by Keyword: Skeleton

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Kuipers, Arthur J., Middelbeek, Jeroen, Vrenken, Kirsten, Pérez-González, Carlos, Poelmans, Geert, Klarenbeek, Jeffrey, Jalink, Kees, Trepat, Xavier, van Leeuwen, Frank N., (2018). TRPM7 controls mesenchymal features of breast cancer cells by tensional regulation of SOX4 Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease , 1864, (7), 2409-2419

Mechanically induced signaling pathways are important drivers of tumor progression. However, if and how mechanical signals affect metastasis or therapy response remains poorly understood. We previously found that the channel-kinase TRPM7, a regulator of cellular tension implicated in mechano-sensory processes, is required for breast cancer metastasis in vitro and in vivo. Here, we show that TRPM7 contributes to maintaining a mesenchymal phenotype in breast cancer cells by tensional regulation of the EMT transcription factor SOX4. The functional consequences of SOX4 knockdown closely mirror those produced by TRPM7 knockdown. By traction force measurements, we demonstrate that TRPM7 reduces cytoskeletal tension through inhibition of myosin II activity. Moreover, we show that SOX4 expression and downstream mesenchymal markers are inversely regulated by cytoskeletal tension and matrix rigidity. Overall, our results identify SOX4 as a transcription factor that is uniquely sensitive to cellular tension and indicate that TRPM7 may contribute to breast cancer progression by tensional regulation of SOX4.

Keywords: TRPM7, SOX4, Epithelial-mesenchymal transition, Cytoskeleton, Mechanotransduction

Matalonga, J., Glaria, E., Bresque, M., Escande, C., Carbó, J. M., Kiefer, K., Vicente, R., León, T. E., Beceiro, S., Pascual-García, M., Serret, J., Sanjurjo, L., Morón-Ros, S., Riera, A., Paytubi, S., Juarez, A., Sotillo, F., Lindbom, L., Caelles, C., Sarrias, M. R., Sancho, J., Castrillo, A., Chini, E. N., Valledor, A. F., (2017). The nuclear receptor LXR limits bacterial infection of host macrophages through a mechanism that impacts cellular NAD metabolism Cell Reports , 18, (5), 1241-1255

Macrophages exert potent effector functions against invading microorganisms but constitute, paradoxically, a preferential niche for many bacterial strains to replicate. Using a model of infection by Salmonella Typhimurium, we have identified a molecular mechanism regulated by the nuclear receptor LXR that limits infection of host macrophages through transcriptional activation of the multifunctional enzyme CD38. LXR agonists reduced the intracellular levels of NAD+ in a CD38-dependent manner, counteracting pathogen-induced changes in macrophage morphology and the distribution of the F-actin cytoskeleton and reducing the capability of non-opsonized Salmonella to infect macrophages. Remarkably, pharmacological treatment with an LXR agonist ameliorated clinical signs associated with Salmonella infection in vivo, and these effects were dependent on CD38 expression in bone-marrow-derived cells. Altogether, this work reveals an unappreciated role for CD38 in bacterial-host cell interaction that can be pharmacologically exploited by activation of the LXR pathway.

Keywords: Bacterial infection, CD38, Cytoskeleton, LXR, Macrophage, NAD, Nuclear receptor

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

Rajasekaran, V., Aranda, J., Casals, A., (2015). Compliant gait assistance triggered by user intention Engineering in Medicine and Biology Society (EMBC) 37th Annual International Conference of the IEEE , IEEE (Milan, Italy) , 3885-3888

An automatic gait initialization strategy based on user intention sensing in the context of rehabilitation with a lower-limb wearable robot is proposed and evaluated. The proposed strategy involves monitoring the human-orthosis interaction torques and initial position deviation to determine the gait initiation instant and to modify orthosis operation for gait assistance, when needed. During gait, the compliant control algorithm relies on the adaptation of the joints' stiffness in function of their interaction torques and their deviation from the desired trajectories, while maintaining the dynamic stability. As a reference input, the average of a set of recorded gaits obtained from healthy subjects is used. 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: Biomedical monitoring, Exoskeletons, Joints, Knee, Legged locomotion, Trajectory, Exoskeleton, adaptive control, gait assistance, gait initiation, rehabilitation, wearable robot

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

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

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

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

Rajasekaran, V., Aranda, J., Casals, A., (2014). Handling disturbances on planned trajectories in robotic rehabilitation therapies IFMBE Proceedings XIII Mediterranean Conference on Medical and Biological Engineering and Computing 2013 (ed. Roa Romero, Laura M.), Springer International Publishing (London, UK) 41, 85-88

Robotic rehabilitation therapies are an emerging tool in the field of Neurorehabilitation in order to achieve an effective therapeutic development in the patient. In this paper, the role of disturbances caused by muscle synergies or unpredictable effects of artificial stimulation in muscles during rehabilitation therapies is analyzed. In terms of gait assistance it is also important to maintain synchronized movements to ensure a dynamically stable gait. Although, disturbances affecting joints are corrected by a force control approach, we define two methods to ensure stability and synchronization of joint movements in the trajectory to be followed. The performance of the presented methods is evaluated in comparison with a preplanned trajectory to be followed by the patients.

Keywords: Exoskeleton, Force control, Gait assistance, Neurorobot, Trajectory planning

Casals, Alicia, Fedele, Pasquale, Marek, Tadeusz, Molfino, Rezia, Muscolo, GiovanniGerardo, Recchiuto, CarmineTommaso, (2014). A robotic suit controlled by the human brain for people suffering from quadriplegia Lecture Notes in Computer Science Towards Autonomous Robotic Systems (ed. Natraj, Ashutosh, Cameron, Stephen, Melhuish, Chris, Witkowski, Mark), Springer Berlin Heidelberg , 294-295

The authors present an introductory work for the implementation of an international cooperative project aimed at designing, developing and validating a new generation of ergonomic robotic suits, wearable by the users and controlled by the human brain. The aim of the proposers is to allow the motion of people affected by paralysis or with reduced motor abilities. Therefore, the project will focus on the fusion between neuroergonomics and robotics, also by means of brain-machine interfaces. Breakthrough solutions will compose the advanced robotic suit, endowed with soft structures to increment safety and human comfort, and with an advanced real-time control that takes into account the interaction with the human body.

Keywords: Neuroergonomics, Brain computer interfaces, Robotics, Robotic suits, Compliant actuators, Exoskeleton, EEG, Dynamic balance control

Barreto, S., Clausen, C. H., Perrault, C. M., Fletcher, D. A., Lacroix, D., (2013). A multi-structural single cell model of force-induced interactions of cytoskeletal components Biomaterials , 34, (26), 6119-6126

Several computational models based on experimental techniques and theories have been proposed to describe cytoskeleton (CSK) mechanics. Tensegrity is a prominent model for force generation, but it cannot predict mechanics of individual CSK components, nor explain the discrepancies from the different single cell stimulating techniques studies combined with cytoskeleton-disruptors. A new numerical concept that defines a multi-structural 3D finite element (FE) model of a single-adherent cell is proposed to investigate the biophysical and biochemical differences of the mechanical role of each cytoskeleton component under loading. The model includes prestressed actin bundles and microtubule within cytoplasm and nucleus surrounded by the actin cortex. We performed numerical simulations of atomic force microscopy (AFM) experiments by subjecting the cell model to compressive loads. The numerical role of the CSK components was corroborated with AFM force measurements on U2OS-osteosarcoma cells and NIH-3T3 fibroblasts exposed to different cytoskeleton-disrupting drugs. Computational simulation showed that actin cortex and microtubules are the major components targeted in resisting compression. This is a new numerical tool that explains the specific role of the cortex and overcomes the difficulty of isolating this component from other networks invitro. This illustrates that a combination ofcytoskeletal structures with their own properties is necessary for a complete description of cellular mechanics.

Keywords: Actin bundles, Actin cortex, AFM (atomic force microscopy), Cytoskeleton, Finite element modeling, Microtubules

Roca-Cusachs, P., Iskratsch, T., Sheetz, M. P., (2012). Finding the weakest link: exploring integrin-mediated mechanical molecular pathways Journal of Cell Science , 125, (13), 3025-3038

From the extracellular matrix to the cytoskeleton, a network of molecular links connects cells to their environment. Molecules in this network transmit and detect mechanical forces, which subsequently determine cell behavior and fate. Here, we reconstruct the mechanical pathway followed by these forces. From matrix proteins to actin through integrins and adaptor proteins, we review how forces affect the lifetime of bonds and stretch or alter the conformation of proteins, and how these mechanical changes are converted into biochemical signals in mechanotransduction events. We evaluate which of the proteins in the network can participate in mechanotransduction and which are simply responsible for transmitting forces in a dynamic network. Besides their individual properties, we also analyze how the mechanical responses of a protein are determined by their serial connections from the matrix to actin, their parallel connections in integrin clusters and by the rate at which force is applied to them. All these define mechanical molecular pathways in cells, which are emerging as key regulators of cell function alongside better studied biochemical pathways.

Keywords: Cell adhesion, Cytoskeleton, Mechanotransduction

Amigo, L. E., Fernandez, Q., Giralt, X., Casals, A., Amat, J., (2012). Study of patient-orthosis interaction forces in rehabilitation therapies IEEE Conference Publications 4th IEEE RAS & EMBS International Conference on Biomedical Robotics and Biomechatronics (BioRob) , IEEE (Roma, Italy) , 1098-1103

The design of mechanical joints that kinematically behave as their biological counterparts is a challenge that if not addressed properly can cause inadequate forces transmission between robot and patient. This paper studies the interaction forces in rehabilitation therapies of the elbow joint. To measure the effect of orthosis-patient misalignments, a force sensor with a novel distributed architecture has been designed and used for this study. A test-bed based on an industrial robot acting as a virtual exoskeleton that emulates the action of a therapist has been developed and the interaction forces analyzed.

Keywords: Force, Force measurement, Force sensors, Joints, Medical treatment, Robot sensing systems, Force sensors, Medical robotics, Patient rehabilitation, Biological counterparts, Distributed architecture, Elbow joint, Force sensor, Inadequate forces transmission, Industrial robot, Mechanical joints design, Orthosis-patient misalignments, Patient-orthosis interaction forces, Rehabilitation therapies, Robot, Test-bed, Virtual exoskeleton

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

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

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

Zhou, E. H., Trepat, X., Park, C. Y., Lenormand, G., Oliver, M. N., Mijailovich, S. M., Hardin, C., Weitz, D. A., Butler, J. P., Fredberg, J. J., (2009). Universal behavior of the osmotically compressed cell and its analogy to the colloidal glass transition Proceedings of the National Academy of Sciences of the United States of America 106, (26), 10632-10637

Mechanical robustness of the cell under different modes of stress and deformation is essential to its survival and function. Under tension, mechanical rigidity is provided by the cytoskeletal network; with increasing stress, this network stiffens, providing increased resistance to deformation. However, a cell must also resist compression, which will inevitably occur whenever cell volume is decreased during such biologically important processes as anhydrobiosis and apoptosis. Under compression, individual filaments can buckle, thereby reducing the stiffness and weakening the cytoskeletal network. However, the intracellular space is crowded with macromolecules and organelles that can resist compression. A simple picture describing their behavior is that of colloidal particles; colloids exhibit a sharp increase in viscosity with increasing volume fraction, ultimately undergoing a glass transition and becoming a solid. We investigate the consequences of these 2 competing effects and show that as a cell is compressed by hyperosmotic stress it becomes progressively more rigid. Although this stiffening behavior depends somewhat on cell type, starting conditions, molecular motors, and cytoskeletal contributions, its dependence on solid volume fraction is exponential in every instance. This universal behavior suggests that compression-induced weakening of the network is overwhelmed by crowding-induced stiffening of the cytoplasm. We also show that compression dramatically slows intracellular relaxation processes. The increase in stiffness, combined with the slowing of relaxation processes, is reminiscent of a glass transition of colloidal suspensions, but only when comprised of deformable particles. Our work provides a means to probe the physical nature of the cytoplasm under compression, and leads to results that are universal across cell type.

Keywords: Compression, Cytoplasm, Cytoskeleton, Mechanotransduction, Stiffness

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

Gavara, N., Roca-Cusachs, P., Sunyer, R., Farre, R., Navajas, D., (2008). Mapping cell-matrix stresses during stretch reveals inelastic reorganization of the cytoskeleton Biophysical Journal , 95, (1), 464-471

The mechanical properties of the living cell are intimately related to cell signaling biology through cytoskeletal tension. The tension borne by the cytoskeleton (CSK) is in part generated internally by the actomyosin machinery and externally by stretch. Here we studied how cytoskeletal tension is modified during stretch and the tensional changes undergone by the sites of cell-matrix interaction. To this end we developed a novel technique to map cell-matrix stresses during application of stretch. We found that cell-matrix stresses increased with imposition of stretch but dropped below baseline levels on stretch release. Inhibition of the actomyosin machinery resulted in a larger relative increase in CSK tension with stretch and in a smaller drop in tension after stretch release. Cell-matrix stress maps showed that the loci of cell adhesion initially bearing greater stress also exhibited larger drops in traction forces after stretch removal. Our results suggest that stretch partially disrupts the actin-myosin apparatus and the cytoskeletal structures that support the largest CSK tension. These findings indicate that cells use the mechanical energy injected by stretch to rapidly reorganize their structure and redistribute tension.

Keywords: Cell Line, Computer Simulation, Cytoskeleton/ physiology, Elasticity, Epithelial Cells/ physiology, Extracellular Matrix/ physiology, Humans, Mechanotransduction, Cellular/ physiology, Models, Biological, Stress, Mechanical