Despite intense interests in developing blood measurements of Alzheimer's disease (AD), the progress has been confounded by limited sensitivity and poor correlation to brain pathology. Here, we ...present a dedicated analytical platform for measuring different populations of circulating amyloid β (Aβ) proteins - exosome-bound vs. unbound - directly from blood. The technology, termed amplified plasmonic exosome (APEX), leverages in situ enzymatic conversion of localized optical deposits and double-layered plasmonic nanostructures to enable sensitive, multiplexed population analysis. It demonstrates superior sensitivity (~200 exosomes), and enables diverse target co-localization in exosomes. Employing the platform, we find that prefibrillar Aβ aggregates preferentially bind with exosomes. We thus define a population of Aβ as exosome-bound (Aβ42+ CD63+) and measure its abundance directly from AD and control blood samples. As compared to the unbound or total circulating Aβ, the exosome-bound Aβ measurement could better reflect PET imaging of brain amyloid plaques and differentiate various clinical groups.
One of the most striking observations made by Parker Solar Probe during its first solar encounter is the omnipresence of rapid polarity reversals in a magnetic field that is otherwise mostly radial. ...These so-called switchbacks strongly affect the dynamics of the magnetic field. We concentrate here on their macroscopic properties. First, we find that these structures are self-similar, and have neither a characteristic magnitude, nor a characteristic duration. Their waiting time statistics show evidence of aggregation. The associated long memory resides in their occurrence rate, and is not inherent to the background fluctuations. Interestingly, the spectral properties of inertial range turbulence differ inside and outside of switchback structures; in the latter the 1/f range extends to higher frequencies. These results suggest that outside of these structures we are in the presence of lower-amplitude fluctuations with a shorter turbulent inertial range. We conjecture that these correspond to a pristine solar wind.
Mechanical stresses are ever present in the cellular environment, whether through external forces that are applied to tissues or endogenous forces that are generated within the active cytoskeleton. ...Despite the wide array of studies demonstrating that such forces affect cellular signaling and function, it remains unclear whether mechanotransduction in different contexts shares common mechanisms. Here, I discuss possible mechanisms by which applied forces, cell-generated forces and changes in substrate mechanics could exert changes in cell function through common mechanotransduction machinery. I draw from examples that are primarily focused on the role of adhesions in transducing mechanical forces. Based on this discussion, emerging themes arise that connect these different areas of inquiry and suggest multiple avenues for future studies.
Biomaterials engineered with specific bioactive ligands, tunable mechanical properties, and complex architectural features have emerged as powerful tools to probe how cells sense and respond to the ...physical properties of their material surroundings, and ultimately provide designer approaches to control cell function.
Much of our understanding of the biological mechanisms that underlie cellular functions, such as migration, differentiation and force-sensing has been garnered from studying cells cultured on ...two-dimensional (2D) glass or plastic surfaces. However, more recently the cell biology field has come to appreciate the dissimilarity between these flat surfaces and the topographically complex, three-dimensional (3D) extracellular environments in which cells routinely operate in vivo. This has spurred substantial efforts towards the development of in vitro 3D biomimetic environments and has encouraged much cross-disciplinary work among biologists, material scientists and tissue engineers. As we move towards more-physiological culture systems for studying fundamental cellular processes, it is crucial to define exactly which factors are operative in 3D microenvironments. Thus, the focus of this Commentary will be on identifying and describing the fundamental features of 3D cell culture systems that influence cell structure, adhesion, mechanotransduction and signaling in response to soluble factors, which - in turn - regulate overall cellular function in ways that depart dramatically from traditional 2D culture formats. Additionally, we will describe experimental scenarios in which 3D culture is particularly relevant, highlight recent advances in materials engineering for studying cell biology, and discuss examples where studying cells in a 3D context provided insights that would not have been observed in traditional 2D systems.
The development of an electronic skin is critical to the realization of artificial intelligence that comes into direct contact with humans, and to biomedical applications such as prosthetic skin. To ...mimic the tactile sensing properties of natural skin, large arrays of pixel pressure sensors on a flexible and stretchable substrate are required. We demonstrate flexible, capacitive pressure sensors with unprecedented sensitivity and very short response times that can be inexpensively fabricated over large areas by microstructuring of thin films of the biocompatible elastomer polydimethylsiloxane. The pressure sensitivity of the microstructured films far surpassed that exhibited by unstructured elastomeric films of similar thickness, and is tunable by using different microstructures. The microstructured films were integrated into organic field-effect transistors as the dielectric layer, forming a new type of active sensor device with similarly excellent sensitivity and response times.
Fluid shear stress (FSS) from blood flow acting on the endothelium critically regulates vascular morphogenesis, blood pressure, and atherosclerosis 1. FSS applied to endothelial cells (ECs) triggers ...signaling events including opening of ion channels, activation of signaling pathways, and changes in gene expression. Elucidating how ECs sense flow is important for understanding both normal vascular function and disease. EC responses to FSS are mediated in part by a junctional mechanosensory complex consisting of VE-cadherin, PECAM-1, and VEGFR2 2. Previous work suggested that flow increases force on PECAM-1, which initiates signaling 2–4. Deletion of PECAM-1 blocks responses to flow in vitro and flow-dependent vascular remodeling in vivo 2, 5. To understand this process, we developed and validated FRET-based tension sensors for VE-cadherin and PECAM-1 using our previously developed FRET tension biosensor 6. FRET measurements showed that in static culture, VE-cadherin in cell-cell junctions bears significant myosin-dependent tension, whereas there was no detectable tension on VE-cadherin outside of junctions. Onset of shear stress triggered a rapid (<30 s) decrease in tension across VE-cadherin, which paralleled a decrease in total cell-cell junctional tension. Flow triggered a simultaneous increase in tension across junctional PECAM-1, while nonjunctional PECAM-1 was unaffected. Tension on PECAM-1 was mediated by flow-stimulated association with vimentin. These data confirm the prediction that shear increases force on PECAM-1. However, they also argue against the current model of passive transfer of force through the cytoskeleton to the junctions 7, showing instead that flow triggers cytoskeletal remodeling, which alters forces across the junctional receptors.
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•VE-cadherin is under myosin-dependent tension•Flow triggers decreased tension on VE-cadherin by reducing overall contractility•Flow triggers increased tension on PECAM-1 through attachment to vimentin•The data suggest that an unidentified upstream mechanosensor initiates signaling
Forces generated by cells are critical regulators of cell adhesion, signaling, and function, and they are also essential drivers in the morphogenetic events of development. Over the past 20 years, ...several methods have been developed to measure these forces. However, despite recent substantial interest in understanding the contribution of these forces in biology, implementation and adoption of the developed methods by the broader biological community remain challenging because of the inherently multidisciplinary expertise required to conduct and interpret the measurements. In this review, we introduce the established methods and highlight the technical challenges associated with implementing each technique in a biological laboratory.
Observations in the solar wind suggest that the compressive component of inertial-range solar-wind turbulence is dominated by slow modes. The low collisionality of the solar wind allows for ...nonthermal features to survive, which suggests the requirement of a kinetic plasma description. The least-damped kinetic slow mode is associated with the ion-acoustic (IA) wave and a nonpropagating (NP) mode. We derive analytical expressions for the IA-wave dispersion relation in an anisotropic plasma in the framework of gyrokinetics and then compare them to fully kinetic numerical calculations, results from two-fluid theory, and magnetohydrodynamics (MHD). This comparison shows major discrepancies in the predicted wave phase speeds from MHD and kinetic theory at moderate to high β. MHD and kinetic theory also dictate that all plasma normal modes exhibit a unique signature in terms of their polarization. We quantify the relative amplitude of fluctuations in the three lowest particle velocity moments associated with IA and NP modes in the gyrokinetic limit and compare these predictions with MHD results and in situ observations of the solar-wind turbulence. The agreement between the observations of the wave polarization and our MHD predictions is better than the kinetic predictions, which suggests that the plasma behaves more like a fluid in the solar wind than expected.
Cells from many different tissues sense the stiffness and spatial patterning of their microenvironment to modulate their shape and cortical stiffness. It is currently unknown how substrate stiffness, ...cell shape, and cell stiffness modulate or interact with one another. Here, we use microcontact printing and microfabricated arrays of elastomeric posts to independently and simultaneously control cell shape and substrate stiffness. Our experiments show that cell cortical stiffness increases as a function of both substrate stiffness and spread area. For soft substrates, the influence of substrate stiffness on cell cortical stiffness is more prominent than that of cell shape, since increasing adherent area does not lead to cell stiffening. On the other hand, for cells constrained to a small area, cell shape effects are more dominant than substrate stiffness, since increasing substrate stiffness no longer affects cell stiffness. These results suggest that cell size and substrate stiffness can interact in a complex fashion to either enhance or antagonize each other's effect on cell morphology and mechanics.
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