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Verschure, P., (2018). The architecture of mind and brain Living machines: A handbook of research in biomimetics and biohybrid systems (ed. Prescott, T. J., Lepora, Nathan, Verschure, P.), Oxford Scholarship (Oxford, UK) , 338-345

The components of a Living Machine must be integrated into a functioning whole, which requires a detailed understanding of the architecture of living machines. This chapter starts with a conceptual and historical analysis which from Plato brings us to nineteenth-century neuroscience and early concepts of the layered structure of nervous systems. These concepts were further captured in the cognitive behaviorism of Tolman and came to full fruition in the cognitive revolution of the second half of the twentieth century. Verschure subsequently describes the most relevant proposals of cognitive architectures followed by an overview of the few proposals stemming from modern neuroscience on the architecture of the brain. Subsequently, we will look at contemporary contenders that mediate between cognitive and brain architecture. An important challenge to any model of cognitive architectures is how to benchmark it. Verschure proposes the Unified Theories of Embodied Minds (UTEM) benchmark which advances from Newell’s classic Unified Theories of Cognition benchmark.

Keywords: Architecture, Mind, Brain, Organization, System, Virtualization, Abstraction layers


Klein, S., Schierwagen, R., Uschner, F. E., Trebicka, J., (2017). Mouse and rat models of induction of hepatic fibrosis and assessment of portal hypertension Fibrosis (Methods in Molecular Biology) (ed. Rittié, L.), Humana Press (New York, USA) 1627, 91-116

Portal hypertension either develops due to progressive liver fibrosis or is the consequence of vascular liver diseases such as portal vein thrombosis or non-cirrhotic portal hypertension. This chapter focuses on different rodent models of liver fibrosis with portal hypertension and also in few non-cirrhotic portal hypertension models. Importantly, after the development of portal hypertension, the proper assessment of drug effects in the portal and systemic circulation should be discussed. The last part of the chapter is dedicated in these techniques to assess the in vivo hemodynamics and the ex vivo techniques of the isolated liver perfusion and vascular contractility.

Keywords: Aortic ring contraction, Bile duct ligation, Carbon tetrachloride, Colored microsphere technique, High-fat diet, Isolated in situ liver perfusion, Methionine-choline-deficient diet, Partial portal vein ligation, Portal hypertension


Przybyla, L., Lakins, J. N., Sunyer, R., Trepat, X., Weaver, V. M., (2016). Monitoring developmental force distributions in reconstituted embryonic epithelia Methods , 94, 101-113

The way cells are organized within a tissue dictates how they sense and respond to extracellular signals, as cues are received and interpreted based on expression and organization of receptors, downstream signaling proteins, and transcription factors. Part of this microenvironmental context is the result of forces acting on the cell, including forces from other cells or from the cellular substrate or basement membrane. However, measuring forces exerted on and by cells is difficult, particularly in an in vivo context, and interpreting how forces affect downstream cellular processes poses an even greater challenge. Here, we present a simple method for monitoring and analyzing forces generated from cell collectives. We demonstrate the ability to generate traction force data from human embryonic stem cells grown in large organized epithelial sheets to determine the magnitude and organization of cell-ECM and cell-cell forces within a self-renewing colony. We show that this method can be used to measure forces in a dynamic hESC system and demonstrate the ability to map intracolony protein localization to force organization.

Keywords: Epiblast, Human embryonic stem cells, Mechanotransduction, Monolayer stress microscopy, Self-organization, Traction force


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

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

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


Arcentales, A., Rivera, P., Caminal, P., Voss, A., Bayés-Genís, A., Giraldo, B. F., (2016). Analysis of blood pressure signal in patients with different ventricular ejection fraction using linear and non-linear methods Engineering in Medicine and Biology Society (EMBC) 38th Annual International Conference of the IEEE , IEEE (Orlando, USA) , 2700-2703

Changes in the left ventricle function produce alternans in the hemodynamic and electric behavior of the cardiovascular system. A total of 49 cardiomyopathy patients have been studied based on the blood pressure signal (BP), and were classified according to the left ventricular ejection fraction (LVEF) in low risk (LR: LVEF>35%, 17 patients) and high risk (HR: LVEF≤35, 32 patients) groups. We propose to characterize these patients using a linear and a nonlinear methods, based on the spectral estimation and the recurrence plot, respectively. From BP signal, we extracted each systolic time interval (STI), upward systolic slope (BPsl), and the difference between systolic and diastolic BP, defined as pulse pressure (PP). After, the best subset of parameters were obtained through the sequential feature selection (SFS) method. According to the results, the best classification was obtained using a combination of linear and nonlinear features from STI and PP parameters. For STI, the best combination was obtained considering the frequency peak and the diagonal structures of RP, with an area under the curve (AUC) of 79%. The same results were obtained when comparing PP values. Consequently, the use of combined linear and nonlinear parameters could improve the risk stratification of cardiomyopathy patients.

Keywords: Feature extraction, Blood pressure, Heart rate, Estimation, Data mining, Covariance matrices, Hospitals


Argerich, S., Herrera, S., Benito, S., Giraldo, J., (2016). Evaluation of periodic breathing in respiratory flow signal of elderly patients using SVM and linear discriminant analysis Engineering in Medicine and Biology Society (EMBC) 38th Annual International Conference of the IEEE , IEEE (Orlando, USA) , 4276-4279

Aging population is a major concern that is reflected in the increase of chronic diseases. Heart Failure (HF) is one of the most common chronic diseases of elderly people that is punctuated with acute episodes, which result in hospitalization. The periodic modulation of the amplitude of the breathing pattern is proved to be one of the multiple symptoms of an acute episode, and thus, the features extracted from its characterization contribute in the improvement of the first diagnosis of the clinical practice. The main objective of this study is to evaluate if the features extracted from the breathing pattern along with common clinical variables are reliable enough to detect Periodic Breathing (PB). A dataset of 44 elderly patients containing clinical information and a short record of electrocardiogram and respiratory flow signal was used to train two machine learning classification methods: Support Vector Machine (SVM) and Linear Discriminant Analysis (LDA). All the available clinical parameters within the dataset along with the parameters characterizing the respiratory pattern were used to classify the observations into two groups. SVM classification was optimized and performed using a = -8 and C = 10.04 giving an accuracy of 88.2 % sensitivity of 90 % and specificity of 85.7 % Similar results were achieved with LDA classifying with an accuracy of 82.4 %, a sensitivity of 81.8% and specificity of 83.3 % PB has been accurately detected using both classifiers.

Keywords: Support vector machines, Feature extraction, Training, Senior citizens, Standards, Training data, Hospitals


Brask, J. B., Singla-Buxarrais, G., Uroz, M., Vincent, R., Trepat, X., (2015). Compressed sensing traction force microscopy Acta Biomaterialia 26, 286-294

Adherent cells exert traction forces on their substrate, and these forces play important roles in biological functions such as mechanosensing, cell differentiation and cancer invasion. The method of choice to assess these active forces is traction force microscopy (TFM). Despite recent advances, TFM remains highly sensitive to measurement noise and exhibits limited spatial resolution. To improve the resolution and noise robustness of TFM, here we adapt techniques from compressed sensing (CS) to the reconstruction of the traction field from the substrate displacement field. CS enables the recovery of sparse signals at higher resolution from lower resolution data. Focal adhesions (FAs) of adherent cells are spatially sparse implying that traction fields are also sparse. Here we show, by simulation and by experiment, that the CS approach enables circumventing the Nyquist-Shannon sampling theorem to faithfully reconstruct the traction field at a higher resolution than that of the displacement field. This allows reaching state-of-the-art resolution using only a medium magnification objective. We also find that CS improves reconstruction quality in the presence of noise. Statement of Significance A great scientific advance of the past decade is the recognition that physical forces determine an increasing list of biological processes. Traction force microscopy which measures the forces that cells exert on their surroundings has seen significant recent improvements, however the technique remains sensitive to measurement noise and severely limited in spatial resolution. We exploit the fact that the force fields are sparse to boost the spatial resolution and noise robustness by applying ideas from compressed sensing. The novel method allows high resolution on a larger field of view. This may in turn allow better understanding of the cell forces at the multicellular level, which are known to be important in wound healing and cancer invasion.

Keywords: Compressed sensing, High resolution, Traction force microscopy


Reginensi, Diego, Carulla, Patricia, Nocentini, Sara, Seira, Oscar, Serra-Picamal, Xavier, Torres-Espín, Abel, Matamoros-Angles, Andreu, Gavín, Rosalina, Moreno-Flores, María Teresa, Wandosell, Francisco, Samitier, Josep, Trepat, Xavier, Navarro, Xavier, del Río, José Antonio, (2015). Increased migration of olfactory ensheathing cells secreting the Nogo receptor ectodomain over inhibitory substrates and lesioned spinal cord Cellular and Molecular Life Sciences , 72, (14), 2719-2737

Olfactory ensheathing cell (OEC) transplantation emerged some years ago as a promising therapeutic strategy to repair injured spinal cord. However, inhibitory molecules are present for long periods of time in lesioned spinal cord, inhibiting both OEC migration and axonal regrowth. Two families of these molecules, chondroitin sulphate proteoglycans (CSPG) and myelin-derived inhibitors (MAIs), are able to trigger inhibitory responses in lesioned axons. Mounting evidence suggests that OEC migration is inhibited by myelin. Here we demonstrate that OEC migration is largely inhibited by CSPGs and that inhibition can be overcome by the bacterial enzyme Chondroitinase ABC. In parallel, we have generated a stable OEC cell line overexpressing the Nogo receptor (NgR) ectodomain to reduce MAI-associated inhibition in vitro and in vivo. Results indicate that engineered cells migrate longer distances than unmodified OECs over myelin or oligodendrocyte-myelin glycoprotein (OMgp)-coated substrates. In addition, they also show improved migration in lesioned spinal cord. Our results provide new insights toward the improvement of the mechanisms of action and optimization of OEC-based cell therapy for spinal cord lesion.

Keywords: Olfactory ensheathing cells, Traction force microscopy, Chondroitin sulphate proteoglycans, Cell migration, Nogo receptor ectodomain


Mrkonji, Garcia-Elias, A., Pardo-Pastor, C., Bazellières, E., Trepat, X., Vriens, J., Ghosh, D., Voets, T., Vicente, R., Valverde, M. A., (2015). TRPV4 participates in the establishment of trailing adhesions and directional persistence of migrating cells Pflugers Archiv European Journal of Physiology , 467, (10), 2107-2119

Calcium signaling participates in different cellular processes leading to cell migration. TRPV4, a non-selective cation channel that responds to mechano-osmotic stimulation and heat, is also involved in cell migration. However, the mechanistic involvement of TRPV4 in cell migration is currently unknown. We now report that expression of the mutant channel TRPV4-121AAWAA (lacking the phosphoinositide-binding site 121KRWRK125 and the response to physiological stimuli) altered HEK293 cell migration. Altered migration patterns included periods of fast and persistent motion followed by periods of stalling and turning, and the extension of multiple long cellular protrusions. TRPV4-WT overexpressing cells showed almost complete loss of directionality with frequent turns, no progression, and absence of long protrusions. Traction microscopy revealed higher tractions forces in the tail of TRPV4-121AAWAA than in TRPV4-WT expressing cells. These results are consistent with a defective and augmented tail retraction in TRPV4-121AAWAA- and TRPV4-WT-expressing cells, respectively. The activity of calpain, a protease implicated in focal adhesion (FA) disassembly, was decreased in TRPV4-121AAWAA compared with TRPV4-WT-expressing cells. Consistently, larger focal adhesions were seen in TRPV4-121AAWAA compared with TRPV4-WT-expressing HEK293 cells, a result that was also reproduced in T47D and U87 cells. Similarly, overexpression of the pore-dead mutant TRPV4-M680D resumed the TRPV4-121AAWAA phenotype presenting larger FA. The migratory phenotype obtained in HEK293 cells overexpressing TRPV4-121AAWAA was mimicked by knocking-down TRPC1, a cationic channel that participates in cell migration. Together, our results point to the participation of TRPV4 in the dynamics of trailing adhesions, a function that may require the interplay of TRPV4 with other cation channels or proteins present at the FA sites.

Keywords: Calcium, Calpain, Focal adhesion, Migration, Traction forces, TRPV4


Serra-Picamal, Xavier, Conte, Vito, Sunyer, Raimon, Muñoz, José J., Trepat, Xavier, (2015). Mapping forces and kinematics during collective cell migration Methods in Cell Biology - Biophysical Methods in Cell Biology (ed. Wilson, L., Tran, P.), Academic Press (Santa Barbara, USA) 125, 309-330

Abstract Fundamental biological processes including morphogenesis and tissue repair require cells to migrate collectively. In these processes, epithelial or endothelial cells move in a cooperative manner coupled by intercellular junctions. Ultimately, the movement of these multicellular systems occurs through the generation of cellular forces, exerted either on the substrate via focal adhesions (cell–substrate forces) or on neighboring cells through cell–cell junctions (cell–cell forces). Quantitative measurements of multicellular forces and kinematics with cellular or subcellular resolution have become possible only in recent years. In this chapter, we describe some of these techniques, which include particle image velocimetry to map cell velocities, traction force microscopy to map forces exerted by cells on the substrate, and monolayer stress microscopy to map forces within and between cells. We also describe experimental protocols to perform these measurements. The combination of these techniques with high-resolution imaging tools and molecular perturbations will lead to a better understanding of the mechanisms underlying collective cell migration in health and disease.

Keywords: Collective cell migration, Monolayer stress microscopy, Traction force microscopy


Fresco-Cala, B., Jimenez-Soto, J. M., Cardenas, S., Valcarcel, M., (2014). Single-walled carbon nanohorns immobilized on a microporous hollow polypropylene fiber as a sorbent for the extraction of volatile organic compounds from water samples Microchimica Acta , 181, (9-10), 1117-1124

We have evaluated the behavior of single-walled carbon nanohorns as a sorbent for headspace and direct immersion (micro)solid phase extraction using volatile organic compounds (VOCs) as model analytes. The conical carbon nanohorns were first oxidized in order to increase their solubility in water and organic solvents. A microporous hollow polypropylene fiber served as a mechanical support that provides a high surface area for nanoparticle retention. The extraction unit was directly placed in the liquid sample or the headspace of an aqueous standard or a water sample to extract and preconcentrate the VOCs. The variables affecting extraction have been optimized. The VOCs were then identified and quantified by GC/MS. We conclude that direct immersion of the fiber is the most adequate method for the extraction of VOCs from both liquid samples and headspace. Detection limits range from 3.5 to 4.3 ng L-1 (excepted for toluene with 25 ng L-1), and the precision (expressed as relative standard deviation) is between 3.9 and 9.6 %. The method was applied to the determination of toluene, ethylbenzene, various xylene isomers and styrene in bottled, river and tap waters, and the respective average recoveries of spiked samples are 95.6, 98.2 and 86.0 %.

Keywords: (Micro)solid phase extraction, Nanotechnology, Oxidized single-walled carbon nanohorns, Volatiles compounds, Waters


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

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

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


Giraldo, B. F., Chaparro, J. A., Caminal, P., Benito, S., (2013). Characterization of the respiratory pattern variability of patients with different pressure support levels Engineering in Medicine and Biology Society (EMBC) 35th Annual International Conference of the IEEE , IEEE (Osaka, Japan) , 3849-3852

One of the most challenging problems in intensive care is still the process of discontinuing mechanical ventilation, called weaning process. Both an unnecessary delay in the discontinuation process and a weaning trial that is undertaken too early are undesirable. In this study, we analyzed respiratory pattern variability using the respiratory volume signal of patients submitted to two different levels of pressure support ventilation (PSV), prior to withdrawal of the mechanical ventilation. In order to characterize the respiratory pattern, we analyzed the following time series: inspiratory time, expiratory time, breath duration, tidal volume, fractional inspiratory time, mean inspiratory flow and rapid shallow breathing. Several autoregressive modeling techniques were considered: autoregressive models (AR), autoregressive moving average models (ARMA), and autoregressive models with exogenous input (ARX). The following classification methods were used: logistic regression (LR), linear discriminant analysis (LDA) and support vector machines (SVM). 20 patients on weaning trials from mechanical ventilation were analyzed. The patients, submitted to two different levels of PSV, were classified as low PSV and high PSV. The variability of the respiratory patterns of these patients were analyzed. The most relevant parameters were extracted using the classifiers methods. The best results were obtained with the interquartile range and the final prediction errors of AR, ARMA and ARX models. An accuracy of 95% (93% sensitivity and 90% specificity) was obtained when the interquartile range of the expiratory time and the breath duration time series were used a LDA model. All classifiers showed a good compromise between sensitivity and specificity.

Keywords: autoregressive moving average processes, feature extraction, medical signal processing, patient care, pneumodynamics, signal classification, support vector machines, time series, ARX, autoregressive modeling techniques, autoregressive models with exogenous input, autoregressive moving average model, breath duration time series, classification method, classifier method, discontinuing mechanical ventilation, expiratory time, feature extraction, final prediction errors, fractional inspiratory time, intensive care, interquartile range, linear discriminant analysis, logistic regression analysis, mean inspiratory flow, patient respiratory volume signal, pressure support level, pressure support ventilation, rapid shallow breathing, respiratory pattern variability characterization, support vector machines, tidal volume, weaning trial, Analytical models, Autoregressive processes, Biological system modeling, Estimation, Support vector machines, Time series analysis, Ventilation


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

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

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


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

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

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


Nocentini, S., Reginensi, D., Garcia, S., Carulla, P., Moreno-Flores, Wandosell, F., Trepat, X., Bribian, A., Del Rí, (2012). Myelin-associated proteins block the migration of olfactory ensheathing cells: an in vitro study using single-cell tracking and traction force microscopy Cellular and Molecular Life Sciences , 69, (10), 1689-1703

Newly generated olfactory receptor axons grow from the peripheral to the central nervous system aided by olfactory ensheathing cells (OECs). Thus, OEC transplantation has emerged as a promising therapy for spinal cord injuries and for other neural diseases. However, these cells do not present a uniform population, but instead a functionally heterogeneous population that exhibits a variety of responses including adhesion, repulsion, and crossover during cell–cell and cell–matrix interactions. Some studies report that the migratory properties of OECs are compromised by inhibitory molecules and potentiated by chemical gradients. Here, we demonstrated that rodent OECs express all the components of the Nogo receptor complex and that their migration is blocked by myelin. Next, we used cell tracking and traction force microscopy to analyze OEC migration and its mechanical properties over myelin. Our data relate the decrease of traction force of OEC with lower migratory capacity over myelin, which correlates with changes in the F-actin cytoskeleton and focal adhesion distribution. Lastly, OEC traction force and migratory capacity is enhanced after cell incubation with the Nogo receptor inhibitor NEP1-40.

Keywords: Ensheathing glia, Traction force, microscopy, Migration, Myelin-associated inhibitors


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


Moore, S. W., Roca-Cusachs, P., Sheetz, M. P., (2010). Stretchy proteins on stretchy substrates: The important elements of integrin-mediated rigidity sensing Developmental Cell 19, (2), 194-206

Matrix and tissue rigidity guides many cellular processes, including the differentiation of stem cells and the migration of cells in health and disease. Cells actively and transiently test rigidity using mechanisms limited by inherent physical parameters that include the strength of extracellular attachments, the pulling capacity on these attachments, and the sensitivity of the mechanotransduction system. Here, we focus on rigidity sensing mediated through the integrin family of extracellular matrix receptors and linked proteins and discuss the evidence supporting these proteins as mechanosensors.

Keywords: Focal adhesion kinase, Atomic Force Microscopy, Smooth-muscle cells, Traction forces, Living cells, Mechanical force, Locomoting cells


Morgenstern, C., Schwaibold, M., Randerath, W., Bolz, A., Jané, R., (2010). Automatic non-invasive differentiation of obstructive and central hypopneas with nasal airflow compared to esophageal pressure Engineering in Medicine and Biology Society (EMBC) 32nd Annual International Conference of the IEEE , IEEE (Buenos Aires, Argentina) , 6142-6145

The differentiation of obstructive and central respiratory events is a major challenge in the diagnosis of sleep disordered breathing. Esophageal pressure (Pes) measurement is the gold-standard method to identify these events but its invasiveness deters its usage in clinical routine. Flattening patterns appear in the airflow signal during episodes of inspiratory flow limitation (IFL) and have been shown with invasive techniques to be useful to differentiate between central and obstructive hypopneas. In this study we present a new method for the automatic non-invasive differentiation of obstructive and central hypopneas solely with nasal airflow. An overall of 36 patients underwent full night polysomnography with systematic Pes recording and a total of 1069 hypopneas were manually scored by human experts to create a gold-standard annotation set. Features were automatically extracted from the nasal airflow signal to train and test our automatic classifier (Discriminant Analysis). Flattening patterns were non-invasively assessed in the airflow signal using spectral and time analysis. The automatic non-invasive classifier obtained a sensitivity of 0.71 and an accuracy of 0.69, similar to the results obtained with a manual non-invasive classification algorithm. Hence, flattening airflow patterns seem promising for the non-invasive differentiation of obstructive and central hypopneas.

Keywords: Practical, Experimental/ biomedical measurement, Feature extraction, Flow measurement, Medical disorders, Medical signal processing, Patient diagnosis, Pneumodynamics, Pressure measurement, Signal classification, Sleep, Spectral analysis/ automatic noninvasive differentiation, Obstructive hypopnea, Central hypopnea, Inspiratory flow limitation, Nasal airflow, Esophageal pressure, Polysomnography, Feature extraction, Discriminant analysis, Spectral analysis


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

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

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


Sunyer, R., Trepat, X., Fredberg, J. J., Farre, R., Navajas, D., (2009). The temperature dependence of cell mechanics measured by atomic force microscopy Physical Biology , 6, (2), 25009

The cytoskeleton is a complex polymer network that regulates the structural stability of living cells. Although the cytoskeleton plays a key role in many important cell functions, the mechanisms that regulate its mechanical behaviour are poorly understood. Potential mechanisms include the entropic elasticity of cytoskeletal filaments, glassy-like inelastic rearrangements of cross-linking proteins and the activity of contractile molecular motors that sets the tensional stress (prestress) borne by the cytoskeleton filaments. The contribution of these mechanisms can be assessed by studying how cell mechanics depends on temperature. The aim of this work was to elucidate the effect of temperature on cell mechanics using atomic force microscopy. We measured the complex shear modulus (G*) of human alveolar epithelial cells over a wide frequency range (0.1-25.6 Hz) at different temperatures (13-37 degrees C). In addition, we probed cell prestress by mapping the contractile forces that cells exert on the substrate by means of traction microscopy. To assess the role of actomyosin contraction in the temperature-induced changes in G* and cell prestress, we inhibited the Rho kinase pathway of the myosin light chain phosphorylation with Y-27632. Our results show that with increasing temperature, cells become stiffer and more solid-like. Cell prestress also increases with temperature. Inhibiting actomyosin contraction attenuated the temperature dependence of G* and prestress. We conclude that the dependence of cell mechanics with temperature is dominated by the contractile activity of molecular motors.

Keywords: Membrane Stress Failure, Frog Skeletal-Muscle, Extracellular-Matrix, Glass-Transition, Energy Landscape, Actin-Filaments, Living Cell, Single, Traction, Cytoskeleton


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

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

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