Activation of integrins is crucial for recruitment of flowing leukocytes to inflammatory or injured vascular sites, but their spatiotemporal characteristics are incompletely understood. We discovered that β2-integrin activation over the entire surface of neutrophils on immobilized P-selectin occurred via mitogen-activated protein kinase (MAPK) or non-MAPK signaling with a minute-level timescale in a force-dependent manner. In flow, MAPK signaling required intracellular Ca2+ release to activate integrin within 2 min. Integrin activation via non-MAPK signaling occurred first locally in the vicinity of ligated P-selectin glycoprotein ligand-1 (PSGL-1) within sub-seconds, and then over the entire cell surface within 1 min in an extracellular Ca2+ influx-dependent manner. The transition from a local (but rapid) to global (but slow) activation mode was triggered by ligating the freshly activated integrin. Lipid rafts, moesin, actin, and talin were involved in non-MAPK signaling. Fluid loads had a slight effect on local integrin activation with a second-level timescale, but served as enhancers of global integrin activation.
Background: Early accurate detection of coronary artery disease (CAD) is one of the most important medical research areas. Researchers are motivated to utilize machine learning techniques for quick and accurate detection of CAD. Methods: To obtain the high quality of features used for machine learning, we here extracted the coronary bifurcation features from the coronary computed tomography angiography (CCTA) images by using the morphometric method. The machine learning classifier algorithms, such as logistic regression (LR), decision tree (DT), linear discriminant analysis (LDA), k-nearest neighbors (k-NN), artificial neural network (ANN), and support vector machine (SVM) were applied for estimating the performance by using the measured features. Results: The results showed that in comparison with other machine learning methods, the polynomial-SVM with the use of the grid search optimization method had the best performance for the detection of CAD and had yielded the classification accuracy of 100.00%. Among six examined coronary bifurcation features, the exponent of vessel diameter (n) and the area expansion ratio (AER) were two key features in the detection of CAD. Conclusions: This study could aid the clinicians to detect CAD accurately, which may probably provide an alternative method for the non-invasive diagnosis in clinical.
Integrin activation is a predominant step for cell–cell and cell–ECM interactions. Talin and Kindlin are mechanosensitive adaptor proteins that bind to the integrin cytoplasmic tail and mediate integrin activation, cytoskeleton rearrangement, and focal adhesion assembly. However, knowledge about how Talin and Kindlin synergistically assist integrin activation remains unclear. Here, we performed so-called “ramp-clamp” SMD simulations, which modeled the mechanosignaling from Kindlin, to investigate the effect of tension on the interaction of the β1 integrin cytoplasmic tail with the Talin-F3 domain. The present results showed that mild but not excessive stretching enhanced the binding of integrin with Talin. This mechanical regulation on integrin affinity to Talin referred to an event cascade, in which under stretching, the integrin cytoplasmic tail adopted allostery in response to the mechanical stimulus, remodeling of integrin in favor of Talin-association ensued, and finally, a stable, close-knit complex was formed. In the cascade, the torsion angle transition of integrin was the cue for the stable interaction of the complex under tensile force. The present work suggested a model for Talin and Kindlin to synergistically activate integrin. It should help understand integrin activation and its mechanochemical regulation mechanism, integrin-related innate cellular immune responses, cell adhesion, cell–cell interaction, and integrin-related drug development.
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