Differential Signaling by Protease-Activated Receptors: Implications for Therapeutic Targeting

Protease-activated receptors (PARs) are a family of four G protein-coupled receptors that exhibit increasingly appreciated differences in signaling and regulation both within and between the receptor class. By nature of their proteolytic self-activation mechanism, PARs have unique processes of receptor activation, “ligand” binding, and desensitization/resensitization. These distinctive aspects have presented both challenges and opportunities in the targeting of PARs for therapeutic benefit—the most notable example of which is inhibition of PAR1 on platelets for the prevention of arterial thrombosis. However, more recent studies have uncovered further distinguishing features of PAR-mediated signaling, revealing mechanisms by which identical proteases elicit distinct effects in the same cell, as well as how distinct proteases produce different cellular consequences via the same receptor. Here we review this differential signaling by PARs, highlight how important distinctions between PAR1 and PAR4 are impacting on the progress of a new class of anti-thrombotic drugs, and discuss how these more recent insights into PAR signaling may present further opportunities for manipulating PAR activation and signaling in the development of novel therapies.     

Optimization of Mixing and Mass Transfer in In-line Multi-Jet Ozone Contactors Using Computational Fluid Dynamics

Typical ozone mixing and mass transfer calculations are lumped approaches based on ideal operating conditions and can misrepresent behavior in real-life installations. This article models the effect of local hydrodynamics and mixing on the overall mass transfer of ozone into water with the aid of multiphase computational fluid dynamics (CFD). CFD models were validated with measured data from a pipeline ozone contactor installation which was optimized for more rapid, uniform mixing and mass transfer. Results emphasize the sensitivity of mixing quality to nozzle placement, size, orientation and spacing relative to main pipeline diameter and flows.     

The effects of a moisture-wicking fabric shirt on the physiological and perceptual responses during acute exercise in the heat

This study investigated the effects that a form fitted, moisture-wicking fabric shirt, promoted to have improved evaporative and ventilation properties, has on the physiological and perceptual responses during exercise in the heat. Ten healthy male participants completed two heat stress tests consisting of 45 min of exercise (50% VO_2peak) in a hot environment (33 °C, 60% RH). One heat stress test was conducted with the participant wearing a 100% cotton short sleeved t-shirt and the other heat stress test was conducted with the participant wearing a short sleeved synthetic shirt (81% polyester and 19% elastane). Rectal temperature was significantly lower (P < 0.05) in the synthetic condition during the last 15 min of exercise. Furthermore, the synthetic polyester shirt retained less sweat (P < 0.05). As exercise duration increases, the ventilation and evaporation properties of the synthetic garment may prove beneficial in the preservation of body temperature during exercise in the heat.     

Role of salt on adhesion of an epoxy/aluminum (oxide) interface in aqueous environments

Joints held by polymeric adhesives are commonplace in many engineered products, but normal service can require exposure to environmental conditions that present a significant challenge for maintaining the structural integrity of the interface. In particular, aqueous environments can wreak havoc on the joint strength. Here, a mechanistic approach is used to understand the difference in the debonding behavior of an epoxy/aluminum (oxide) interface when exposed to deionized (DI) water and aqueous sodium chloride by correlating macroscopic failure with the sorption of salt and water into the adhesive and its nanoscale distribution. For the epoxy‐aluminum system examined here, the presence of sodium chloride increases the resistance to crack growth in comparison to DI water. The debonding appears to be controlled by water near the buried interface. Salt water decreases the solubility of water in the epoxy and decreases the concentration of water near the buried interface, but the concentration of salt that enters the epoxy is below the detection limit. Thus, even if ions cannot penetrate or sorb into the adhesive, the presence of salt can significantly alter the water distribution within the adhesive and ultimately the strength of the joint. POLYM. ENG. SCI., 56:18–26, 2016. © 2015 Society of Plastics Engineers     

Surface degradation and nanoparticle release of a commercial nanosilica/polyurethane coating under UV exposure

Many coating properties such as mechanical, electrical, and ultraviolet (UV) resistance are greatly enhanced by the addition of nanoparticles, which can potentially increase the use of nanocoatings for many outdoor applications. However, because polymers used in all coatings are susceptible to degradation by weathering, nanoparticles in a coating may be brought to the surface and released into the environment during the life cycle of a nanocoating. Therefore, the goal of this study is to investigate the process and mechanism of surface degradation and potential particle release from a commercial nanosilica/polyurethane coating under accelerated UV exposure. Recent research at the National Institute of Standards and Technology (NIST) has shown that the matrix in an epoxy nanocomposite undergoes photodegradation during exposure to UV radiation, resulting in surface accumulation of nanoparticles and subsequent release from the composite. In this study, specimens of a commercial polyurethane (PU) coating, to which a 5 mass% surface-treated silica nanoparticle solution was added, were exposed to well-controlled, accelerated UV environments. The nanocoating surface morphological changes and surface accumulation of nanoparticles as a function of UV exposure were measured, along with chemical change and mass loss using a variety of techniques. Particles from the surface of the coating were collected using a simulated rain process developed at NIST, and the collected runoff specimens were measured using inductively coupled plasma optical emission spectroscopy to determine the amount of silicon released from the nanocoatings. The results demonstrated that the added silica nanoparticle solution decreased the photodegradation rate (i.e., stabilization) of the commercial PU nanocoating. Although the degradation was slower than the previous nanosilica epoxy model system, the degradation of the PU matrix resulted in accumulation of silica nanoparticles on the nanocoating surface and release to the environment by simulated rain. These experimental data are valuable for developing models to predict the long-term release of nanosilica from commercial PU nanocoatings used outdoors and, therefore, are essential for assessing the health and environmental risks during the service life of exterior PU nanocoatings.     

Physiologic Insulin Resensitization as a Treatment Modality for Insulin Resistance Pathophysiology

Prevalence of type 2 diabetes increased from 2.5% of the US population in 1990 to 10.5% in 2018. This creates a major public health problem, due to increases in long-term complications of diabetes, including neuropathy, retinopathy, nephropathy, skin ulcers, amputations, and atherosclerotic cardiovascular disease. In this review, we evaluated the scientific basis that supports the use of physiologic insulin resensitization. Insulin resistance is the primary cause of type 2 diabetes. Insulin resistance leads to increasing insulin secretion, leading to beta-cell exhaustion or burnout. This triggers a cascade leading to islet cell destruction and the long-term complications of type 2 diabetes. Concurrent with insulin resistance, the regular bursts of insulin from the pancreas become irregular. This has been treated by the precise administration of insulin more physiologically. There is consistent evidence that this treatment modality can reverse the diabetes-associated complications of neuropathy, diabetic ulcers, nephropathy, and retinopathy, and that it lowers HbA1c. In conclusion, physiologic insulin resensitization has a persuasive scientific basis, significant treatment potential, and likely cost benefits.     

Deformation and water loss from solvent filled microcapsules under compressive loads

Microcapsules filled with liquid solvents for CO₂ absorption can be easily deformed due to their elastic polymer shells. We present a combination of experiments and model predictions to demonstrate that modest compressive forces can lead to significant capsule deformation and performance issues for this enabling technology. Contrary to expectations based on Raoult's law, capsules containing aqueous carbonate solution were found to lose water to flows of humidified nitrogen in centimeter-scale packed beds. Water loss increased with gas velocity, suggesting compression was responsible for mass transfer, an interpretation supported by microscope images of deformed and broken capsules. A model for compression induced mass transfer under packed/fluidized bed operating conditions was developed and validated with the experimental data for a range of conditions (gas velocities, temperatures, humidities). Design criteria for future generations of microcapsules that will more effectively resist compression are evaluated.