Cyclic stretching-induced epithelial cell reorientation is driven by microtubule-modulated transverse extension during the relaxation phase.
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ABSTRACT:
SUBMITTER: Lien JC
PROVIDER: S-EPMC8292395 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mechanical cues from the extracellular microenvironment play a central role in regulating the structure, function and fate of living cells. Nevertheless, the precise nature of the mechanisms and processes underlying this crucial cellular mechanosensitivity remains a fundamental open problem. Here we provide a novel framework for addressing cellular sensitivity and response to external forces by experimentally and theoretically studying one of its most striking manifestations--cell reorientation to a uniform angle in response to cyclic stretching of the underlying substrate. We first show that existing approaches are incompatible with our extensive measurements of cell reorientation. We then propose a fundamentally new theory that shows that dissipative relaxation of the cell's passively-stored, two-dimensional, elastic energy to its minimum actively drives the reorientation process. Our theory is in excellent quantitative agreement with the complete temporal reorientation dynamics of individual cells measured over a wide range of experimental conditions, thus elucidating a basic aspect of mechanosensitivity.
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Project description:Vascular smooth muscle cells (VSMCs) are subjected to various types of mechanical forces within the vessel wall. Although it is known that VSMCs undergo cell body reorientation in response to mechanical stimulation, how this mechanical stretch is transduced within the cell into biochemical signals causing cytoskeleton reorganization remains unclear. Cofilin, a protein that controls actin dynamics, is activated by Slingshot phosphatase-dependent serine 3 dephosphorylation by redox-dependent mechanisms. Nox4 is a main source of reactive oxygen species (ROS) in the vessel wall that localizes in association with the cytoskeleton. Therefore, we hypothesize that Nox4 mediates redox-dependent activation of cofilin, which is required for cytoskeletal reorganization and cell reorientation after mechanical stimulation. In this study, we found that mechanical stretch stimulates ROS production in VSMCs and that the signaling that leads to cell reorientation requires hydrogen peroxide but not superoxide. Indeed, mechanical stretch induces cofilin activation and stretch-induced cytoskeletal reorganization, and cell reorientation is inhibited in cells where cofilin activity has been downregulated. Importantly, Nox4-deficient cells fail to activate cofilin and to undergo cell reorientation, a phenotype rescued by the expression of a constitutively active cofilin mutant. Our results demonstrate that in VSMCs mechanical stimulation activates cofilin by a Nox4-dependent mechanism and that this pathway is required for cytoskeleton reorganization and cell reorientation.
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Project description:We present the first steps in applying transverse relaxation-optimized spectroscopy (TROSY) techniques to the study of allosterism. Each beta-chain of the hemoglobin (Hb) tetramer has 17 valine residues. We have (15)N-labeled the beta-chain Val residues and detected 16 of the 17 (1)H-(15)N correlation peaks for beta-chain Val of the R state CO-Hb structure by using the TROSY technique. Sequence-specific assignments are suggested, based mainly on analysis of the (1)H pseudocontact-shift increments produced by oxidizing the diamagnetic R state HbCO to the paramagnetic R state fluoromet form. When possible, we support these assignments with sequential nuclear Overhauser effect (NOE) information obtained from a two-dimensional [(1)H,(1)H]-NOESY-TROSY experiment (NOESY, NOE spectroscopy). We have induced further the R-T conformational change by adding the allosteric effector, inositol hexaphosphate, to the fluoromet-Hb sample. This change induces substantial increments in the (1)H and (15)N chemical shifts, and we discuss the implication of these findings in the context of the tentative sequence assignments. These preliminary results suggest that amide nitrogen and amide proton chemical shifts in a selectively labeled sample are site-specific probes for monitoring the allosteric response of the ensemble-averaged solution structure of Hb. More important, the chemical-shift dispersion obtained is adequate to permit a complete assignment of the backbone (15)N/(13)C resonances upon nonselective labeling.
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Project description:The invasion of red blood cells (RBCs) by malaria parasites is a complex dynamic process, in which the infected RBCs gradually lose their deformability and their ability to recover their original shape is greatly reduced with the maturation of the parasites. In this work, we developed two types of cell model, one with an included parasite, and the other without an included parasite. The former is a representation of real malaria-infected RBCs, in which the parasite is treated as a rigid body. In the latter, where the parasite is absent, the membrane modulus and viscosity are elevated so as to produce the same features present in the parasite model. In both cases, the cell membrane is modeled as a viscoelastic triangular network connected by wormlike chains. We studied the transient behaviors of stretching deformation and shape relaxation of malaria-infected RBCs based on these two models and found that both models can generate results in agreement with those of previously published studies. With the parasite maturation, the shape deformation becomes smaller and smaller due to increasing cell rigidity, whereas the shape relaxation time becomes longer and longer due to the cell's reduced ability to recover its original shape.
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Project description:PURPOSE:To evaluate the biophysical processes that generate specific T2 values and their relationship to specific cerebrospinal fluid (CSF) content. MATERIALS AND METHODS:CSF T2s were measured ex vivo (14.1T) from isolated CSF collected from human, rat and non-human primate. CSF T2s were also measured in vivo at different field strength in human (3 and 7T) and rodent (1, 4.7, 9,4 and 11.7T) using different pulse sequences. Then, relaxivities of CSF constituents were measured, in vitro, to determine the major molecule responsible for shortening CSF T2 (2s) compared to saline T2 (3s). The impact of this major molecule on CSF T2 was then validated in rodent, in vivo, by the simultaneous measurement of the major molecule concentration and CSF T2. RESULTS:Ex vivo CSF T2 was about 2.0s at 14.1T for all species. In vivo human CSF T2 approached ex vivo values at 3T (2.0s) but was significantly shorter at 7T (0.9s). In vivo rodent CSF T2 decreased with increasing magnetic field and T2 values similar to the in vitro ones were reached at 1T (1.6s). Glucose had the largest contribution of shortening CSF T2in vitro. This result was validated in rodent in vivo, showing that an acute change in CSF glucose by infusion of glucose into the blood, can be monitored via changes in CSF T2 values. CONCLUSION:This study opens the possibility of monitoring glucose regulation of CSF at the resolution of MRI by quantitating T2.
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Project description:White matter of the brain has been demonstrated to have multiple relaxation components. Among them, the short transverse relaxation time component (T2<40 ms; T2?<25 ms at 3 T) has been suggested to originate from myelin water whereas long transverse relaxation time components have been associated with axonal and/or interstitial water. In myelin water imaging, T2 or T2? signal decay is measured to estimate myelin water fraction based on T2 or T2? differences among the water components. This method has been demonstrated to be sensitive to demyelination in the brain but suffers from low SNR and image artifacts originating from ill-conditioned multi-exponential fitting. In this study, a novel approach that selectively acquires short transverse relaxation time signal is proposed. The method utilizes a double inversion RF pair to suppress a range of long T1 signal. This suppression leaves short T2? signal, which has been suggested to have short T1, as the primary source of the image. The experimental results confirm that after suppression of long T1 signals, the image is dominated by short T2? in the range of myelin water, allowing us to directly visualize the short transverse relaxation time component in the brain. Compared to conventional myelin water imaging, this new method of direct visualization of short relaxation time component (ViSTa) provides high quality images. When applied to multiple sclerosis patients, chronic lesions show significantly reduced signal intensity in ViSTa images suggesting sensitivity to demyelination.
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Project description:BACKGROUND:Flexibility, agility and muscle strength are key factors to either win or lose a game. Recently the effect of a new technique, deep transverse friction massage (DTFM) on muscle extensibility as compared to traditional stretching techniques has been examined. AIM:To compare the effect of DTFM vs static and dynamic stretching techniques on the hamstring's extensibility, agility, and strength amongst Lebanese and Syrian football players. Recording the incidence of non-contact hamstring muscle injury was a secondary objective. METHODS:This study is a single-blinded prospective longitudinal randomized controlled trial. The experiment took place over a period of four weeks. Football players were randomized into three intervention groups (static stretching; dynamic stretching; DTFM). Participants of each group were followed-up carefully by assessors during their intervention sessions three times per week, for a total of 12 sessions and during the data collection. Extensibility, agility, and strength were compared between intervention groups at (baseline; acute; and chronic) phases. Straight leg raise and 1 repetition maximum tests were used to measure the dominant leg hamstring muscle extensibility and maximal strength respectively. T-drill test was used to assess the lower extremities agility. RESULTS:Of 103 Lebanese and Syrian male football players aged between 18 and 35 were sampled from Damascus-Syria and South of Lebanon to participate in this study. Between-groups measures of acute strength (P = 0.011) and chronic extensibility (P = 0.000) solely showed a significant difference, and the static group showed to be superior as compared to the other groups. No loss to follow-up or protocol violation was recorded. CONCLUSION:Static stretching is showing to be superior to the other techniques used, regarding gaining long-term extensibility and short-term maximal muscle strength. In addition, DTFM showed improvements but did not outweigh the effects on footballers' performance when comparing it to static and dynamic techniques. Finally, no difference between the interventions is recorded regarding the rate of muscle injuries incidence.
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Project description:The origin of fracture in epithelial cell sheets subject to stretch is commonly attributed to excess tension in the cells' cytoskeleton, in the plasma membrane, or in cell-cell contacts. Here, we demonstrate that for a variety of synthetic and physiological hydrogel substrates the formation of epithelial cracks is caused by tissue stretching independently of epithelial tension. We show that the origin of the cracks is hydraulic; they result from a transient pressure build-up in the substrate during stretch and compression manoeuvres. After pressure equilibration, cracks heal readily through actomyosin-dependent mechanisms. The observed phenomenology is captured by the theory of poroelasticity, which predicts the size and healing dynamics of epithelial cracks as a function of the stiffness, geometry and composition of the hydrogel substrate. Our findings demonstrate that epithelial integrity is determined in a tension-independent manner by the coupling between tissue stretching and matrix hydraulics.
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Project description:Aromatic side chains are prevalent in protein binding sites, perform functional roles in enzymatic catalysis, and form an integral part of the hydrophobic core of proteins. Thus, it is of great interest to probe the conformational dynamics of aromatic side chains and its response to biologically relevant events. Indeed, measurements of (13)C relaxation rates in aromatic moieties have a long history in biomolecular NMR, primarily in the context of samples without isotope enrichment that avoid complications due to the strong coupling between neighboring (13)C spins present in uniformly enriched proteins. Recently established protocols for specific (13)C labeling of aromatic side chains enable measurement of (13)C relaxation that can be analyzed in a straightforward manner. Here we present longitudinal- and transverse-relaxation optimized pulse sequences for measuring R (1), R (2), and {(1)H}-(13)C NOE in specifically (13)C-labeled aromatic side chains. The optimized R (1) and R (2) experiments offer an increase in sensitivity of up to 35 % for medium-sized proteins, and increasingly greater gains are expected with increasing molecular weight and higher static magnetic field strengths. Our results highlight the importance of controlling the magnetizations of water and aliphatic protons during the relaxation period in order to obtain accurate relaxation rate measurements and achieve full sensitivity enhancement. We further demonstrate that potential complications due to residual two-bond (13)C-(13)C scalar couplings or dipolar interactions with neighboring (1)H spins do not significantly affect the experiments. The approach presented here should serve as a valuable complement to methods developed for other types of protein side chains.
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Project description:An integrative model is proposed to describe the dependence of the transverse relaxation rate of blood water protons (R2blood = 1/T2blood ) on hematocrit fraction and oxygenation fraction (Y). This unified model takes into account (a) the diamagnetic effects of albumin, hemoglobin and the cell membrane; (b) the paramagnetic effect of hemoglobin; (c) the effect of compartmental exchange between plasma and erythrocytes under both fast and slow exchange conditions that vary depending on field strength and compartmental relaxation rates and (d) the effect of diffusion through field gradients near the erythrocyte membrane. To validate the model, whole-blood and lysed-blood R2 data acquired previously using Carr-Purcell-Meiboom-Gill measurements as a function of inter-echo spacing τcp at magnetic fields of 3.0, 7.0, 9.4 and 11.7 T were fitted to determine the lifetimes (field-independent physiological constants) for water diffusion and exchange, as well as several physical constants, some of which are field-independent (magnetic susceptibilities) and some are field-dependent (relaxation rates for water protons in solutions of albumin and oxygenated and deoxygenated hemoglobin, ie, blood plasma and erythrocytes, respectively). This combined exchange-diffusion model allowed excellent fitting of the curve of the τcp -dependent relaxation rate dispersion at all four fields using a single average erythrocyte water lifetime, τery = 9.1 ± 1.4 ms, and an averaged diffusional correlation time, τD = 3.15 ± 0.43 ms. Using this model and the determined physiological time constants and relaxation parameters, blood T2 values published by multiple groups based on measurements at magnetic field strengths of 1.5 T and higher could be predicted correctly within error. Establishment of this theory is a fundamental step for quantitative modeling of the BOLD effect underlying functional MRI.
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