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This paper suggests a chemical mechanism for the earliest stages of Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) flow stresses provide the energy needed to induce molecular conformation changes leading to AD by initiating amyloid-β (Aβ) and tau aggregation. Shear and extensional flow stresses initiate aggregation in the laboratory and in natural biophysical processes. Energy-rich CSF flow regions are mainly found in lower brain regions. MRI studies reveal flow stress “hot spots” in basal cisterns and brain ventricles that have chaotic flow properties that can distort molecules such as Aβ and tau trapped in these regions into unusual conformations. Such fluid disturbance is surrounded by tissue deformation. There is strong mapping overlap between the locations of these hot spots and of early-stage AD pathology. Our mechanism creates pure and mixed protein dimers, followed by tissue surface adsorption, and long-term tissue agitation ultimately inducing chemical reactions forming more stable, toxic oligomer seeds that initiate AD. It is proposed that different flow stress energies and flow types in different basal brain regions produce different neurotoxic aggregates. Proliferating artery hardening is responsible for enhanced heart systolic pulses that drive energetic CSF pulses, whose critical maximum systolic pulse energy location migrates further from the heart with increasing vascular disease. Two glymphatic systems, carotid and basilar, are suggested to contain the earliest Aβ and tau AD disease pathologies. A key to the proposed AD mechanism is a comparison of early chronic traumatic encephalopathy and AD pathologies. Experiments that test the proposed mechanism are needed.

Running is a popular form of exercise that is easily accessible to various populations; endurance running, defined as distances beyond 5 km, continues to grow within the sport. Endurance running-related injuries are common in the lower extremities and are primarily overuse related. A multitude of risk factors for injury exist, including extrinsic factors, such as running distance and frequency, and intrinsic factors, such as biomechanics and nutrition status. Training and rehabilitation techniques vary with a general focus on strengthening and gradual increase in activity, but evidence is mixed, and it is difficult to generalize programs across different running populations. Management of specific running groups, including youth runners, is an area in which additional research is needed. New treatments, such as orthobiologics and wearable technology, have promising potential to optimize performance and recovery and minimize injury. However, they need to be further evaluated with high-quality studies.

Running is a popular form of exercise that is easily accessible to various populations; endurance running, defined as distances beyond 5 km, continues to grow within the sport. Endurance running-related injuries are common in the lower extremities and are primarily overuse related. A multitude of risk factors for injury exist, including extrinsic factors, such as running distance and frequency, and intrinsic factors, such as biomechanics and nutrition status. Training and rehabilitation techniques vary with a general focus on strengthening and gradual increase in activity, but evidence is mixed, and it is difficult to generalize programs across different running populations. Management of specific running groups, including youth runners, is an area in which additional research is needed. New treatments, such as orthobiologics and wearable technology, have promising potential to optimize performance and recovery and minimize injury. However, they need to be further evaluated with high-quality studies.

Cerebrospinal fluid (CSF) flowing through periarterial spaces is integral to the brain’s mechanism for clearing metabolic waste products. Experiments that track tracer particles injected into the cisterna magna (CM) of mouse brains have shown evidence of pulsatile CSF flow in perivascular spaces surrounding pial arteries, with a bulk flow in the same direction as blood flow. However, the driving mechanism remains elusive. Several studies have suggested that the bulk flow might be an artifact, driven by the injection itself. Here, we address this hypothesis with new in vivo experiments where tracer particles are injected into the CM using a dual-syringe system, with simultaneous injection and withdrawal of equal amounts of fluid. This method produces no net increase in CSF volume and no significant increase in intracranial pressure. Yet, particle-tracking reveals flows that are consistent in all respects with the flows observed in earlier experiments with single-syringe injection.

The flow of cerebrospinal fluid (CSF) through perivascular spaces surrounding the vasculature is thought to be an important part of the brain9s mechanism for clearing metabolic waste products, including those associated with disorders such as Alzheimer9s disease. Experiments that track tracer particles injected into the cisterna magna of mouse brains have shown evidence of pulsatile CSF flow in perivascular spaces around pial (surface) arteries, with a bulk (average) flow in the same direction as the blood flow. Although measurements are consistent with the idea that this flow is driven primarily by arterial pulsations, the driving mechanism is still not completely understood, and several published articles have suggested that the bulk flow might be an artifact, driven by the injection itself. Here we address this hypothesis with new in vivo experiments in which the injection of suspended tracer particles into the cisterna magna is done with a dual-syringe system, with simultaneous injection and withdrawal of equal amounts of fluid. This method produces no net increase in CSF volume and no significant increase in intracranial pressure, and yet particle-tracking reveals flows in the pial periarterial spaces that are completely consistent with the flows observed in earlier experiments with single-syringe injection.

The ring-sheared drop is a module for the International Space Station to study sheared fluid interfaces and their influence on amyloid fibril formation. A 2.54-cm diameter drop is constrained by a stationary sharp-edged ring at some latitude and sheared by the rotation of another ring in the other hemisphere. Shearing motion is conveyed primarily by the action of surface shear viscosity. Here, we simulate microgravity in the laboratory using a density-matched liquid surrounding the drop. Upon shearing, the drop’s deformation away from spherical is found to be a result of viscous and inertial forces balanced against the capillary force. We also present evidence that the deformation increases with increasing surface shear viscosity.

Disability is a significant public health problem in the United States with dynamic and complex factors. A holistic approach should be taken towards early intervention and early return to work in order to reduce absence with the goals of maximizing physical, mental, social and economic function in these individuals

Microgravity is potentially a powerful tool for investigating processes that are sensitive to the presence of solid walls, since fluid containment can be achieved by surface tension. One such process is the transformation of protein in solution into amyloid fibrils; these are protein aggregates associated with neurodegenerative diseases such as Alzheimer’s and Parkinson’s. In addition to solid walls, experiments with gravity are also subject to influences from sedimentation of aggregates and buoyancy-driven convection. The ring-sheared drop (RSD) module is a flow apparatus currently under development to study formation of amyloid fibrils aboard the International Space Station (ISS). A 25 mm diameter drop of protein solution will be contained by surface tension and constrained by a pair of sharp-edged tubes, forming two contact rings. Shear can be imparted by rotating one ring with the other ring kept stationary. Here we report on parabolic flights conducted to test the growth and pinning of 10 mm diameter drops of water in under 10 s of microgravity. Finite element method (FEM) based fluid dynamics computations using a commercial package (COMSOL) assisted in the design of the parabolic flight experiments. Prior to the parabolic flights, the code was validated against experiments in the lab (1 g), on the growth of sessile and pendant droplets. The simulations show good agreement with the experiments. This modeling capability will enable the development of the RSD at the 25 mm scale for the ISS.

Predicting the non-Newtonian shear response of soft interfaces in biophysical systems and engineered products has been compromised by the use of linear (Newtonian) constitutive equations. We present a generalized constitutive equation, with tractable material properties, governing the response of Newtonian and non-Newtonian interfaces subjected to a wide range of steady shear. With experiments spanning six decades of shear rate, we capture and unify divergent reports of shear-thinning behavior of monomolecular films of the lipid dipalmitoylphosphatidylcholine, the primary constituent of mammalian cell walls and lung surfactant, at near-physiological packing densities.

The flow in the bulk driven by a viscous interfacial film set in motion by a rotating sharp circular knife edge has been examined through experiments and computations. In the experiments, the water surface is covered by an insoluble monomolecular film of dipalmitoylphosphatidylcholine (DPPC), a molecule of wide interest in biology and medicine. It is shown that the viscous coupling between the interfacial film and the bulk liquid leads to a strong bulk flow. Depending on the surface packing and corresponding surface tension, DPPC monolayers exhibit a wide range of phase morphologies. Upon shearing the monolayer, its viscous response varies from that of an essentially inviscid film at low surface packing, to that of a highly viscous non-Newtonian (shear thinning) film when the packing is dense. The more viscous the film, the stronger the driven bulk flow. We have examined this behaviour for hydrodynamic regimes straddling the Stokes flow regime and where flow inertia is important.

Amyloidogenesis of proteins is of wide interest because amyloid structures are associated with many diseases, including Alzheimer's and type II diabetes. Dozens of different proteins of various sizes are known to form amyloid fibrils. While there are numerous studies on the fibrillization of insulin induced by various perturbations, shearing at fluid interfaces has not received as much attention. Here, we present a study of human insulin fibrillization at room temperature using a deep-channel surface viscometer. The hydrodynamics of the bulk flow equilibrates in just over a minute, but the proteins at the air-water interface exhibit a very slow development during which the surface (excess) shear viscosity deduced from a Newtonian surface model increases slightly over a period of a day and a half. Then, there is a very rapid increase in the surface shear viscosity to effectively unbounded levels as the interface becomes immobilized. Atomic force microscopy shows that fibrils appear at the interface after it becomes immobilized. Fibrillization in the bulk does not occur until much later. This has been verified by concurrent atomic force microscopy and circular dichroism spectroscopy of samples from the bulk. The immobilized interface has zero in-plane shear rate, however due to the bulk flow, there is an increase in the strength of the normal component of the shear rate at the interface, implicating this component of shear in the fibrillization process ultimately resulting in a thick weave of fibrils on the interface. Real-time detection of fibrillization via interfacial rheology may find utility in other studies of proteins at sheared interfaces.