Neurodegenerative Diseases: Unraveling the Heterogeneity of Astrocytes.

The astrocyte population, around 50% of human brain cells, plays a crucial role in maintaining the overall health and functionality of the central nervous system (CNS). Astrocytes are vital in orchestrating neuronal development by releasing synaptogenic molecules and eliminating excessive synapses. They also modulate neuronal excitability and contribute to CNS homeostasis, promoting neuronal survival by clearance of neurotransmitters, transporting metabolites, and secreting trophic factors. Astrocytes are highly heterogeneous and respond to CNS injuries and diseases through a process known as reactive astrogliosis, which can contribute to both inflammation and its resolution. Recent evidence has revealed remarkable alterations in astrocyte transcriptomes in response to several diseases, identifying at least two distinct phenotypes called A1 or neurotoxic and A2 or neuroprotective astrocytes. However, due to the vast heterogeneity of these cells, it is limited to classify them into only two phenotypes. This review explores the various physiological and pathophysiological roles, potential markers, and pathways that might be activated in different astrocytic phenotypes. Furthermore, we discuss the astrocyte heterogeneity in the main neurodegenerative diseases and identify potential therapeutic strategies. Understanding the underlying mechanisms in the differentiation and imbalance of the astrocytic population will allow the identification of specific biomarkers and timely therapeutic approaches in various neurodegenerative diseases.

Advancing Alzheimer's Therapeutics: Exploring the Impact of Physical Exercise in Animal Models and Patients.

Alzheimer's disease (AD) is the main neurodegenerative disorder characterized by several pathophysiological features, including the misfolding of the tau protein and the amyloid beta (Aß) peptide, neuroinflammation, oxidative stress, synaptic dysfunction, metabolic alterations, and cognitive impairment. These mechanisms collectively contribute to neurodegeneration, necessitating the exploration of therapeutic approaches with multiple targets. Physical exercise has emerged as a promising non-pharmacological intervention for AD, with demonstrated effects on promoting neurogenesis, activating neurotrophic factors, reducing Aß aggregates, minimizing the formation of neurofibrillary tangles (NFTs), dampening inflammatory processes, mitigating oxidative stress, and improving the functionality of the neurovascular unit (NVU). Overall, the neuroprotective effects of exercise are not singular, but are multi-targets. Numerous studies have investigated physical exercise's potential in both AD patients and animal models, employing various exercise protocols to elucidate the underlying neurobiological mechanisms and effects. The objective of this review is to analyze the neurological therapeutic effects of these exercise protocols in animal models and compare them with studies conducted in AD patients. By translating findings from different approaches, this review aims to identify opportune, specific, and personalized therapeutic windows, thus advancing research on the use of physical exercise with AD patients.

Patterns of asexual reproduction of the soybean aphid, Aphis glycines (Matsumura), with and without the secondary symbionts Wolbachia and Arsenophonus, on susceptible and resistant soybean genotypes.

Plant breeding is used to develop crops with host resistance to aphids, however, virulent biotypes often develop that overcome host resistance genes. We tested whether the symbionts, Arsenophonus (A) and Wolbachia (W), affect virulence and fecundity in soybean aphid biotypes Bt1 and Bt3 cultured on whole plants and detached leaves of three resistant, Rag1, Rag2 and Rag1 + 2, and one susceptible, W82, soybean genotypes. Whole plants and individual aphid experiments of A. glycines with and without Arsenophonus and Wolbachia did not show differences in overall fecundity. Differences were observed in peak fecundity, first day of deposition, and day of maximum nymph deposition of individual aphids on detached leaves. Bt3 had higher fecundity than Bt1 on detached leaves of all plant genotypes regardless of bacterial profile. Symbionts did not affect peak fecundity of Bt1 but increased it in Bt3 (A+W+) and all Bt3 strains began to deposit nymphs earlier than the Bt1 (A+W-). Arsenophonus in Bt1 delayed the first day of nymph deposition in comparison to aposymbiotic Bt1 except when reared on Rag1 + 2. For the Bt1 and Bt3 strains, symbionts did not result in a significant difference in the day they deposited the maximum number of nymphs nor was there a difference in survival or variability in number of nymphs deposited. Variability of number of aphids deposited was higher in aphids feeding on resistant plant genotypes. The impact of Arsenophonus on soybean aphid patterns of fecundity was dependent on the aphid biotype and plant genotype. Wolbachia alone had no detectable impact but may have contributed to the increased fecundity of Bt3 (A+W+). An individual based model, using data from the detached leaves experiment and with intraspecific competition removed, found patterns similar to those observed in the greenhouse and growth chamber experiments including a significant interaction between soybean genotype and aphid strain. Combining individual data with the individual based model of population growth isolated the impact of fecundity and host resistance from intraspecific competition and host health. Changes to patterns of fecundity, influenced by the composition and concentration of symbionts, may contribute to competitive interactions among aphid genotypes and influence selection on virulent aphid populations.

Effects of Voluntary Physical Exercise on the Neurovascular Unit in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Histopathologically, AD presents two pathognomonic hallmarks: (1) neurofibrillary tangles, characterized by intracellular deposits of hyperphosphorylated tau protein, and (2) extracellular amyloid deposits (amyloid plaques) in the brain vasculature (cerebral amyloid angiopathy; CAA). It has been proposed that vascular amyloid deposits could trigger neurovascular unit (NVU) dysfunction in AD. The NVU is composed primarily of astrocytic feet, endothelial cells, pericytes, and basement membrane. Although physical exercise is hypothesized to have beneficial effects against AD, it is unknown whether its positive effects extend to ameliorating CAA and improving the physiology of the NVU. We used the triple transgenic animal model for AD (3xTg-AD) at 13 months old and analyzed through behavioral and histological assays, the effect of voluntary physical exercise on cognitive functions, amyloid angiopathy, and the NVU. Our results show that 3xTg-AD mice develop vascular amyloid deposits which correlate with cognitive deficits and NVU alteration. Interestingly, the physical exercise regimen decreases amyloid angiopathy and correlates with an improvement in cognitive function as well as in the underlying integrity of the NVU components. Physical exercise could represent a key therapeutic approach in cerebral amyloid angiopathy and NVU stability in AD patients.

Effect of the density of pillar-patterned substrates on contact mechanics: Transition from top to mixed contact with a detailed pressure-field description.

Different contact regimes between a spherical lens and a periodically patterned substrate are observed, when they are pressed against each other. Top contact occurs when only the highest substrate sections touch the lens, whereas mixed contact implies that both the highest and the lowest substrate sections come into contact with the lens. In this paper, we study how the pattern density of the substrate, along with its physical properties and those of the lens, determine the transition from top contact to mixed contact. Experiments and numerical simulations had been performed, as complementary approaches to obtain data, and a theoretical analysis has been developed to gain insight on the effect of the physical parameters on the contact transition. As a result, a phase diagram is presented, in terms of the load and the contact radius, that combines the observations of the three approaches (experimental, numerical, and theoretical), unveiling the boundaries of three contact regimes: (1) deterministic-driven contact, (2) top contact, and (3) mixed contact.

Triple Leidenfrost Effect: Preventing Coalescence of Drops on a Hot Plate.

We report on the collision-coalescence dynamics of drops in Leidenfrost state using liquids with different physicochemical properties. Drops of the same liquid deposited on a hot concave surface coalesce practically at contact, but when drops of different liquids collide, they can bounce several times before finally coalescing when the one that evaporates faster reaches a size similar to its capillary length. The bouncing dynamics is produced because the drops are not only in Leidenfrost state with the substrate, they also experience Leidenfrost effect between them at the moment of collision. This happens due to their different boiling temperatures, and therefore, the hotter drop works as a hot surface for the drop with lower boiling point, producing three contact zones of Leidenfrost state simultaneously. We called this scenario the triple Leidenfrost effect.

Deformation of a Liquid Near an AFM Tip: Molecular Dynamics Approach.

The interaction between an atomic force microscopy (AFM) probe and a thin film of water deposited over a flat substrate is studied using molecular dynamics (MD). The effects of the film thickness and the probe radius on both the deformation height of the liquid interface and the distance of the jump to contact at which the liquid comes in direct contact with the probe are investigated. The dynamics of the surface deformation and the role of interface fluctuations are studied in detail. The systems considered belong to the thin-film regime described in a semianalytical model previously established by Ledesma-Alonso et al. (Langmuir 2013, 29, 7749-7757). MD simulations predict that for shallow films, both the distance at which the jump to contact occurs and the surface maximal deformation height increase steadily with the layer thickness regardless of the probe radius, which is in agreement with the previously proposed theoretical model. The deformation of the surface was shown to be unstable because of the strong effect of thermal fluctuations. For each of the considered systems, the film thickness was such that interface fluctuations induced the jump to contact. The comparison of the deformation obtained in MD with the profiles predicted by the continuous model points out the complementarity between the two approaches. The results of the molecular approach not only are consistent with those of the continuous model but also provide more information on the description of nanoscale phenomena. In particular, MD results point out the importance of fluctuations when it comes to the description of the particular dynamics of nanosystems involving soft interfaces. This shows the need to improve continuous models by complementing them with a molecular approach for a better accuracy.

Effect of the image resolution on the statistical descriptors of heterogeneous media.

The characterization and reconstruction of heterogeneous materials, such as porous media and electrode materials, involve the application of image processing methods to data acquired by scanning electron microscopy or other microscopy techniques. Among them, binarization and decimation are critical in order to compute the correlation functions that characterize the microstructure of the above-mentioned materials. In this study, we present a theoretical analysis of the effects of the image-size reduction, due to the progressive and sequential decimation of the original image. Three different decimation procedures (random, bilinear, and bicubic) were implemented and their consequences on the discrete correlation functions (two-point, line-path, and pore-size distribution) and the coarseness (derived from the local volume fraction) are reported and analyzed. The chosen statistical descriptors (correlation functions and coarseness) are typically employed to characterize and reconstruct heterogeneous materials. A normalization for each of the correlation functions has been performed. When the loss of statistical information has not been significant for a decimated image, its normalized correlation function is forecast by the trend of the original image (reference function). In contrast, when the decimated image does not hold statistical evidence of the original one, the normalized correlation function diverts from the reference function. Moreover, the equally weighted sum of the average of the squared difference, between the discrete correlation functions of the decimated images and the reference functions, leads to a definition of an overall error. During the first stages of the gradual decimation, the error remains relatively small and independent of the decimation procedure. Above a threshold defined by the correlation length of the reference function, the error becomes a function of the number of decimation steps. At this stage, some statistical information is lost and the error becomes dependent on the decimation procedure. These results may help us to restrict the amount of information that one can afford to lose during a decimation process, in order to reduce the computational and memory cost, when one aims to diminish the time consumed by a characterization or reconstruction technique, yet maintaining the statistical quality of the digitized sample.

Active versus Passive Hard Disks against a Membrane: Mechanical Pressure and Instability.

We experimentally study the mechanical pressure exerted by a set of respectively passive isotropic and self-propelled polar disks onto two different flexible unidimensional membranes. In the case of the isotropic disks, the mechanical pressure, inferred from the shape of the membrane, is identical for both membranes and follows the equilibrium equation of state for hard disks. On the contrary, for the self-propelled disks, the mechanical pressure strongly depends on the membrane in use and thus is not a state variable. When self-propelled disks are present on both sides of the membrane, we observe an instability of the membrane akin to the one predicted theoretically for active Brownian particles against a soft wall. In that case, the integrated mechanical pressure difference across the membrane cannot be computed from the sole knowledge of the packing fractions on both sides, further evidence of the absence of an equation of state.

Liquid Droplets Act as "Compass Needles" for the Stresses in a Deformable Membrane.

We examine the shape of droplets atop deformable thin elastomeric films prepared with an anisotropic tension. As the droplets generate a deformation in the taut film through capillary forces, they assume a shape that is elongated along the high tension direction. By measuring the contact line profile, the tension in the membrane can be completely determined. Minimal theoretical arguments lead to predictions for the droplet shape and membrane deformation that are in excellent agreement with the data. On the whole, the results demonstrate that droplets can be used as probes to map out the stress field in a membrane.

van der Waals interaction between a moving nano-cylinder and a liquid thin film.

We study the static and dynamic interaction between a horizontal cylindrical nano-probe and a thin liquid film. The effects of the physical and geometrical parameters, with a special focus on the film thickness, the probe speed, and the distance between the probe and the free surface are analyzed. Deformation profiles have been computed numerically from a Reynolds lubrication equation, coupled to a modified Young-Laplace equation, which takes into account the probe/liquid and the liquid/substrate non-retarded van der Waals interactions. We have found that the film thickness and the probe speed have a significant effect on the threshold separation distance below which the jump-to-contact instability is triggered. These results encourage the use of horizontal cylindrical nano-probes to scan thin liquid films, in order to determine either the physical or geometrical properties of the latter, through the measurement of interaction forces.

Near-field deformation of a liquid interface by atomic force microscopy.

We experiment the interaction between a liquid puddle and a spherical probe by Atomic Force Microscopy (AFM) for a probe radius R ranging from 10 nm to 30 µm. We have developed a new experimental setup by coupling an AFM with a high-speed camera and an inverted optical microscope. Interaction force-distance curves (in contact mode) and frequency shift-distance curves (in frequency modulation mode) are measured for different bulk model liquids for which the probe-liquid Hamaker constant H_{pl} is known. The experimental results, analyzed in the frame of the theoretical model developed in Phys. Rev. Lett. 108, 106104 (2012)PRLTAO0031-900710.1103/PhysRevLett.108.106104 and Phys. Rev. E 85, 061602 (2012)PLEEE81539-375510.1103/PhysRevE.85.061602, allow to determine the "jump-to-contact" critical distance d_{min} below which the liquid jumps and wets the probe. Comparison between theory and experiments shows that the probe-liquid interaction at nanoscale is controlled by the liquid interface deformation. This work shows a very good agreement between the theoretical model and the experiments and paves the way to experimental studies of liquids at the nanoscale.

Stress concentration in periodically rough Hertzian contact: Hertz to soft-flat-punch transition.

We report on the elastic contact between a spherical lens and a patterned substrate, composed of a hexagonal lattice of cylindrical pillars. The stress field and the size of the contact area are obtained by means of numerical methods: a superposition method of discrete pressure elements and an iterative bisection-like method. For small indentations, a transition from a Hertzian to a soft-flat-punch behaviour is observed when the surface fraction of the substrate that is covered by the pillars is increased. In particular, we present a master curve defined by two dimensionless parameters, which allows one to predict the stress at the centre of the contact region in terms of the surface fraction occupied by pillars. The transition between the limiting contact regimes, Hertzian and soft-flat-punch, is well described by a rational function. Additionally, a simple model to describe the Boussinesq-Cerruti-like contact between the lens and a single elastic pillar, which takes into account the pillar geometry and the elastic properties of the two bodies, is presented.

Dynamics of a thin liquid film interacting with an oscillating nano-probe.

The dynamic interaction between a local probe and a viscous liquid film, which provokes the deformation of the latter, has been studied. The pressure difference across the air-liquid interface is calculated with a modified Young-Laplace equation, which takes into account the effects of gravity, surface tension, and liquid film-substrate and probe-liquid attractive interaction potentials. This pressure difference is injected into the lubrication approximation equation, in order to depict the evolution of a viscous thin-film. Additionally, a simple periodic function is added to an average separation distance, in order to define the probe motion. The aforementioned coupled equations, which describe the liquid film dynamics, were analysed and numerically solved. The liquid surface undergoes a periodic motion: the approaching probe provides an input energy to the film, which is stored by the latter by increasing its surface deformation; afterwards, when the probe moves away, an energy dissipation process occurs as the surface attempts to recover its original flat shape. Asymptotic regimes of the film surface oscillation are discerned, for extreme probe oscillation frequencies, and several length, wavenumber and time scales are yielded from our analysis, which is based on the Hankel transform. For a given probe-liquid-substrate system, with well-known physical and geometric parameters, a periodic stationary regime and instantaneous and delayed probe wetting events are discerned from the numerical results, depending on the combination of oscillation parameters. Our results provide an interpretation of the probe-liquid film coupling phenomenon, which occurs whenever an AFM test is performed over a liquid sample.

AFM tip effect on a thin liquid film.

We study the interaction between an AFM probe and a liquid film deposited over a flat substrate. We investigate the effects of the physical and geometrical parameters, with a special focus on the film thickness E, the probe radius R, and the distance D between the probe and the free surface. Deformation profiles have been calculated from the numerical simulations of the Young-Laplace equation by taking into account the probe/liquid and the liquid/substrate interactions, characterized by the Hamaker constants, Hpl and Hls. We demonstrate that the deformation of a shallow film is determined by a particular characteristic length λF = (2πγE(4)/Hls)(1/2), resulting from the balance between the capillary force (γ is the surface tension) and the van der Waals liquid/substrate attraction. For the case of a bulk liquid, the extent of the interface deformation is simply controlled by the capillary length λC = (γ/Δρg)(1/2). These trends point out two asymptotic regimes, which in turn are bounded by two characteristic film thicknesses Eg = (Hls/2πΔρg)(1/4) and Eγ = (R(2)Hls/2πγ)(1/4). For E > Eg, the bulk behavior is recovered, and for E < Eγ, we show the existence of a particular shallow film regime in which a localized tip effect is observed. This tip effect is characterized by the small magnitude of the deformation and an important restriction of its radial extent λF localized below the probe. In addition, we have found that the film thickness has a significant effect on the threshold separation distance Dmin below which the irreversible jump-to-contact process occurs: Dmin is probe radius-dependent for the bulk whereas it is film-thickness-dependent for shallow films. These results have an important impact on the optimal AFM scanning conditions.

Multiscale deformation of a liquid surface in interaction with a nanoprobe.

The interaction between a nanoprobe and a liquid surface is studied. The surface deformation depends on physical and geometric parameters, which are depicted by employing three dimensionless parameters: Bond number B_{o}, modified Hamaker number H_{a}, and dimensionless separation distance D. The evolution of the deformation is described by a strongly nonlinear partial differential equation, which is solved by means of numerical methods. The dynamic analysis of the liquid profile points out the existence of a critical distance D_{min}, below which the irreversible wetting process of the nanoprobe happens. For D ≥ D_{min}, the numerical results show the existence of two deformation profiles, one stable and another unstable from the energetic point of view. Different deformation length-scales, characterizing the stable liquid equilibrium interface, define the near- and the far-field deformation zones, where self-similar profiles are found. Finally, our results allow us to provide simple relationships between the parameters, which leads to determine the optimal conditions when performing atomic force microscope measurements over liquids.

Nanoscale deformation of a liquid surface.

We study the interaction between a solid particle and a liquid interface. A semianalytical solution of the nonlinear equation that describes the interface deformation points out the existence of a bifurcation behavior for the apex deformation as a function of the distance. We show that the apex curvature obeys a simple power-law dependency on the deformation. Relationships between physical parameters disclose the threshold distance at which the particle can approach the liquid before capillarity provokes a "jump to contact." A prediction of the interface original position before deformation takes place, as well as the attraction force measured by an approaching probe, are produced. The results of our analysis agree with the force curves obtained from atomic force microscopy experiments over a liquid puddle.

Study of the velocity and strain fields in the flow through prosthetic heart valves.

A comparative experimental study of the velocity field and the strain field produced down-stream of biological and mechanical artificial valves is presented. In order to determine the spatial and temporal distributions of these fields, a phase-locked stereoscopic particle image velocimetry (or 3D-PIV) technique was implemented. Emphasis was placed on the identification of the fundamental differences between the extensional and the shear components of the strain tensor. The analysis of the characteristic flows reveal that the strains in every direction may reach high values at different times during the cardiac cycle. It was found that elevated strain levels persist throughout the cardiac cycle as a result of all these contributions. Finally, it is suggested that the frequency with which the strain variations occur at particular instants and locations could be associated to the cumulative damage process of the blood constituents and should be taken into account in the overall assessment of existing valve types, as well as in future design efforts.