodization step allows crystallization of several phases such as CU1.75Te, Cu0.664Te0.336 and CU7Te4. This type of sample was found to be photoactive. The prepared films are p-type and have carrier concentrations in the order of 10(21) CM-3, suitable for CdTe-CU2-xTe contacts.

Keywords: Copper telluride, Electrochemical signal, XRD, Morphology, EIS, Photocurrent, Telluride thin-films, Solar cells, Deposition, Cu

Sanzana, E. S., Navarro, M., Macule, F., Suso, S., Planell, J. A., Ginebra, M. P., (2008). Of the in vivo behavior of calcium phosphate cements and glasses as bone substitutes Acta Biomaterialia 4, (6), 1924-1933

The use of injectable self-setting calcium phosphate cements or soluble glass granules represent two different strategies for bone regeneration, each with distinct advantages and potential applications. This study compares the in vivo behavior of two calcium phosphate cements and two phosphate glasses with different composition, microstructure and solubility, using autologous bone as a control, in a rabbit model. The implanted materials were alpha-tricalcium phosphate cement (cement H), calcium sodium potassium phosphate cement (cement R), and two phosphate glasses in the P2O5-CaO-Na2O and P2O5-CaO-Na2O-TiO2 systems. The four materials were osteoconductive, biocompatible and biodegradable. Radiological and histological studies demonstrated correct osteointegration and substitution of the implants by new bone. The reactivity of the different materials, which depends on their solubility, porosity and specific surface area, affected the resorption rate and bone formation mainly during the early stages of implantation, although this effect was weak. Thus, at 4 weeks the degradation was slightly higher in cements than in glasses, especially for cement R. However, after 12 weeks of implantation all materials showed a similar degradation degree and promoted bone neoformation equivalent to that of the control group.

Keywords: Calcium phosphates, Calcium phosphate cements, Phosphate glasses, Bone grafts, Bone regenerations

Udina, S., Carmona, M., Carles, G., Santander, J., Fonseca, L., Marco, S., (2008). A micromachined thermoelectric sensor for natural gas analysis: Thermal model and experimental results Sensors and Actuators B: Chemical 134, (2), 551-558

Natural gas may show significant changes in its chemical composition depending on its origin. Typically, natural gas analysis is carried out using process gas chromatography. However, other methods based on the evaluation of physical properties have recently been reported. Thermal conductivity sensors are currently used in the analysis of binary mixtures of dissimilar gases. In contrast, natural gas is a complex mixture of mainly hydrocarbons, plus other residual gases as carbon dioxide and nitrogen. In this work, the response of a micromachined sensor integrating a heater and a thermopile is studied, regarding its potential use for natural gas analysis. A finite element thermal model of the device is described, and thermal operation simulations as well as a preliminary sensitivity analysis are reported. Experimental data has been collected and compared with simulated data, showing very good agreement. Results show that small variations in the gas mixture composition can be clearly detected. The sensor appears as a good candidate to be included in low-cost natural gas property analysis and quality control systems.

Keywords: Natural gas, Thermopile, MEMS, Thermal conductivity, Modeling, FEM simulation

Farre, R., Montserrat, J. M., Navajas, D., (2008). Morbidity due to obstructive sleep apnea: insights from animal models Current Opinion in Pulmonary Medicine , 14, (6), 530-536

PURPOSE OF REVIEW: Obstructive sleep apnea (OSA) is a prevalent disorder with clinically well known mid-term and long-term consequences. It is difficult, however, to investigate the mechanisms causing morbidity in OSA from human studies, owing to confounding factors in patients. Animal research is useful to analyze the various injurious stimuli--intermittent hypoxia/hypercapnia, mechanical stress and sleep disruption--that potentially cause OSA morbidity. This review is focused on the most recent advances in our understanding of the consequences of OSA, achieved as a result of animal models. RECENT FINDINGS: Animal research has improved our knowledge of various aspects of the cardiovascular consequences of OSA: myocardial damage, left ventricular dysfunction, vasoconstriction, hypertension and atherosclerosis. The systemic and metabolic consequences of OSA--inflammation, insulin resistance, alterations in lipid metabolism and hepatic morbidity--have also been investigated with animal models. Our understanding of the mechanisms involved in the neurocognitive consequences of OSA--neuronal and brain alterations and cognitive dysfunctions--has also been improved through animal research. Moreover, animal models have recently been used to investigate the mechanisms of upper airway inflammation and dysfunction. SUMMARY: The simple experimental models used to investigate OSA morbidity are useful for investigating isolated mechanisms. However, more complex and realistic models incorporating the various injurious challenges characterizing OSA are required to more precisely translate the results of animal research to patients and to design potentially preventive and therapeutic strategies.

Keywords: Animal model, Morbidity, Sleep apnea, Translational research

Farre, R., Montserrat, J. M., Navajas, D., (2008). Assessment of upper airway mechanics during sleep Respiratory Physiology & Neurobiology , 163, (1-3), 74-81

Obstructive sleep apnea, which is the most prevalent sleep breathing disorder, is characterized by recurrent episodes of upper airway collapse and reopening. However, the mechanical properties of the upper airway are not directly measured in routine polysomnography because only qualitative sensors (thermistors for flow and thoraco-abdominal bands for pressure) are used. This review focuses on two techniques that quantify upper airway obstruction during sleep. A Starling model of collapsible conduit allows us to interpret the mechanics of the upper airway by means of two parameters: the critical pressure (Pcrit) and the upstream resistance (Rup). A simple technique to measure Pcrit and Rup involves the application of different levels of continuous positive airway pressure (CPAP) during sleep. The forced oscillation technique is another non-invasive procedure for quantifying upper airway impedance during the breathing cycle in sleep studies. The latest developments in these two methods allow them to be easily applied on a routine basis in order to more fully characterize upper airway mechanics in patients with sleep breathing disorders.

Keywords: Obstructive sleep apnea, Upper airway, Airway resistance, Critical pressure, Respiratory impedance

Sabella, C., Faszewski, E., Himic, L., Colpitts, K. M., Kaltenbach, J., Burger, M. M., Fernàndez-Busquets, X., (2007). Cyclosporin A suspends transplantation reactions in the marine sponge Microciona prolifera Journal of Immunology , 179, (9), 5927-5935

Sponges are the simplest extant animals but nevertheless possess self-nonself recognition that rivals the specificity of the vertebrate MHC. We have used dissociated cell assays and grafting techniques to study tissue acceptance and rejection in the marine sponge Microciona prolifera. Our data show that allogeneic, but not isogeneic, cell contacts trigger cell death and an increased expression of cell adhesion and apoptosis markers in cells that accumulate in graft interfaces. Experiments investigating the possible existence of immune memory in sponges indicate that faster second set reactions are nonspecific. Among the different cellular types, gray cells have been proposed to be the sponge immunocytes. Fluorescence confocal microscopy results from intact live grafts show the migration of autofluorescent gray cells toward graft contact zones and the inhibition of gray cell movements in the presence of nontoxic concentrations of cyclosporin A. These results suggest that cell motility is an important factor involved in sponge self/nonself recognition. Communication between gray cells in grafted tissues does not require cell contact and is carried by an extracellular diffusible marker. The finding that a commonly used immunosuppressor in human transplantation such as cyclosporin A blocks tissue rejection in marine sponges indicates that the cellular mechanisms for regulating this process in vertebrates might have appeared at the very start of metazoan evolution.

Díez-Pérez, Ismael, Guell, Aleix Garcia, Sanz, Fausto, Gorostiza, Pau, (2006). Conductance maps by electrochemical tunneling spectroscopy to fingerprint the electrode electronic structure Analytical Chemistry , 78, (20), 7325-7329

We describe a methodology to perform reliable tunneling spectroscopy in electrochemical media. Sequential in situ tunneling spectra are recorded while the electrochemical potential of the electrode is scanned. Spectroscopic data are presented as conductance maps or conductograms that show the in situ electronic structure of an electrode surface while it undergoes an electrochemical reaction. The conductance map or conductogram represents the redox fingerprint of an electrode/liquid interface in a specific medium and can serve to predict its electrochemical behavior in a quantitative energy scale. The methodology is validated studying the reversible oxidation and passivity of an iron electrode in borate buffer, and we describe the main quantitative information that can be extracted concerning the semiconducting properties of the Fe passive film. This methodology is useful to study heterogeneous catalysis, electrochemical sensing and bioelectronic systems.

Keywords: Passive film, Oxide-film, Stainless-steel, Iron, Microscope, Surfaces, STM, Probes

Castellarnau, Marc, Errachid, Abdelhamid, Madrid, Cristina, Juárez, Antonio, Samitier, Josep, (2006). Dielectrophoresis as a tool to characterize and differentiate isogenic mutants of Escherichia coli Biophysical Journal , 91, (10), 3937-3945

In this study we report on an experimental method based on dielectrophoretic analysis to identify changes in four Escherichia coli isogenic strains that differed exclusively in one mutant allele. The dielectrophoretic properties of wild-type cells were compared to those of hns, hha, and hha hns mutant derivatives. The hns and hha genes code respectively for the global regulators Hha and H-NS. The Hha and H-NS proteins modulate gene expression in Escherichia coli and other Gram negative bacteria. Mutations in either hha or hns genes result in a pleiotropic phenotype. A two-shell prolate ellipsoidal model has been used to fit the experimental data, obtained from dielectrophoresis measurements, and to study the differences in the dielectric properties of the bacterial strains. The experimental results show that the mutant genotype can be predicted from the dielectrophoretic analysis of the corresponding cultures, opening the way to the development of microdevices for specific identification. Therefore, this study shows that dielectrophoresis can be a valuable tool to study bacterial populations which, although apparently homogeneous, may present phenotypic variability.

Keywords: H-NS, Dielectric behaviour, Hemolysin genes, Cells, Separation, Expression, Proteins, HHA, Electrorotation, Polarization