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Journal articles on the topic 'Railway, degraded adhesion, adhesion model'
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1
Meli, E., A. Ridolfi, and A. Rindi. "An innovative degraded adhesion model for railway vehicles: development and experimental validation." Meccanica 49, no. 4 (December 5, 2013): 919–37. http://dx.doi.org/10.1007/s11012-013-9839-z.
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Meli, E., L. Pugi, and A. Ridolfi. "An innovative degraded adhesion model for multibody applications in the railway field." Multibody System Dynamics 32, no. 2 (October 11, 2013): 133–57. http://dx.doi.org/10.1007/s11044-013-9400-9.
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Meli, E., and A. Ridolfi. "An innovative wheel–rail contact model for railway vehicles under degraded adhesion conditions." Multibody System Dynamics 33, no. 3 (December 7, 2013): 285–313. http://dx.doi.org/10.1007/s11044-013-9405-4.
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Allotta, B., E. Meli, A. Ridolfi, and A. Rindi. "Development of an innovative wheel–rail contact model for the analysis of degraded adhesion in railway systems." Tribology International 69 (January 2014): 128–40. http://dx.doi.org/10.1016/j.triboint.2013.09.013.
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Allotta, B., R. Conti, E. Meli, L. Pugi, and A. Ridolfi. "Development of a HIL railway roller rig model for the traction and braking testing activities under degraded adhesion conditions." International Journal of Non-Linear Mechanics 57 (December 2013): 50–64. http://dx.doi.org/10.1016/j.ijnonlinmec.2013.06.003.
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Zirek, Abdulkadir, and Altan Onat. "A novel anti-slip control approach for railway vehicles with traction based on adhesion estimation with swarm intelligence." Railway Engineering Science 28, no. 4 (November 24, 2020): 346–64. http://dx.doi.org/10.1007/s40534-020-00223-w.
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AbstractAnti-slip control systems are essential for railway vehicle systems with traction. In order to propose an effective anti-slip control system, adhesion information between wheel and rail can be useful. However, direct measurement or observation of adhesion condition for a railway vehicle in operation is quite demanding. Therefore, a proportional–integral controller, which operates simultaneously with a recently proposed swarm intelligence-based adhesion estimation algorithm, is proposed in this study. This approach provides determination of the adhesion optimum on the adhesion-slip curve so that a reference slip value for the controller can be determined according to the adhesion conditions between wheel and rail. To validate the methodology, a tram wheel test stand with an independently rotating wheel, which is a model of some low floor trams produced in Czechia, is considered. Results reveal that this new approach is more effective than a conventional controller without adhesion condition estimation.
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Uyulan, Çağlar, and Metin Gokasan. "Modeling, simulation and re-adhesion control of an induction motor–based railway electric traction system." Proceedings of the Institution of Mechanical Engineers, Part I: Journal of Systems and Control Engineering 232, no. 1 (September 30, 2017): 3–11. http://dx.doi.org/10.1177/0959651817732487.
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Increasing the traction force is a complex problem in the design of railway vehicles; therefore, effective traction systems and algorithms have to be developed. During the traction process, the verification of traction algorithms and control strategies are based on simulations covering all locomotive dynamics. In this article, traction model of a railway vehicle and re-adhesion control method based on simulation approach are investigated to obtain more effective results. The longitudinal dynamic of a railway vehicle having traction system, which comprises two parallel motor groups, each of which has two field-oriented induction motor connected in series, is simulated to examine time-dependent changes in motor stator currents, traction torque, adhesion and resistance forces according to a given speed reference. The interaction between the adhesion force and the slip ratio is established according to the Burckhardt adhesion model, and a modified super-twisting sliding mode slip control is implemented in a computer simulation under various contact conditions so that simulation results approve the presented control method works under the maximum adhesion force. The comparison between the classical and modified version of the proposed control strategy was made to better evaluate the performance of the control system and to better optimize the traction system.
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Bureika, Gintautas. "A MATHEMATICAL MODEL OF TRAIN CONTINUOUS MOTION UPHILL." TRANSPORT 23, no. 2 (June 30, 2008): 135–37. http://dx.doi.org/10.3846/1648-4142.2008.23.135-137.
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The determination problem of adhesion coefficient of locomotives’ wheels with rails is described in this paper. The use of methods of mathematical statistics and theory of probability provides wider possibilities for determining the most acceptable (suitable) value of the adhesion coefficient. The random factors influencing on this value are analysed. The use of the adhesion coefficient values based on reliable research results could help maintain uninterrupted (continuous) traffic of heavy freight trains and increase not only the carrying capacity, but also the volume of the transported goods. The paper considers a mathematical model of steady traffic of heavy freight trains pulled by upgraded locomotives of the series 2M62M on railway line with a gradient. The research results show that the actual values of the adhesion coefficient and the total resistance are distributed according to the normal distribution law. A mode of locomotive motion largely depends on the relationship between the total train's running resistance and locomotive tractive force. Finally, basic conclusions are given.
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Li, Yun Feng, Xiao Yun Feng, and Rui Kuo Liu. "Maximum Adhesion Control of Railway Based on Sliding Mode Control System." Advanced Materials Research 383-390 (November 2011): 5242–49. http://dx.doi.org/10.4028/www.scientific.net/amr.383-390.5242.
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The wheels will idle when the relative slipping speed between the wheel and rail exceeds the reference slipping speed. In order to avoid this phenomenon, the simplified model of wheel-rail traction torque transmission was established. And the adhesion coefficient and vehicle velocity are got through the disturbance observer. Then the recursive least squares method was used to forecast the slope of the adhesion-slip curve. Sliding variable structure controller was used to control the error of wheel velocity and reference velocity. From the results of simulation, this method can be effective to maintain the adhesion coefficient around the maximum. And the slipping speed approached the reference value, so the damage for wheel and rail was effectively prevented which achieved the desired effect.
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Olofsson, U. "A multi-layer model of low adhesion between railway wheel and rail." Proceedings of the Institution of Mechanical Engineers, Part F: Journal of Rail and Rapid Transit 221, no. 3 (May 2007): 385–89. http://dx.doi.org/10.1243/09544097jrrt111.
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Tsai, S.-W., J.-F. Fang, C.-L. Yang, J.-H. Chen, L.-T. Su, and S.-H. Jan. "Preparation and Evaluation of a Hyaluronate-Collagen Film for Preventing Post-Surgical Adhesion." Journal of International Medical Research 33, no. 1 (February 2005): 68–76. http://dx.doi.org/10.1177/147323000503300106.
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Post-surgical adhesion occurs when fibrous strands of scar tissue form, leading to the abnormal joining of anatomical structures. Patients undergoing abdominal surgery are at risk of the complications associated with intraperitoneal adhesions. Hyaluronic acid (HA) is a biocompatible, biodegradable and non-toxic natural polymer, which is gaining popularity as a barrier agent for preventing post-surgical adhesions. As HA is water-soluble and rapidly degraded in vivo, chemical modification is required to produce a non-soluble sheet that might be used to prevent tissue adhesion. We developed a range of biocompatible cross-linked HA-collagen composites and then evaluated them in a rat model of post-surgical adhesion. The results showed that cross-linked HA-collagen was almost totally resistant to hyaluronidase digestion. HA-collagen membranes induced minimal tissue reactions and were bioresorbed within 14 days post-surgery. These results suggest that cross-linked HA-collagen membrane may be a valuable anti-adhesion material to prevent post-surgical intraperitoneal adhesion.
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Allota, B., R. Conti, E. Meli, L. Pugi, and A. Ridolfi. "Railway Vehicle Dynamics under Degraded Adhesion Conditions: An Innovative HIL Architecture for Braking Tests on Full-Scale Roller-Rigs." International Journal of Railway Technology 2, no. 3 (2013): 21–53. http://dx.doi.org/10.4203/ijrt.2.3.2.
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Allotta, Benedetto, Roberto Conti, Enrico Meli, and Alessandro Ridolfi. "Modeling and Control of a Full-Scale Roller-Rig for the Analysis of Railway Braking Under Degraded Adhesion Conditions." IEEE Transactions on Control Systems Technology 23, no. 1 (January 2015): 186–96. http://dx.doi.org/10.1109/tcst.2014.2320672.
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Conti, R., E. Meli, A. Ridolfi, and A. Rindi. "An innovative hardware in the loop architecture for the analysis of railway braking under degraded adhesion conditions through roller-rigs." Mechatronics 24, no. 2 (March 2014): 139–50. http://dx.doi.org/10.1016/j.mechatronics.2013.12.011.
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Choi, J. J., S. H. Park, and J. S. Kim. "Dynamic adhesion model and adaptive sliding mode brake control system for the railway rolling stocks." Proceedings of the Institution of Mechanical Engineers, Part F: Journal of Rail and Rapid Transit 221, no. 3 (May 2007): 313–20. http://dx.doi.org/10.1243/09544097jrrt71.
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Nagase, K., Y. Wakabayashi, and H. Sakahara. "A study of the phenomenon of wheel climb derailment: Results of basic experiments using model bogies." Proceedings of the Institution of Mechanical Engineers, Part F: Journal of Rail and Rapid Transit 216, no. 4 (July 1, 2002): 237–47. http://dx.doi.org/10.1243/095440902321029190.
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Wheel climb derailment sometimes occurs when a train passes through a steep curve on a railway track at low speeds. The authors conducted experiments on the phenomenon of wheel climb derailment using model bogies and a model track. The Nadal formula (Nadal limit) is used to evaluate the risk of derailment. Because the friction coefficient between the rail and the wheel has a considerable influence on the critical values to be calculated using the Nadal formula, it is inappropriate to evaluate the risk of derailment by using the Nadal formula alone. The risk of derailment can be determined in a straightforward way by measuring the wheel vertical displacement. In this study, to measure the wheel vertical displacement accurately, a high-precision laser displacement sensor was used. The experimental results revealed that a wheel both slips downwards and climbs up simultaneously and that vertical displacement of the wheel occurs when the degree of wheel climb-up exceeds the degree of wheel slip-down. Although the friction coefficient between the rail and the wheel is a primary factor responsible for causing wheel climb derailment, measurement of the friction coefficient is difficult to achieve. Therefore, a model slipping adhesion bogie was used to measure the adhesion coefficient instead of the friction coefficient. The data obtained from the experiments were analysed in order to verify the relationship between the adhesion coefficient and the wheel climb-up behaviour. As a result, it was found that the adhesion coefficient has a major influence on the occurrence of wheel climb derailment.
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Barski, Dimitri, Holger Gerullis, Thorsten Ecke, Gabriella Varga, Mihaly Boros, Isabel Pintelon, Jean-Pierre Timmermans, and Thomas Otto. "Human Amniotic Membrane Is Not Suitable for the Grafting of Colon Lesions and Prevention of Adhesions in a Xenograft Rat Model." Surgical Innovation 24, no. 4 (May 26, 2017): 313–20. http://dx.doi.org/10.1177/1553350617709828.
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Introduction. New biological materials are needed for specific applications in reconstructive bowel surgery and for the prevention of adhesion formation. Amniotic membranes (AMs) are assumed to have a number of unique characteristics that enhance the ingrowth of the surrounding tissue. The aim of the present study was to provide proof of these qualities in a xenograft model. Materials and methods. A multilayer human AM (HAM) was applied to repair defined colon wall defects in Sprague-Dawley rats (n = 18). The control group was repaired with a suture (n = 6). The animals were killed humanely at 7, 21, and 42 days after implantation. Adhesions and perioperative complications were examined. Histological and immunohistological analyses were performed to assess a number of parameters, including degradation of the HAM, inflammation, graft rejection, and smooth muscle ingrowth. Results. Two rats in the treated group died. No other severe complications were observed. Adhesion formation was more prominently visible in the HAM group ( P < .05). The initially increased inflammation in the HAM group reduced over time but remained significantly increased ( P < .05). The HAM degraded over time and a subtle transient glomerulitis could be observed. Conclusion. HAMs were found to increase adhesion formation and were not suitable for bowel augmentation in the presented xenograft model.
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Borisov, Stanislav, Ekaterina Koltunova, and Sergei Kladiev. "Traction asynchronous electric drive of mine electric locomotivesimulation model structure improvement." Journal of Mining Institute 247 (March 16, 2021): 1–8. http://dx.doi.org/10.31897/pmi.2021.1.12.
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The article discusses the solution to the problem of underground railway transport slipping in dynamic modes, which occurs when there is a significant difference in the speeds of the driving and driven pairs of wheels. The state of the rail surfaces largely determines the coefficient of adhesion, therefore, using a mathematical model, the condition for the dependence of the magnitude of slipping and tractive effort is selected. For effective acceleration and deceleration of an electric locomotive, it is necessary to control the coefficient of adhesion at a certain level. A simulation model of rolling stock has been created, which for the first time takes into account a mechanical system with distributed parameters. In the structural diagram of the automatic control system of traction electric drives with frequency regulation, such factors as the volume of goods being moved, rolling friction, slope (rise) levels and the state of the rail track are taken into account. The simulation results show the features of the movement and stops of the freight train not only by the diagrams of speed and forces in the modes of acceleration-deceleration and uniform movement, but also the positions of the plungers and tractive forces on the couplings of the electric locomotive and all trolleys involved in the movement of goods. The practical application of the proposed method lies in the possibility of starting a heavily laden train from its place on the ascent section in conditions of insufficient adhesion coefficient with contaminated roads.
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Savos’kin, A. N., and N. D. Shilin. "Analysis of wheel pairs slip control of electric freight locomotive with asynchronous traction motors." RUSSIAN RAILWAY SCIENCE JOURNAL 81, no. 3 (September 6, 2022): 230–39. http://dx.doi.org/10.21780/2223-9731-2022-81-3-230-239.
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Introduction. Every year, the amount of electric rolling stock with asynchronous traction motors is continuously increasing on the Russian railway network, since such traction drives have a number of advantages over drives with DC motors. One of the problems associated with the introduction of asynchronous motors and an increase in the mass of trains is the implementation of the maximum traction force by an electric locomotive at the threshold in terms of wheel – rail adhesion. Timely recognition of excessive slip of wheel pairs is the most important indicator of the efficiency of the traction drive in realising the maximum traction properties of the electric locomotive at all axles.Materials and methods. The article reflects the results of the study of slip of electric locomotive wheel pairs with asynchronous traction motors and axial control of the traction force, obtained during experimental runs on a railway section under various adhesion conditions. The article presents a technique for studying the wheel pair adhesion failure of electric locomotives with asynchronous traction motors.Results. During the comparison of the obtained experimental results with the calculated parameters by the O. Polach mathematical model, an updated range of the relative slip of wheel pairs is given, in which the electric locomotive control system could realise the maximum tractive effort. Exceeding this range will lead to increased wear of wheel pairs without increasing traction properties.Discussion and conclusion. It is advisable to use the results of the study in the future when developing systems for controlling the tractive effort at the limit of adhesion and systems for controlling the slip of wheel pairs of electric freight locomotives with asynchronous traction motors.
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Huang, Xuhui, Ciaron Hamilton, Zonglin Li, Lalita Udpa, Satish S. Udpa, and Yiming Deng. "Capacitive imaging for adhesive bonds and quality evaluation." Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences 378, no. 2182 (September 14, 2020): 20190590. http://dx.doi.org/10.1098/rsta.2019.0590.
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Defective adhesive bonds pose significant threats towards structural integrity due to reduced joint strength. The nature of the adhesion of two solids remains poorly understood since the adhesion phenomenon is relevant to so many scientific and technological areas. A concept that has been gaining our attention from the perspective of non-destructive testing is the properties discontinuity of the adhesion. Discontinued properties depend significantly on the quality of the interface that is formed between adhesive and substrate. In this research, discontinued electrical properties at the interface are considered. The simplified model is free from multidisciplinary knowledge of chemistry, fracture mechanics, mechanics of materials, rheology and other subjects. From a practical standpoint, this emphasizes the need to establish a good relationship between electrical properties of adhesive bonds and corresponding measurements. Capacitive imaging (CI) is a technique where the dielectric property of an object is determined from external capacitance measurements. Thus, it is potentially promising since adhesive and substrate differ in terms of dielectric property. At the interface between adhesive and substrate, discontinuity of the dielectric properties causes abrupt changes in electric field spatial distribution and thus alters capacitance measurement by simulating defects in adhesive joints regarding permittivity uncertainties. Further understanding of the cause of degraded adhesion quality can be obtained. This article is part of the theme issue ‘Advanced electromagnetic non-destructive evaluation and smart monitoring’.
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Lillehoj, E. P., S. W. Hyun, B. T. Kim, X. G. Zhang, D. I. Lee, S. Rowland, and K. C. Kim. "Muc1 mucins on the cell surface are adhesion sites forPseudomonas aeruginosa." American Journal of Physiology-Lung Cellular and Molecular Physiology 280, no. 1 (January 1, 2001): L181—L187. http://dx.doi.org/10.1152/ajplung.2001.280.1.l181.
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Recently, we cloned and characterized a full-length cDNA of the hamster Muc1 gene, the expression of which appears to be associated with secretory cell differentiation (Park HR, Hyun SW, and Kim KC. Am J Respir Cell Mol Biol 15: 237–244, 1996). The role of Muc1 mucins in the airway, however, is unknown. In this study, we investigated whether cell surface mucins are adhesion sites for Pseudomonas aeruginosa. Chinese hamster ovary (CHO) cells not normally expressing Muc1 mucin were stably transfected with the hamster Muc1 cDNA, and binding to P. aeruginosa was examined. Our results showed that 1) stably transfected CHO cells expressed both Muc1 mRNA and Muc1 mucins based on Northern and Western blot analyses, 2) Muc1 mucins present on the cell surface were degraded by neutrophil elastase, and 3) expression of Muc1 mucins on the cell surface resulted in a significant increase in adhesion of P. aeruginosa that was completely abolished by either proteolytic cleavage with neutrophil elastase or deletion of the extracellular domain by mutation. We conclude that Muc1 mucins expressed on the surface of CHO cells serve as adhesion sites for P. aeruginosa, suggesting a possible role for these glycoproteins in the early stage of airway infection and providing a model system for studying epithelial cell responses to bacterial adhesion that leads to airway inflammation in general and cystic fibrosis in particular.
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Conti, Roberto, Enrico Meli, Luca Pugi, Monica Malvezzi, Fabio Bartolini, Benedetto Allotta, Andrea Rindi, and Paolo Toni. "A numerical model of a HIL scaled roller rig for simulation of wheel–rail degraded adhesion condition." Vehicle System Dynamics 50, no. 5 (May 2012): 775–804. http://dx.doi.org/10.1080/00423114.2011.640402.
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Meacci, Martina, Zhiyong Shi, Elisa Butini, Lorenzo Marini, Enrico Meli, and Andrea Rindi. "A local degraded adhesion model for creep forces evaluation: An approximate approach to the tangential contact problem." Wear 440-441 (December 2019): 203084. http://dx.doi.org/10.1016/j.wear.2019.203084.
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Bobo, S. N. "Fatigue Life of Aircraft Tires." Tire Science and Technology 16, no. 4 (October 1, 1988): 208–22. http://dx.doi.org/10.2346/1.2148807.
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Abstract A study was conducted to determine if a safe upper service limit can be set for aircraft tires, based on an operation profile of the aircraft using the tires. The study consisted of three parts: development of a tire heating model, experimental confirmation, and determination of tire degradation as a function of time at temperature. Three operational profiles were identified: long, intermediate, and short haul; these stressed tires in different ways. The mathematical model, which calculated temperature as a function of time for various axial and lateral forces at different speeds, was developed and confirmed by experiment. It predicted the time at temperature of the hottest part of a tire that is exposed to the operating environment of the profiles. The impact of heating was found from a determination of ply adhesion as a function of time at temperature. The end of tire life was judged to occur when ply adhesion was degraded by 50%.
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Alturbeh, Hamid, Julian Stow, Gareth Tucker, and Alan Lawton. "Modelling and simulation of the train brake system in low adhesion conditions." Proceedings of the Institution of Mechanical Engineers, Part F: Journal of Rail and Rapid Transit 234, no. 3 (September 19, 2018): 301–20. http://dx.doi.org/10.1177/0954409718800579.
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This paper describes the current version of the Low Adhesion Braking Dynamic Optimisation for Rolling Stock (LABRADOR) simulation tool that can predict the train brake system performance and support decision-making in the design and optimisation of the braking system including wheel slide protection, sanders and the blending and control of friction and dynamic brakes in low adhesion conditions. The model has been developed in MATLAB/Simulink and is intended to mimic the braking performance of both older and newer generations of multiple unit passenger trains. LABRADOR models have been initially validated by comparing simulation results for a single car train (Class 153) and two-car train (Class 158) in dry conditions with experimental tests, for tare and crush laden vehicles. This project is supported by RSSB and a technical steering group composed of railway braking experts, suppliers and train operators and manufacturers.
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Dybala, Vojtech, Martin Libensky, Bohumil Sulc, and Cyril Oswald. "Slip and Adhesion in a Railway Wheelset Simulink Model Proposed for Detection Driving Conditions Via Neural Networks." Transactions of the VŠB - Technical University of Ostrava, Mechanical Series 64, no. 1 (July 19, 2018): 1–13. http://dx.doi.org/10.22223/tr.2018-1/2038.
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Ashaie, Maeirah, and Ezharul Hoque Chowdhury. "Nanoparticles-Facilitated Intracellular Transport of siRNAs against Individual Integrin Subunits Inhibits Growth of Breast Cancer Cells." Applied Sciences 11, no. 22 (November 15, 2021): 10782. http://dx.doi.org/10.3390/app112210782.
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For cells and tissues, cell–cell and cell–extracellular matrix adhesion is important for proliferation, differentiation, and response to mechanical stimuli. This adhesion is provided by various cell adhesion molecules (CAMs). However, in breast cancer, depending upon the type and stage, this adherence is dysregulated where the expression of these cell adhesion molecules is either overregulated or unregulated, triggering essential oncogenic pathways. Thus, to control the invasiveness of tumor cells, and reduce metastasis, regulating the homophilic and heterophilic interaction of these molecules and controlling the essential cell pathways is important. In this study, we targeted critical CAMs- integrins to regulate their aberrated behavior via siRNAs delivery. However, as due to charge repulsion and propensity to be degraded by nucleases prior to reaching the target site, naked siRNAs are unable to cross plasma membrane, use of a suitable carrier vehicle is essential. Thus, we employed carbonate apatite (CA), to deliver the selected siRNAs targeting integrin αv, α6, β1, β3, β4, β5, and β6 subunits to various breast cancer cell lines and 4T1-breast cancer induced murine model. Delivery of individual integrin siRNAs complexed with CA nanoparticles (NPs) reduced cell viability and caused decrease in tumor burden. To check the gene knockdown effects on phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and extracellular signal–regulated kinases/mitogen-activated protein kinase (ERK/MAPK) pathways, Western blot analysis was performed, revealing downregulation of the signaling molecules. Thus, CA-facilitated gene therapy targeting various integrins could poise potential therapeutic modality against breast cancer.
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Suhr, Bettina, William A. Skipper, Roger Lewis, and Klaus Six. "Sanded Wheel–Rail Contacts: Experiments on Sand Crushing Behaviour." Lubricants 11, no. 2 (January 20, 2023): 38. http://dx.doi.org/10.3390/lubricants11020038.
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In railway operation, the sanding process is used to overcome low adhesion conditions in the wheel–rail contact. In the literature, previously conducted research has been experimental, e.g., measuring adhesion coefficients (ACs) under different contact conditions (dry, wet, …) or applying different sands. Under dry conditions, sanding can reduce measured ACs, while under wet conditions different types of rail sand can leave ACs unchanged or increase adhesion. Despite active research, the physical mechanisms causing the change in ACs under sanded conditions are still poorly understood. A possible remedy is the development of advanced models of sanding including local effects. As a basis for such a model, this study presents experimental results concerning single grain crushing behaviour of two types of rail sand under dry and wet contact conditions. Firstly, initial breakage behaviour is investigated with focus on the particle fragments’ size and spread as only fragments within the running band are available to influence the AC during roll-over. Secondly, single grain crushing tests are conducted under realistic wheel–rail load showing the formation of solidified clusters of sand fragments, as well as their size and thickness. This information is important for understanding mechanisms and for future physics-based modelling of the sanding process in wheel–rail contacts.
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Arianna, Carpentieri, Cozzoli Eliana, Acri Flavio, Ranalli Marco, Diedenhofen Giacomo, Scimeca Manuel, Bonanno Elena, and Gambacurta Alessandra. "Rapid Rapamycin-Only Induced Osteogenic Differentiation of Blood-Derived Stem Cells and Their Adhesion to Natural and Artificial Scaffolds." Stem Cells International 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/2976541.
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Stem cells are a centerpiece of regenerative medicine research, and the recent development of adult stem cell-based therapy systems has vigorously expanded the scope and depth of this scientific field. The regeneration of damaged and/or degraded bone tissue in orthopedic, dental, or maxillofacial surgery is one of the main areas where stem cells and their regenerative potential could be used successfully, requiring tissue engineering solutions incorporating an ideal stem cell type paired with the correct mechanical support. Our contribution to this ongoing research provides a new model of in vitro osteogenic differentiation using blood-derived stem cells (BDSCs) and rapamycin, visibly expressing typical osteogenic markers within ten days of treatment. In depth imaging studies allowed us to observe the adhesion, proliferation, and differentiation of BDSCs to both titanium and bone scaffolds. We demonstrate that BDSCs can differentiate towards the osteogenic lineage rapidly, while readily adhering to the scaffolds we exposed them to. Our results show that our model can be a valid tool to study the molecular mechanisms of osteogenesis while tailoring tissue engineering solutions to these new insights.
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Trimpe, Fritz, Sönke Lück, Rolf Naumann, and Corinna Salander. "Simulation of Torsional Vibration of Driven Railway Wheelsets Respecting the Drive Control Response on the Vibration Excitation in the Wheel-Rail Contact Point." Vibration 4, no. 1 (December 25, 2020): 30–48. http://dx.doi.org/10.3390/vibration4010003.
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For the stability verification of railway wheelsets in Germany, dynamic torsional stresses must be respected as they affect the axle and press fit stability of a wheelset. These dynamic stresses are applied to a wheelset by torsional vibration. However, dynamic stresses cannot be predicted by calculation, and so time-consuming and cost-intensive test runs are performed to measure the maximum dynamic stresses. Therefore, this article deals with the setup of a simulation model that shall enable the simulative prediction of maximum dynamic torsional stresses. This model respects that vibration excitation originates from the wheel-rail contact point and that the vibration energy input comes from a high-frequency drive train control. The first results show successful simulation of vibration excitation and correlations between adhesion change and maximum dynamic stresses.
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Dolatabadi, Nader, Ramin Rahmani, Stephanos Theodossiades, Homer Rahnejat, Guy Blundell, and Guillaume Bernard. "Tribodynamics of hydraulic actuated clutch system for engine-downsizing in heavy duty off-highway vehicles." Proceedings of the Institution of Mechanical Engineers, Part D: Journal of Automobile Engineering 233, no. 4 (February 25, 2018): 976–93. http://dx.doi.org/10.1177/0954407018756789.
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Engine downsizing is desired for modern heavy-duty vehicles to enhance fuel economy and reduce emissions. However, the smaller engines usually cannot overcome the parasitic loads during engine start-up. A new clutch system is designed to disconnect the downsized engine from the parasitic losses prior to the idling speed. A multi-scale, multi-physics model is developed to study the clutch system. Multi-body dynamics is used to study the combined translational–rotational motions of the clutch components. A micro-scale contact model is incorporated to represent the frictional characteristics of the sliding surfaces. Although the clutch is designed for dry contact operation, leakage of actuating hydraulic fluid can affect the interfacial frictional characteristics. These are integrated into the multi-body dynamic analysis through tribometric studies of partially wetted surfaces using fresh and shear-degraded lubricants. Multi-scale simulations include sensitivity analysis of key operating parameters, such as contact pressure. This multi-physics approach is not hitherto reported in the literature. The study shows the importance of adhesion in dry clutch engagement, enabling full torque capacity. The same is also noted for any leakage of significantly shear-degraded lubricant into the clutch interfaces. However, the ingression of fresh lubricant into the contact is found to reduce the clutch torque capacity.
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Kruchek, Victor, Aleksander Grishenko, and Tamila Tytova. "Utilization factor of adhesive weight of a locomotive with group tractive engine drive of wheelsets." Proceedings of Petersburg Transport University, no. 2 (June 20, 2017): 267–79. http://dx.doi.org/10.20295/1815-588x-2017-2-267-279.
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Objective: To improve accuracy of analytical calculation of adhesive weight of constructed and newly projected locomotives with wheelset group tractive drive. To bring out analytical dependence of a locomotive’s adhesive weight usage coefficient from a number of wheelsets in a group tractive engine considering constructive features of a vehicle, operating conditions and power equipment cycle of operation. Methods: Analytical dependences and a mathematical model were obtained on the basis of higher mathematics, laws of theoretical mechanics, reliability theory, probability theory, wheel-rail adhesion theory and the laws of self-excited frictional oscillations during slippage. Results: Mathematical model was developed to determine the highest value of a twisting moment, in the process of which occurs different slippage of a wheelset group tractive drive of a locomotive, taking into account the stochastic character of wheel-rail adhesion, shaking at the moment of starting and in the process of running. Characteristic curve of equalizing factor was plotted from a generalized parameter of a locomotive tractive drive. Practical importance: Analytical dependences make it possible to identify the right adhesive weight of a locomotive with wheelset group tractive drive for conducting traction calculations and the assessment of locomotive’s tractive capacity in the process of operation on different cycles of power equipment and movement speed. The level of dynamic load on group tractive drive components was determined, taking into account constructive features of trucks and power transmission, such as the jet thrust location of wheelset axial gear units, as well as maintenance conditions – movement speed and irregularities of a railway track. The results of the study may be applied in projecting the new and constructed locomotives.
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Tudorache, Cristina Mihaela, Razvan Andrei Oprea, and Cornelia Stan. "On the Simulation of Powered Axles Stick-Slip." Applied Mechanics and Materials 809-810 (November 2015): 610–15. http://dx.doi.org/10.4028/www.scientific.net/amm.809-810.610.
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The use of high power railway vehicles requires enhanced control of wheel-rail adherence. When setting the train in motion, driving axles can exhibit torsional vibrations resulting in poor adherence and even axle damage. A significant number of railway authorities safety warnings and accident reports were issued related to the above phenomena. Adhesion saturation and negative slope are the characteristics which lead to self-sustained axial vibration. The aim of the present work is to prove the appropriateness of non-smooth models in the study of the axle torsional stick-slip vibrations which may occur when traction vehicles are set into motion. The model is simple, observes the main friction characteristics and provides the basis for efficient dynamics simulation. An experimental setup comprising a reduced scale wheel set is analyzed in order to validate the model proposed. The friction parameters are then identified using the proposed force-creepage relationship. Validation and verification is further carried out in frequency domain using both steady state and transient manoeuvres. Specific phenomena like discontinuities in the time-history friction force values occur. Validation and verification is carried out in frequency domain using both steady state and transient manoeuvres. From the comparison between the numerical and experimental results, it can be concluded that the setup is modeled accurately. Related problems may be solved using the present method, as it is pointed out in the article.
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Hodivala-Dilke, Kairbaan, and Richard Hynes. "Insights and Questions Arising from Studies of a Mouse Model of Glanzmann Thrombasthenia." Thrombosis and Haemostasis 82, no. 08 (1999): 481–85. http://dx.doi.org/10.1055/s-0037-1615868.
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IntroductionStudies of patients suffering from Glanzmann thrombasthenia (GT) have provided many insights into the role of platelet adhesion in hemostasis and thrombosis,1-3 but they also have raised some unanswered questions. This genetically inherited bleeding disorder arises from mutations in the genes for either subunit of the major platelet integrin, αIIbβ3, or glycoprotein IIb/IIIa (CD41/CD61). These mutations lead to reduced or absent expression of this integrin on platelet surfaces or, in a few cases, to normal levels of expression of functionally defective forms of αIIbβ3.1-6 Normally, αIIbβ3 functions as one of the major adhesion receptors on platelets. It also serves as a receptor for fibrinogen during platelet aggregation and as a receptor for von Willebrand factor (vWF) during platelet adhesion to a damaged vessel wall.7,8 In addition, αIIbβ3 can also act as a fibronectin receptor9,10 or a thrombospondin receptor,11 though the exact importance of these interactions in platelet adhesion and/or aggregation remains unclear.GT patients lacking αIIbβ3, or who express reduced levels or defective forms, have a number of characteristic defects in platelet function. These include defective platelet aggregation in response to a variety of agonists, failure to retract a fibrin clot, and reduced or absent intracellular fibrinogen.1-4 Patients show prolonged bleeding times and spontaneous mucocutaneous and gastrointestinal hemorrhage. Occasional bleeding crises can usually be managed by platelet transfusions, so the mortality is relatively low. Both male and female patients are fertile, and pregnancies can be carried to term, although postpartum hemorrhage and menorrhagia can occur.The features of GT described above are common among patients with mutations in the αIIβ gene or the β3 gene. At one level, that is to be expected, since absence of either subunit destroys the functional heterodimeric integrin, and, indeed, compromises the export of the partner subunit to the surface. As a result, the partner subunit is degraded intracellularly.1-4 However, a complication arises in that the β3 subunit can also partner with another subunit, αv. The αvβ3 receptor is normally present at low levels (50 to 100 copies per platelet compared with 40,000 to 80,000 copies of αIIbβ3 per platelet), and its levels reportedly do not change on GT platelets lacking αIIb. Naturally, it is absent from β3-null platelets, but no defects attributable to the additional absence of αvβ3 have been described.Given the low levels of αvβ3 on platelets, one might not expect a serious hemostatic consequence associated with its loss. However, αvβ3 is also expressed by many other cell types, in contrast with αIIbβ3, which is platelet-specific. Most notably, αvβ3 is expressed by endothelial cells during angiogenesis and has been implicated functionally in angiogenesis.12,13 It is also apparently an integrin of major importance on osteoclasts, where it is believed to play a role in bone remodeling.14,15 The αvβ3 receptor is also expressed by neutrophils, monocytes, macrophages, some T cells, melanomas, glioblastomas, and neural crest cells, among others.16-20 Given this widespread expression and the data implicating αvβ3 in important developmental and physiological processes, one would have predicted that mutations in the β3 gene would have much more severe consequences than the platelet-specific defects associated with mutations in the αIIb gene. Nonetheless, the clinical data on GT patients have failed to reveal clear distinctions between those defective in αIIb and those defective in β3.1-4 At least some of the β3 mutations are nulls, so it is unclear whether such GT patients might exhibit additional defects, for example in angiogenesis, wound repair, or bone remodeling. A few studies have been performed involving limited numbers of GT patients, but there are obvious limitations to the extent of experimentation that can be performed on these patients. Simply put, there are few GT patients, and ethical considerations severely limit possible interventions.
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Rohwerder, M., and M. Stratmann. "Surface Modification by Ordered Monolayers: New Ways of Protecting Materials Against Corrosion." MRS Bulletin 24, no. 7 (July 1999): 43–47. http://dx.doi.org/10.1557/s0883769400052696.
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Metal/polymer composites are used in numerous technical applications. For example, polymer coatings on metal surfaces are used for corrosion protection, metal films on polymers inhibit static buildup, and polymers between two metals can serve as a “glue” for connecting materials that cannot be welded. Polymer/metal composites also play an important role in modern electronics. In condensers, polymers serve as insulating layers between metallic leads and are used to encapsulate entire electronic circuits. In all circumstances, interfaces are formed between the two different materials, and since the chemistry and structure change abruptly, interfacial failure is frequently observed.The cause of failure may just be mechanical (e.g., shrinkage of the polymer during curing), or the interface stability may be degraded by attack of aggressive species, resulting in delamination. More specifically, loss of adhesion is directly caused by interfacial electrochemical reactions that nucleate at a defect and progress into intact regions of the interface. This occurs for encapsulated electronic parts in humid atmospheres as well as for lacquers on automotive parts.Thus the investigation of corrosion reactions at a buried interface is an important area of research, but it is made very difficult by the fact that most electrochemical methods do not give information on localized reaction kinetics at a buried (metal/polymer) interface. This situation has changed with the invention and development of the scanning Kelvin probe (SKP). This method allows, for the first time, local analysis of reactions occurring at a buried metal/polymer interface. Based on the results obtained with the SKP, a detailed reaction model for the delamination process has been developed. This understanding has led to the development of new approaches that protect the interface from delamination. The idea is to chemically modify the interface using Afunctional molecules that promote adhesion between metal and polymer surfaces.
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Liu, Song, Jean Pierre Boutrand, and Marc Tadie. "Use of a collagen-based sealant to prevent in vivo epidural adhesions in an adult rat laminectomy model." Journal of Neurosurgery: Spine 94, no. 1 (January 2001): 61–67. http://dx.doi.org/10.3171/spi.2001.94.1.0061.
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Object. The authors investigated the effect of a collagen-based sealant, Gel Amidon Oxydé (GAO), in the prevention of epidural scar adhesions in an adult rat model of laminectomy. Methods. Seventy-two adult Sprague—Dawley rats underwent an L5–6 laminectomy, after which the dura mater and the left L-4 and L-5 nerve roots were exposed. In the 36 animals that received GAO, the sealant was applied over the dura and around the nerve roots, and it was used to fill the laminectomy cavity before it polymerized. In 36 control animals, the same surgical treatment was performed, but the rats did not receive GAO. During the early postoperative period, a significant decrease in the occurrence of epidural hematoma was found in the GAO-treated rats. In contrast to findings in control rats, a thin white connective tissue layer was found between the dura and surrounding muscles after GAO had degraded and been absorbed. One month posttreatment, no epidural scar adhesion was found between the tissue layer and the dura in the GAO-treated animals. Three months postoperatively, both gross inspection and histological examination further confirmed that formation of epidural adhesions was significantly inhibited in the rats treated with GAO. No special inflammatory reaction was observed, and the healing of skin and muscle lesions was not affected by either treatment. Conclusions. The data obtained in this study suggest that the GAO collagen—based sealant may be an effective biomaterial to prevent epidural adhesions in vivo after laminectomy.
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Jin, Xuesong. "Research Progress of High-Speed Wheel–Rail Relationship." Lubricants 10, no. 10 (September 30, 2022): 248. http://dx.doi.org/10.3390/lubricants10100248.
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The research on wheel–rail relationship includes the basic theoretical models and corresponding numerical methods of wheel–rail in rolling contact, geometric parameter matching and material matching of them, friction and wear, wheel–rail rolling contact fatigue, wheel–rail adhesion and noise. They are also key theoretical and technical problems of the high-speed train/track coupling system. The basic theoretical models of wheel–rail in rolling contact and the corresponding numerical methods are the basis and one of the basic means for solving other wheel–rail relationship problems. The other is the experimental means. Moreover, the modeling and analysis of coupling behavior of the train and track can only be realized by means of the wheel–rail rolling contact mechanics model and its corresponding numerical method. This paper mainly discusses some research work and achievements on high-speed wheel–rail relationship problems since China opened a high-speed railway system on a large scale. The discussions in this paper include the classic wheel–rail rolling contact theoretical models (analytical forms) and the modern wheel–rail rolling contact theories (numerical methods), their advantages and disadvantages, their application and future development direction of them. The reviewed research progress on the other wheel–rail relationships mainly expounds the thorny problems of the wheel–rail relationship encountered in the operation of China’s high-speed railway, how to adopt new theoretical analysis methods, test means and take effective measures to solve these problems. It also includes research results of similar important reference values performed by international peer experts in related fields. Challenging and unsolved problems in high-speed wheel–rail relationship research are also reviewed in the full text.
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Saleh, Omar A., Byoung-jin Jeon, and Tim Liedl. "Enzymatic degradation of liquid droplets of DNA is modulated near the phase boundary." Proceedings of the National Academy of Sciences 117, no. 28 (June 29, 2020): 16160–66. http://dx.doi.org/10.1073/pnas.2001654117.
Full textAbstract:
Biomolecules can undergo liquid–liquid phase separation (LLPS), forming dense droplets that are increasingly understood to be important for cellular function. Analogous systems are studied as early-life compartmentalization mechanisms, for applications as protocells, or as drug-delivery vehicles. In many of these situations, interactions between the droplet and enzymatic solutes are important to achieve certain functions. To explore this, we carried out experiments in which a model LLPS system, formed from DNA “nanostar” particles, interacted with a DNA-cleaving restriction enzyme, SmaI, whose activity degraded the droplets, causing them to shrink with time. By controlling adhesion of the DNA droplet to a glass surface, we were able to carry out time-resolved imaging of this “active dissolution” process. We found that the scaling properties of droplet shrinking were sensitive to the proximity to the dissolution (“boiling”) temperature of the dense liquid: For systems far from the boiling point, enzymes acted only on the droplet surface, while systems poised near the boiling point permitted enzyme penetration. This was corroborated by the observation of enzyme-induced vacuole-formation (“bubbling”) events, which can only occur through enzyme internalization, and which occurred only in systems poised near the boiling point. Overall, our results demonstrate a mechanism through which the phase stability of a liquid affects its enzymatic degradation through modulation of enzyme transport properties.
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Qin, Yanghua, Yan Chen, and Qian Shen. "HMGB1-LPS complex promotes the transformation of SFs to a RASF-like phenotype (P4168)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 172.11. http://dx.doi.org/10.4049/jimmunol.190.supp.172.11.
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Abstract The specific pathogenesis of rheumatoid arthritis (RA) remains unclear. Current views hold that some inflammatory antigens recognize the Toll-like receptors on the synovial fibroblasts (SFs) and then activate downstream signals, leading to the formation of RASFs and the induction of RA. Our previous studies showed that intra-articular injection of the complex of HMGB1 and lipopolysaccharide (LPS) directly induced experimental arthritis in DBA/1 mice; histopathological analysis further revealed synovial thickening with excessive proliferation of SFs. In the present study, osteoarthritis synovial fibroblasts (OASFs) were co-cultured with HMGB1-LPS complex in vitro for 5-8 generations to induce the transformation of human SFs to RA-like SFs (tOASFs). Then the pathogenicity of tOASFs was evaluated, both in vitro and in vivo. Our results showed that tOASFs attached to, invaded and degraded co-implanted cartilage in a SCID mouse model. In addition, histochemistry showed excessive proliferation of tOASFs and the expression of MMPs. In vitro, cell cycle analysis showed more tOASFs passing through the G1/S checkpoint and moving to S or G2 phase. Flow cytometry and confocal microscopy showed significantly reduced apoptosis and enhanced autophagy in tOASFs compared to OASFs, respectively. Finally, we showed upregulated expression of certain receptors and adhesion molecules in tOASFs. This accumulated evidence led to the conclusion that HMGB1-LPS complex promoted the formation of RASFs.
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Qin, Yanghua, Yan Chen, Weiwei Wang, Zhiwei Wang, Gusheng Tang, Shengming Dai, and Qian Shen. "HMGB1-PAMP complex promote the transformation of SFs to RASFs (171.19)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 171.19. http://dx.doi.org/10.4049/jimmunol.188.supp.171.19.
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Abstract The specific pathogenesis mechanism of rheumatoid arthritis (RA) remains unclear, current views believe the transformation of normal synovial fibroblasts (SFs) to RASFs is crucial for the pathogenesis of RA. Our previous studies showed that HMGB1-PAMP complex directly induced experimental arthritis in DBA/1 mice; pathology showed synovial thickening, and SFs excessive proliferation, suggesting that HMGB1-PAMP complex might induce the formation of RASFs. In current study, osteoarthritis synovial fibroblasts (OASFs) isolated from tissue obtained during reconstructive surgery and cocultured with HMGB1-PAMP complex in vitro for 5-8 generations to induce the transformation of normal SFs to RA-like SF (tOASFs). Then the pathogenicity of tOASFs was evaluated both in vitro and in vivo. Our results showed that tOASFs attached to, invaded into and degraded co-implanted cartilage in SCID mouse model. Histochemitry showed tOASFs excessive proliferation, expression MMPs. In vitro, cell cycle analysis showed more tOASFs pass through the G1/S checkpoint and move to S or G2 phage. Flow cytometry and confocal microscope showed significant reduced apoptosis and enhanced autophagy in tOASFs compared to OASFs, respectively. We further showed up-regulated expression of certain receptors (TLR2, TLR4, and RAGE) and adhesion molecules (ICAM-1 and VCAM-1) in tOASFs. In conclusion, we proved that HMGB1-PAMP complex promoted the formation of RASFs.
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Mitchell, W. Beau, Marketa Jirouskova, JiHong Li, and Barry S. Coller. "Differences in αIIbβ3 Biogenesis Dynamics between Umbilical Cord Blood-Derived Human Megakaryocyte-Like Cells and Transfected HEK293 Cells as Revealed by a Mathematical Model." Blood 104, no. 11 (November 16, 2004): 1559. http://dx.doi.org/10.1182/blood.v104.11.1559.1559.
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Abstract Most studies of αIIbβ3 biogenesis have been conducted in transfected HEK293 and CHO cells or megakaryocyte-like cell lines, but the protein processing mechanisms in native megakaryocytes may differ. To address this issue we have studied αIIbβ3 biogenesis in human megakaryocyte-like cells derived from umbilical cord blood (UCB) and in 293 cells stably expressing αIIbβ3, and developed a mathematical model to express the kinetics. The leukocyte pool of whole UCB units was separated by Dextran and Ficoll sedimentation and enriched for CD34+ progenitor cells by negative selection using a commercial antibody panel. These cells were then cultured in the presence of 20 ng/ml thrombopoietin. By day 10 of culture approximately 90% of cells expressed αIIbβ3, 80% expressed GPIb, 45% expressed α2β1 and 55% expressed P-selectin. The cells adhered to fibrinogen and collagen, spread in a manner similar to platelets, and formed focal adhesions as judged by vinculin and phalloidin (F-actin) staining. While αIIbβ3 on the surface of 293 cells cannot undergo inside-out activation, 18% of the UCB-derived cells exhibited increased binding of PAC-1, an activation-specific monoclonal antibody, in response to TRAP, and the majority bound PAC-1 after adhesion to collagen. The ploidy of the UCB-derived cells ranged from 2 to 128. The dynamics of αIIbβ3 biosynthesis was analyzed by pulse-chase analysis with 35S-Cys/Met followed by immunoprecipitation, SDS-PAGE, and densitometry of exposed x-ray film. Using non-linear regression, curves were fitted to the observed data and a 3-compartment mathematical model (pro-αIIb, mature αIIb in complex with β3, and degraded αIIb) was used to describe the αIIb dynamics. There were important similarities and differences between the two types of cells. In both cell types, pro-αIIb decreased over time in a pattern best described by a simple exponential function, P = (a)exp(-bt), where P is the amount of pro-αIIb, a is the initial amount of pro-αIIb, and b is a rate constant. The half-lives (ln2/b) of pro-αIIb in the UCB-derived cells and the 293 cells were similar (120 and 140 min, respectively). In both cell types, mature αIIb increased over time with a pattern best described by a sigmoidal function, M = c/(1+exp(−(x−x0)/d), where M is the measured amount of mature αIIb, c is the asymptotic value of αIIb, d is the rate constant, and x0 is the time to half maximum mature αIIb. In the megakaryocyte-like cells, the time to half maximum (x0) was 120 min, while in the 293 cells it was only 55 min. The amount of pro-αIIb that has been degraded at any time point (D) can be calculated by subtracting the amounts of pro-αIIb and mature αIIb at that time point from the initial amount of pro-αIIb (D = a-P-M). In the UCB-derived cells ~ 25% of pro-αIIb is degraded without being processed to mature αIIb, while in 293 cells ~ 40% is degraded. In both cell types there is a ~90 minute lag time before the onset of net αIIb degradation. These findings suggest that while the ability to degrade αIIb may be similar between megakaryocytes and 293 cells, the folding, complex formation, and quality control mechanisms are quite different. These observations have implications for the study of integrin dynamics and may be useful in analysis of the molecular mechanisms of integrin biogenesis.
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Sawadkar, Prasad, Nandin Mandakhbayar, Kapil D. Patel, Jennifer Olmas Buitrago, Tae Hyun Kim, Poojitha Rajasekar, Ferdinand Lali, et al. "Three dimensional porous scaffolds derived from collagen, elastin and fibrin proteins orchestrate adipose tissue regeneration." Journal of Tissue Engineering 12 (January 2021): 204173142110192. http://dx.doi.org/10.1177/20417314211019238.
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Current gold standard to treat soft tissue injuries caused by trauma and pathological condition are autografts and off the shelf fillers, but they have inherent weaknesses like donor site morbidity, immuno-compatibility and graft failure. To overcome these limitations, tissue-engineered polymers are seeded with stem cells to improve the potential to restore tissue function. However, their interaction with native tissue is poorly understood so far. To study these interactions and improve outcomes, we have fabricated scaffolds from natural polymers (collagen, fibrin and elastin) by custom-designed processes and their material properties such as surface morphology, swelling, wettability and chemical cross-linking ability were characterised. By using 3D scaffolds, we comprehensive assessed survival, proliferation and phenotype of adipose-derived stem cells in vitro. In vivo, scaffolds were seeded with adipose-derived stem cells and implanted in a rodent model, with X-ray microtomography, histology and immunohistochemistry as read-outs. Collagen-based materials showed higher cell adhesion and proliferation in vitro as well as higher adipogenic properties in vivo. In contrast, fibrin demonstrated poor cellular and adipogenesis properties but higher angiogenesis. Elastin formed the most porous scaffold, with cells displaying a non-aggregated morphology in vitro while in vivo elastin was the most degraded scaffold. These findings of how polymers present in the natural polymers mimicking ECM and seeded with stem cells affect adipogenesis in vitro and in vivo can open avenues to design 3D grafts for soft tissue repair.
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Gaide Chevronnay, Héloïse P., Christine Galant, Pascale Lemoine, Pierre J. Courtoy, Etienne Marbaix, and Patrick Henriet. "Spatiotemporal Coupling of Focal Extracellular Matrix Degradation and Reconstruction in the Menstrual Human Endometrium." Endocrinology 150, no. 11 (October 9, 2009): 5094–105. http://dx.doi.org/10.1210/en.2009-0750.
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Coupling of focal degradation and renewal of the functional layer of menstrual endometrium is a key event of the female reproductive biology. The precise mechanisms by which the various endometrial cell populations control extracellular matrix (ECM) degradation in the functionalis while preserving the basalis and the respective contribution of basalis and functionalis in endometrium regeneration are still unclear. We therefore compared the transcriptome of stromal and glandular cells isolated by laser capture microdissection from the basalis as well as degraded and preserved areas of the functionalis in menstrual endometria. Data were validated by in situ hybridization. Expression profile of selected genes was further analyzed throughout the menstrual cycle, and their response to ovarian steroids withdrawal was studied in a mouse xenograft model. Immunohistochemistry confirmed the results at the protein level. Algorithms for sample clustering segregated biological samples according to cell type and tissue depth, indicating distinct gene expression profiles. Pairwise comparisons identified the greatest numbers of differentially expressed genes in the lysed functionalis when compared with the basalis. Strikingly, in addition to genes products associated with tissue degradation (matrix metalloproteinase and plasmin systems) and apoptosis, superficial lysed stroma was enriched in gene products associated with ECM biosynthesis (collagens and their processing enzymes). These results support the hypothesis that fragments of the functionalis participate in endometrial regeneration during late menstruation. Moreover, menstrual reflux of lysed fragments overexpressing ECM components and adhesion molecules could easily facilitate implantation of endometriotic lesions.
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Hügle, T., S. Nasi, D. Ehirchiou, P. Omoumi, A. So, and N. Busso. "POS0393 FIBRIN DEPOSITION IS AN ACTIVE TRIGGER OF CARTILAGE DEGENERATION IN RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 426.1–426. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2521.
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Background:Fibrin(ogen) maintains inflammation in various disorders but has never been linked to cartilage damage in rheumatoid arthritis (RA) or other forms of inflammatory arthritis.Objectives:To investigate the role of fibrin deposition on cartilage integrity in arthritis.Methods:Fibrin deposition on knee cartilage was analyzed by immunohistochemistry in RA patients and in murine adjuvant-induced arthritis (AIA). In chondrocytes, fibrinogen expression (Fgα, Fgβ, Fgγ) and procoagulant activity were evaluated by qRT-PCR and turbidimetry respectively. Fibrin-induced catabolic genes were assessed by qRT-PCR in chondrocytes. Fibrin-mediated chondro-synovial adhesion (CSA) with subsequent cartilage tears was studied in co-cultures of human RA cartilage with autologous synoviocytes, in the AIA model, and by MRI. The link between fibrin and calcification was examined in human RA cartilage stained for calcific deposits and in vitro in fibrinogen-stimulated chondrocytes.Results:Fibrin deposition on cartilage correlated with the severity of cartilage damage in human RA explants and in AIA wildtype (WT) mice, while fibrinogen deficient (Fg-/-) mice were protected. Accordingly, fibrin upregulated catabolic enzymes (Adamts5 and Mmp13) in chondrocytes. Secondly, CSA was present in fibrin-rich and damaged cartilage in AIA WT but not in Fg-/- mice. In line, autologous human synoviocytes, cultured on RA cartilage explants, adhered exclusively to fibrin-positive degraded areas. Gadolinium-enhanced MRI of human joints showed contrast-enhancement along cartilage surface in RA patients but not in controls. Finally, fibrin co-localized with calcification in human RA cartilage and triggered chondrocyte mineralization inducing pro-calcification genes (Anx5, Pit1, Pc1) and cytokine (IL-6). Although at a much lesser extent, we observed similar fibrin-mediated mechanisms in osteoarthritis (OA).Conclusion:Fibrin deposition directly impacts on cartilage integrity via induction of catabolism, mechanical stress, and calcification. Potentially, fibrin is a key factor of cartilage damage occurring in RA as a secondary consequence of inflammation.Disclosure of Interests:None declared
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Habanjar, Ola, Mona Diab-Assaf, Florence Caldefie-Chezet, and Laetitia Delort. "3D Cell Culture Systems: Tumor Application, Advantages, and Disadvantages." International Journal of Molecular Sciences 22, no. 22 (November 11, 2021): 12200. http://dx.doi.org/10.3390/ijms222212200.
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The traditional two-dimensional (2D) in vitro cell culture system (on a flat support) has long been used in cancer research. However, this system cannot be fully translated into clinical trials to ideally represent physiological conditions. This culture cannot mimic the natural tumor microenvironment due to the lack of cellular communication (cell-cell) and interaction (cell-cell and cell-matrix). To overcome these limitations, three-dimensional (3D) culture systems are increasingly developed in research and have become essential for tumor research, tissue engineering, and basic biology research. 3D culture has received much attention in the field of biomedicine due to its ability to mimic tissue structure and function. The 3D matrix presents a highly dynamic framework where its components are deposited, degraded, or modified to delineate functions and provide a platform where cells attach to perform their specific functions, including adhesion, proliferation, communication, and apoptosis. So far, various types of models belong to this culture: either the culture based on natural or synthetic adherent matrices used to design 3D scaffolds as biomaterials to form a 3D matrix or based on non-adherent and/or matrix-free matrices to form the spheroids. In this review, we first summarize a comparison between 2D and 3D cultures. Then, we focus on the different components of the natural extracellular matrix that can be used as supports in 3D culture. Then we detail different types of natural supports such as matrigel, hydrogels, hard supports, and different synthetic strategies of 3D matrices such as lyophilization, electrospiding, stereolithography, microfluid by citing the advantages and disadvantages of each of them. Finally, we summarize the different methods of generating normal and tumor spheroids, citing their respective advantages and disadvantages in order to obtain an ideal 3D model (matrix) that retains the following characteristics: better biocompatibility, good mechanical properties corresponding to the tumor tissue, degradability, controllable microstructure and chemical components like the tumor tissue, favorable nutrient exchange and easy separation of the cells from the matrix.
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Stephenson, Diane, Tinggui Yin, E. Barry Smalstig, Mei Ann Hsu, Jill Panetta, Sheila Little, and James Clemens. "Transcription Factor Nuclear Factor-Kappa B is Activated in Neurons after Focal Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 20, no. 3 (March 2000): 592–603. http://dx.doi.org/10.1097/00004647-200003000-00017.
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Nuclear factor-kappa B (NF-kB) is a multisubunit transcription factor that when activated induces the expression of genes encoding acute-phase proteins, cell adhesion molecules, cell surface receptors, and cytokines. NF-kB is composed of a variety of protein subunits of which p50-and p65-kDa (RelA) are the most widely studied. Under resting conditions, these subunits reside in the cytoplasm as an inactive complex bound by inhibitor proteins, IkBα and IkBβ. On activation, IkB is phosphorylated by IkB kinase and ubiquitinated and degraded by the proteasome; simultaneously, the active heterodimer translocates to the nucleus where it can initiate gene transcription. In the periphery, NF-kB is involved in inflammation through stimulation of the production of inflammatory mediators. The role of NF-kB in the brain is unclear. In vitro, NF-kB activation can be either protective or deleterious. The role of NF-kB in ischemic neuronal cell death in vivo was investigated. Adult male rats were subjected to 2 hours of focal ischemia induced by middle cerebral artery occlusion (MCAO). At 2, 6, and 12 hours after reperfusion, the expression and transactivation of NF-kB in ischemic versus nonischemic cortex and striatum were determined by immunocytochemistry and by electrophoretic mobility gel-shift analysis. At all time points studied, p50 and p65 immunoreactivity was found exclusively in the nuclei of cortical and striatal neurons in the ischemic hemisphere. The contralateral nonischemic hemisphere showed no evidence of nuclear NF-kB immunoreactivity. Double immunofluorescence confirmed expression of p50 in nuclei of neurons. Increased NF-kB DNA-binding activity in nuclear extracts prepared from the ischemic hemisphere was further substantiated by electrophoretic mobility gel-shift analysis. Because the activation of NF-kB by many stimuli can be blocked by antioxidants in vitro, the effect of the antioxidant, LY341122, previously shown to be neuroprotective, on NF-kB activation in the MCAO model was evaluated. No significant activation of NF-kB was found by electrophoretic mobility gel-shift analysis in animals treated with LY341122. These results demonstrate that transient focal cerebral ischemia results in activation of NF-kB in neurons and supports previous observations that neuroprotective antioxidants may inhibit neuronal death by preventing the activation of NF-kB.
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Elg, Margareta, and Helen Zachrisson. "Effect of AR-H067637, the Active Metabolite of the Oral Anticoagulant AZD0837, on Thrombus Formation Using Human Whole Blood in an In Vitro Flow Chamber Model." Blood 112, no. 11 (November 16, 2008): 4049. http://dx.doi.org/10.1182/blood.v112.11.4049.4049.
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Abstract AR-H067637 is a direct thrombin inhibitor derived in vivo from the orally available prodrug AZD0837. AR-H067637 is a reversible and selective direct thrombin inhibitor, which has an inhibition constant, Ki, of 2–4 nmol/L against human alpha-thrombin. During early development of a new anticoagulant drug, data on antithrombotic doses from animal studies may help guide selection of the dose to use in initial human studies. In the present study, using a flow chamber model developed by Badimon and colleagues (Badimon L, et al. J Lab Clin Med1987;110:706–718), the antithrombotic effect of AR-H067637 was evaluated using pig aorta and human whole blood. Following collection of informed consent, blood was taken from 11 healthy subjects into citrate-containing (10%, 0.109 M) tubes. Subjects were not permitted to receive medication for 7 days prior to blood collection. Blood was also collected in EDTA-containing tubes for cell counting. Denuded pig aorta pieces were used as the thrombogenic surface in the flow chamber. AR-H067637 was added to the blood at final blood concentrations ranging from 0.01 to 10 μmol/L, corresponding to plasma concentrations of 0.02 to 16 μmol/L. The blood was drawn for 5 minutes through the flow chamber with a shear of 220−s which is comparable with venous flow rate. The thrombus formed inside the chamber was degraded by plasmin, and platelets attached to the thrombus were lysed. The degradation product of fibrin, D-dimer, and the expression of the platelet cell adhesion molecule P-selectin were used as indirect measures of fibrin and platelet content in the thrombus, respectively. The anticoagulant effect of AR-H067637 was determined using the activated partial thromboplastin time (APTT) and prothrombin time (PT) assays. When using D-dimer levels as a measure of thrombus size, 25%, 50% and 75% thrombus inhibition was estimated to occur at AR-H067637 plasma concentrations of 0.21, 0.48 and 1.32 μmol/L, respectively. A significant inhibition of P-selectin expression by AR-H067637 was seen only at the highest concentration. APTT and PT were shown to be prolonged in a concentration-dependent manner; 50% inhibition of thrombus formation on the pig aorta was obtained at 1.8 and 1.2 times prolongations of APTT and PT, respectively. Hematological parameters such as WBC, RBC, HCT and platelets were all within the normal range. In conclusion, this study demonstrates that AR-H067637, the active metabolite of the oral prodrug AZD0837, has antithrombotic effects, causing concentration-dependent inhibition of thrombus formation measured as fibrin degradation products on the denuded pig aorta. Only a small effect at the highest concentration was observed on inhibition of platelet content in the thrombus, measured by P-selectin. This is in accordance with thrombin being a very potent platelet agonist. Therefore, higher concentrations of a thrombin inhibitor are needed to totally prevent platelet activation and aggregation, compared to those needed to prevent fibrin formation. APTT and PT prolongation correlated with the antithrombotic effect of AR-H067637 with >75% inhibition of fibrin formation at APTT and PT prolongations of 2.4 and 1.7, respectively.
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Pallis, Flavia Rubia, Camila Bononi Almeida, Marcus Corat, Carolina Lanaro, Nicola Conran, Fernando Ferreira Costa, and Carla Fernanda Franco-Penteado. "Rho-Kinase Inhibition Attenuates Airway Inflammation In An Experimental Asthma Model In Sickle Cell Mice." Blood 122, no. 21 (November 15, 2013): 731. http://dx.doi.org/10.1182/blood.v122.21.731.731.
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Abstract Introduction Asthma in sickle cell disease is known to be associated with increased morbidity and an elevated rate of sickle cell complications, such as acute chest syndrome, stroke, vaso-occlusive episodes and early mortality. Experimental asthma increases eosinophil and collagen deposition in the lungs of SCD mice, induces profound increases in pulmonary inflammation, shifts in TH1 and TH2 cytokine production, and airway resistance. A small GTPase, Rho, and its target molecule, Rho-kinase (ROCK), play an important role in cell functions, including contractility, chemotaxis, adhesion, and migration, where the Rho/ROCK-mediated pathway facilitates infiltration of inflammatory cells both in vitro and in vivo. This study was designed to determine whether the Rho/Rho-kinase pathways are involved in eosinophil recruitment and inflammation. To investigate the role of Rho/ROCK in the pathogenesis of SCD asthma, we investigated the effect of fasudil, a specific inhibitor of Rho-kinase, on acute allergic inflammation in SCD mice model. Methods Berkeley SCD mouse bone marrow was transplanted into lethally-irradiated C57BL/6 animals to generate age- and gender-matched genetically identical cohorts of SCD mice. Female SCD mice were sensitized and challenged with ovalbumin (OVA). OVA-challenge mice were treated intraperitoneally with fasudil (10 mg/kg), 1 h before each OVA-challenge. At 48 h after OVA challenged total cell counts, differential cell counts, cytokines, and chemokine levels were measured by ELISA in bronchoalveolar lavage fluid (BALF), and the mRNA expressions of ROCK-1, ROCK-2, IL-6, MMP-8, MMP-9, MMP-12, TIMP-1, TIMP-2 were measured in lungs by RT-PCR. Results Intranasal challenge of OVA in SCD mice induced airway inflammation after 48h, characterized by increases in total leukocytes numbers (WBC) that were almost exclusively accounted for by eosinophils, when compared with non-sensitized mice (WBC: 12.8 ±1.5 vs 5.5 ± 0.68; eosinophils: 6.67 ± 1.2 vs 0.01 ± 0.01, p<0.05, respectively). When fasudil was administer to OVA-challenged SC mice, increased numbers of total cells and eosinophils in the BALF were significantly attenuated (WBC: 6.8 ± 0.6; eosinophils: 1.14 ± 0.33, p<0.05). The numbers of neutrophils were also reduced in animals treated with fasudil (0.84 ± 0.13 vs 2.32 ± 0.34, p<0.05). However, mononuclear cells were not affected by fasudil treatment. ROCK-1 and ROCK-2 mRNA expressions in mice of the asthmatic group (1.2 ± 0.18 and 0.84 ± 0.10, respectively) were similar than those of the non-sensitized group (1.1±0.05 and 0.97±0.04, respectively). When fasudil was administered, the expressions of ROCK-1 and ROCK-2 mRNA did not alter in the asthmatic group (0.96 ± 0.12 and 0.98 ± 0.15, respectively). MMP-2, MMP-8, MMP-9, MMP-12 and TIMP-1 gene expressions were not significantly different between SCD asthmatic mice and SCD non-sensitized mice. Increased IL-6 mRNA levels were detected in the lungs at 48h after OVA challenge (0.83 ± 0.09 vs 0.4 ± 0.1, p<0.05). Lung mRNA expressions of MMPs, TIMP-1 and cytokines were not significantly reduced in SCD mice treated with fasudil. OVA challenge in sensitized SCD mice induced IL-4, IL-5, IL-6, eotaxin, RANTES, MCP-1, TIMP-1 release into BALF (OVA-sensitized: 11.1 ± 3.2, 31.8 ± 7.7, 20.4 ± 4.0, 8.8 ± 2.2, 11.7 ± 1.8, 46.6 ± 7.1, 2239 ± 424.7, respectively vs OVA-nonsensitized:1.1 ± 0.6; 1.4 ± 0.6, 4.1 ± 2.0, 2.3 ± 1.5; 6.9 ± 1.9; 4.6 ± 0.97; 294.3 ± 45.6 pg/ml, p<0.05). Fasudil reduced levels of IL-5, L-6, RANTES, MCP-1, proMMP-9 and TIMP-1 in BALF of SCD mice after OVA challenges (-46.4 fold, -62.5 fold, -41.4 fold, -48.6 fold, -53.6 fold, p<0.05, respectively). Conclusion Administration of fasudil inhibits eosinophil recruitment in response to allergen challenge. The effects of this agent may be mediated by suppressing the production of chemokine and cytokines related to the pathophysiology of bronchial asthma, such as IL-5, RANTES and MCP-1. In addition, the Rho-kinase inhibitor reduced levels of proteins involved in the degraded the extracelular matrix, such as MMP-9, which directly or indirectly promoted the progression of pulmonary inflammatory responses. Our findings provide evidence that inhibition of the Rho/Rho-kinase pathway may be beneficial for pulmonary complications in sickle cell disease. Financial Support FAPESP/CNPq/INCTS Disclosures: No relevant conflicts of interest to declare.
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Keleku-Lukwete, Nadine, Mikiko Suzuki, Akihito Otsuki, Kouhei Tsuchida, Saori Katayama, Makiko Hayashi, Eriko Naganuma, et al. "Keap1-Nrf2 System: Potential Role in Prevention of Sickle Cell Disease Organs Damages and Inflammation." Blood 126, no. 23 (December 3, 2015): 411. http://dx.doi.org/10.1182/blood.v126.23.411.411.
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Abstract Chronic hemolysis in sickle cell disease (SCD) gives rise to intermittent vessel occlusion. Recurrent ischemia-reperfusion generates high levels of reactive oxygen species (ROS) that leads to cell damage. On the other hand, lysed red blood cells (RBC) released free heme into blood stream, which contributes to generation of oxidant microenvironment. ROS burden generated by heme and ischemia-reperfusion injury contributes to endothelial cell activation that promotes inflammatory response with activation of inflammatory mediators. Sickle cell patients bearing high white blood cell (WBC) count develop severe complications of the disease. Nrf2 is a transcription factor that mediates adaptation to oxidative stress and cell defense. Under homeostatic conditions, Nrf2 is trapped by Keap1 and degraded by proteasome pathway. Upon exposure to stress stimuli, such as ROS and electrophiles, Nrf2 is stabilized and activates transcription of cytoprotective and antioxidants genes. Therefore, we hypothesized that Nrf2 activation might be important for tissue protection in SCD. To evaluate the therapeutic effect of Nrf2 activation on SCD, we used a SCD knock-in mouse model bearing human mutated globin loci. Since Keap1 negatively regulated Nrf2 in normal conditions, we crossed the SCD model mice with Keap1 hypomorphic knockdown (Keap1F/-) mice to generate compound mutant (SCD::Keap1F/-) mice, in which Nrf2 was constitutively activated. Histological analysis of the liver and lung revealed that congestive reaction and necrotic area observed in the SCD mice were significantly reduced in the SCD::Keap1F/- mice. Moreover, liver damage marker alanine transferase (ALT) were also decreased in SCD::Keap1F/- mice compared with SCD mice. We further examined inflammation status using human IL6 reporter mouse system and found that inflammation, which was mainly observed in lung of SCD mice, was markedly improved in the SCD::Keap1F/- mice. Expression levels of inflammatory cytokines IL6 and IL1β in the lung as well as adhesion molecules VCAM and P-selectin in the aorta of SCD::Keap1F/- mice were lower than those of the SCD mice. These results indicate that Nrf2 activation improves organ damage and inflammation in the SCD mice. On the other hand, hemolysis of sickle cells and compensatory stress erythropoiesis did not change substantially between the SCD and the SCD::Keap1F/- mice. These results indicate that Nrf2 activation improves organ damage and inflammation independently from improvement of hemolysis. Previous reports show that free heme released from sickle cells gives rise to ROS-mediate pathological process as inflammation and organ damage in SCD. We therefore measured plasma free heme and downstream product indirect bilirubin in the SCD::Keap1F/- mice, and found that both heme and indirect bilirubin was decreased in the SCD::Keap1F/- mice. These results demonstrate that Nrf2 activation improves SCD symptoms at least in part by elimination of free heme. To determine whether chemical compounds that serve as Nrf2 inducers have a protective potential of SCD mice organs, we treated 6-weeks aged mice with an Nrf2 inducer CDDO-Im (20 μmol/kg) 3 times per week for 3 weeks. CDDO-Im administration progressively reduced WBC numbers in the SCD::Keap1F/- mice. Also we observed decrease in the expression level of IL6 and IL1β in the lung and necrotic area in the liver in CDDO-Im-treated SCD::Keap1F/- mice. These results indicate that administration of a chemical Nrf2 inducer relieves inflammation and organ damage in the SCD mice. Collectively, these data provide the evidence that Nrf2 activation improves ROS-mediated organ damages and inflammation. Associated in the therapy of SCD, Nrf2 inducers could be of benefit to SCD patients. Disclosures No relevant conflicts of interest to declare.
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Schneider, Gabriela, Kim ChiHwa, Ahmed Abdel-Latif, Anna Janowska-Wieczorek, Janina Ratajczak, and Mariusz Z. Ratajczak. "A Novel Perspective On Hematopoietic Stem/Progenitor Cell Homing - an Expanding Family of Bone Marrow Homing Factors That Can Support SDF-1-Mediated Homing or Even Replace SDF-1." Blood 120, no. 21 (November 16, 2012): 1247. http://dx.doi.org/10.1182/blood.v120.21.1247.1247.
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Abstract Abstract 1247 Background. Hematopoietic stem progenitor cells (HSPCs) are retained in bone marrow (BM) niches due to the stromal-derived growth factor-1 (SDF-1)–CXCR4 receptor axis and interactions between Very Late Antigen-4 (VLA-4, also known as α 4β1integrin) and its ligand, Vascular Adhesion Molecule-1 (VCAM-1 or CD106). While HSPCs express CXCR4 and VLA-4, their corresponding ligands, SDF-1 and VCAM-1, are expressed by cells in the BM microenvironment (e.g., osteoblasts and fibroblasts). While a role for the SDF-1–CXCR4 axis in the retention of HSPCs in BM under steady-state conditions is undisputed, its role in stem cell homing needs further clarification. For many years, it has been assumed that the chemotactic SDF-1 gradient across the BM–peripheral blood (PB) barrier determines whether cells home from PB into the BM microenvironment. However, this simple explanation has been challenged by several observations supporting the existence of SDF-1–CXCR4-independent homing mechanisms. For example, i) CXCR4−/− fetal liver HSPCs can home to BM in an SDF-1-independent manner, ii) homing of murine HSPCs made refractory to SDF-1 by preincubation and co-injection with a CXCR4 receptor antagonist (AMD3100) is normal or only mildly reduced, iii) HSPCs in which CXCR4 expression is reduced by a SDF-1 intrakine strategy remain able to engraft in lethally irradiated recipients, and, as we recently reported, iv) myeloablative conditioning for transplantation induces a highly proteolytic microenvironment in BM that leads to proteolytic degradation of SDF-1 (Cancer Res. 2010;70:3402, Leukemia. 2012;26:106). Aim of the study. Based on these observations strongly suggesting the involvement of other factors and/or supportive mechanisms in the SDF-1-mediated homing of HSPCs, we became interested in identifying these unknown factors, which support homing of HSPCs when SDF-1 is degraded in the proteolytic microenvironment of BM or even if it is completely absent. Experimental approach. We tested several growth factors, cytokines, bioactive lipids, extracellular nucleotides, and antimicrobial cationic peptides for their potential involvement in homing by employing i) Transwell migration assays and ii) signaling studies in the presence or absence of specific inhibitors. We studied the chemotactic responsiveness of these factors against BM, umbilical cord blood (UCB), and mobilized peripheral blood (mPB) cells. We also focused on the molecular mechanisms responsible for the observed phenomena. Salient observations. Out of >50 different factors tested in addition to SDF-1, only sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), ATP, UTP, and GTP, which are released by cells after BM microenvironment damaged by radio/chemotherapy conditioning for transplantation, were able to chemoattract BM-purified HSPCs. The responsiveness of HSPCs to these factors was inhibited after exposure to pertussis toxin (PTX) and after inhibiting MAPKp42/44 and AKT. Interestingly, in contrast to BM-isolated HSPCs, the chemotactic responsiveness of UCB and mPB HSPCs to these factors was significantly weaker, which suggests desensitization of the corresponding receptors by factors already present in peripheral blood plasma. We also found that BM stroma exposed to myeloablative doses of radio-chemotherapy secretes two antimicrobial cationic peptides, LL-37 and β2-defensin, that, while not direct chemottractants for HSPCs, strongly enhance the responsiveness of HSPCs to an SDF-1 gradient. This phenomenon plays a crucial role in situations in which the SDF-1 homing gradient is impaired by a highly proteolytic BM microenvironment after myeloablative conditioning for transplantation. Conclusions. Since all these direct chemottractants and priming factors are upregulated in BM after myeloblative conditioning for transplantation, a more complex picture of homing emerges that involves several factors that support, and in some situations even replace, the SDF-1–CXCR4 axis. We also conclude that the priming effects by LL-37 and β2-defensin play a critical role in homing of UCB- and mPB-derived HSPCs, which respond robustly to an SDF-1 gradient. Moreover, data in an animal model lend further support to this concept. Disclosures: No relevant conflicts of interest to declare.