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Respiratory diseases are a global burden, with millions of deaths attributed to pulmonary illnesses and dysfunctions. Therapeutics have been developed, but they present major limitations regarding pulmonary bioavailability and product stability. To circumvent such limitations, we developed room-temperature-stable inhalable lung-derived extracellular vesicles or exosomes (Lung-Exos) as mRNA and protein drug carriers. Compared with standard synthetic nanoparticle liposomes (Lipos), Lung-Exos exhibited superior distribution to the bronchioles and parenchyma and are deliverable to the lungs of rodents and nonhuman primates (NHPs) by dry powder inhalation. In a vaccine application, severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein encoding mRNA-loaded Lung-Exos (S-Exos) elicited greater immunoglobulin G (IgG) and secretory IgA (SIgA) responses than its loaded liposome (S-Lipo) counterpart. Importantly, S-Exos remained functional at room-temperature storage for one month. Our results suggest that extracellular vesicles can serve as an inhaled mRNA drug-delivery system that is superior to synthetic liposomes.

Cell behavior is influenced by the biophysical properties of their microenvironments, and the linear elastic properties of substrates strongly influences adhesion, migration, and differentiation responses. Because most biological tissues exhibit non-linear elastic properties, there is a growing interest in understanding how the viscous component of materials and tissues influences cell fate. Here we describe the use of microgel thin films with controllable non-linear elastic properties for investigating the role of material loss tangent on cell adhesion, migration, and myofibroblastic differentiation, which have implications in fibrotic responses. Fibroblast modes of migration are dictated by film loss tangent; high loss tangent induced ROCK-mediated amoeboid migration while low loss tangent induced Rac-mediated mesenchymal cell migration. Low loss tangent films were also associated with higher levels of myofibroblastic differentiation. These findings have implications in fibrosis and indicate that slight changes in tissue viscoelasticity following injury could contribute to early initiation of fibrotic related responses.

Excessive bleeding and resulting complications are a major cause of death in both trauma and surgical settings. Recently, there have been a number of investigations into the design of synthetic hemostatic agents with platelet-mimicking activity to effectively treat patients suffering from severe hemorrhage. We developed platelet-like particles from microgels composed of polymers carrying polyethylene glycol (PEG) side-chains and fibrin-targeting single domain variable fragment antibodies (PEG-PLPs). Comparable to natural platelets, PEG-PLPs were found to enhance the fibrin network formation in vitro through strong adhesion to the emerging fibrin clot and physical, non-covalent cross-linking of nascent fibrin fibers. Furthermore, the mechanical reinforcement of the fibrin mesh through the incorporation of particles into the network leads to a ∼three-fold decrease of the overall clot permeability as compared to control clots. However, transport of biomolecules through the fibrin clots, such as peptides and larger proteins is not hindered by the presence of PEG-PLPs and the altered microstructure. Compared to control clots with an elastic modulus of 460+/−260 Pa, PEG-PLP-reinforced fibrin clots exhibit higher degrees of stiffness as demonstrated by the significantly increased average Younǵs modulus of 1770 +/±720 Pa, as measured by AFM force spectroscopy. Furthermore, in vitro degradation studies with plasmin demonstrate that fibrin clots formed in presence of PEG-PLPs withstand hydrolysis for 24 h, indicating enhanced stabilization against exogenous fibrinolysis. The entire set of data suggests that the designed platelet-like particles have high potential for use as hemostatic agents in emergency medicine and surgical settings.

Wound healing is a complex, dynamic process required for maintaining homeostasis in an organism. Along with being controlled biochemically, wound healing is also controlled through the transduction of biophysical stimuli through cell interactions with the extracellular matrix (ECM). This review provides an overview of the ECM's role in the wound healing process and subsequently expands on the variety of roles biophysical phenomenon play.

The essay sets out what electric markets might look like if the pricing proposed in value of solar studies were adopted for every resource.

Fibronectin (Fn) is a promiscuous ligand for numerous cell adhesion receptors or integrins. The vast majority of Fn-integrin interactions are mediated through the Fn Arg-Gly-Asp (RGD) motif located within the tenth type III repeat. In the case of integrins αIIbβ3 and α5β1, the integrin binds RGD and the synergy site (PHSRN) located within the adjacent ninth type III repeat. Prior work has shown that these synergy-dependent integrins are exquisitely sensitive to perturbations in the Fn integrin binding domain conformation. Our own prior studies of epithelial cell responses to recombinant fragments of the Fn integrin binding domain led us to hypothesize that integrin α3β1 binding may also be modulated by the synergy site. To explore this hypothesis, we created a variety of recombinant variants of the Fn integrin binding domain: (i) a previously reported (Leu → Pro) stabilizing mutant (FnIII9'10), (ii) an Arg to Ala synergy site mutation (FnIII9(R)→(A)10), (iii) a two-Gly (FnIII9(2G)10) insertion, and (iv) a four-Gly (FNIII9(4G)10) insertion in the interdomain linker region and used surface plasmon resonance to determine binding kinetics of integrin α3β1 to the Fn fragments. Integrin α3β1 had the highest affinity for FnIII9'10 and FnIII9(2G)10. Mutation within the synergy site decreased integrin α3β1 binding 17-fold, and the four-Gly insertion decreased binding 39-fold compared with FnIII9'10. Cell attachment studies demonstrate that α3β1-mediated epithelial cell binding is greater on FnIII9'10 compared with the other fragments. These studies suggest that the presence and spacing of the RGD and synergy sites modulate integrin α3β1 binding to Fn.

A critical evaluation of the arguments used by solar DG advocates shows that those arguments may often overvalue solar DG. It is time to reassess the value of solar DG from production to dispatch and to calibrate our pricing policies to make certain that our efforts are equitable and carrying us in the right direction.

Fibrinogen is one of the primary components of the coagulation cascade and rapidly forms an insoluble matrix following tissue injury. In addition to its important role in hemostasis, fibrin acts as a scaffold for tissue repair and provides important cues for directing cell phenotype following injury. Because of these properties and the ease of polymerization of the material, fibrin has been widely utilized as a biomaterial for over a century. Modifying the macroscopic properties of fibrin, such as elasticity and porosity, has been somewhat elusive until recently, yet with a molecular-level rational design approach it can now be somewhat easily modified through alterations of molecular interactions key to the protein's polymerization process. This review outlines the biochemistry of fibrin and discusses methods for modification of molecular interactions and their application to fibrin based biomaterials.

The development of tissue engineering scaffolds has focused on mimicking the natural biochemical and biophysical environment of the extracellular matrix (ECM). In this review, we describe a variety of strategies aimed at reproducing and also simplifying the ECM. Despite the progress that has been made, the degree of complexity that needs to be incorporated into these scaffolds is still not known. We begin by describing the ECM and its biological functions followed by outlining current efforts to engineer ECMs with both natural and synthetic polymers. We then focus on colloidal particles as potential artificial ECM components that could increase the complexity as modular building blocks. Drawing from examples from the literature we present the broad utility of colloids and describe how these applications could be useful in the development of ECM mimetic systems.

A close look at the details of state and local programs in support of distributed generation raises some questions about the whether the promotion of green DG actually advances environmental objectives, especially when it takes place in a context of ‘net metering’ and flat residential electricity rates. It is time to reassess where we are going and to calibrate our pricing and policies to make certain that our efforts are carrying us in the right direction.

Reforming, reducing, and eliminating parts of the encargos embedded in electric tariffs in Brazil, will allow for sending better price signals to customers and market participants alike, dramatically increase transparency, promote more efficient pricing, remove a major economic burden from customers, and ultimately lead to greater competition in the electricity marketplace.

While the past 20 years have seen the rapid development of wholesale electricity markets, sophisticated wholesale pricing has largely failed to be replicated in state retail markets. The emergence of Smart Grid technology, including metering and use of the Internet, has the very real potential to reduce, if not entirely remove, the disconnect between wholesale and retail markets, and enhance overall economic and energy efficiency.

The relative paucity of jurisdictions that are non-parochial in their siting and eminent domain practices gives pause to those who envision robust regional markets. The situation is such that very serious consideration needs to be given to providing for federal or, possibly, regional siting and eminent domain authority.

By confining regulators to judicial constraints when they are acting in a legislative capacity, the Herculean task of directing the path of electricity restructuring is being undertaken under rules that require decision-makers to be utterly passive and only minimally inquisitive. Regulators should be free, when acting in their quasi-legislative capacities, to act like legislators and not like judges.

Detroit Edison's suit to halt the Michigan Commission's limited retail wheeling experiment could result in two ironies: (1) Edison may still be required to wheel to retail customers, but at rates less likely to be fully compensatory, and (2) its generation will be more devalued than it would have been without the suit.

Fibrin clot formation has been studied to determine the mechanical properties of fibrin fibers modified by blocking the B-b knob-pocket interaction. Synthetic B-knob peptides AHRPYAAC or AHRPYAAC-Peg have been added to a fibrinogen solution to allow for binding to the b-pockets prior to clot formation. After fibrin clot formation, a combined atomic force microscopic (AFM)/optical microscopic technique was used to study the properties of individual fibrin fibers in buffer. Mechanical testing of fibers was done using the AFM to laterally stretch individual fibers suspended over 13.5μm wide groves in a transparent substrate. The optical microscope, located below the sample, was used to monitor the stretching process. We found that the density and lateral aggregation of fibers was hindered by blocking the b-pockets with the synthetic B-knobs. Fibrin fibers modified with the synthetic peptide AHRPYAAC-Peg were found to stretch to 2.27 times their original length before rupturing compared to unmodified fibrin fibers which were found to stretch to 2.47 times their original length. From these results it is expected that synthetic B-knob concentration impacts the mechanical properties of modified fibrin fibers. The binding constants for AHRPYAAC were found to be 30.3 μM and 80.1 μM while the binding constants for AHRPYAAC-Peg were found to be 1.75 mM and 57.2 μM.