Forced, not voluntary, exercise effectively induces neuroprotection in stroke

Previous treadmill exercise studies showing neuroprotective effects have raised questions as to whether exercise or the stress related to it may be key etiologic factors. In this study, we examined different exercise regimens (forced and voluntary exercise) and compared them with the effect of stress-only on stroke protection. Adult male Sprague-Dawley rats (n = 65) were randomly assigned to treatment groups for 3 weeks. These groups included control, treadmill exercise, voluntary running wheel exercise, restraint, and electric shock. Levels of the stress hormone, corticosterone, were measured in the different groups using ELISA. Animals from each group were then subjected to stroke induced by a 2-h middle cerebral artery (MCA) occlusion followed by 48-h reperfusion. Infarct volume was determined in each group, while changes in gene expression of stress-induced heat shock proteins (Hsp) 27 and 70 were compared using real-time PCR between voluntary and treadmill exercise groups. The level of corticosterone was significantly higher in both stress (P < 0.05) and treadmill exercise (P < 0.05) groups, but not in the voluntary exercise group. Infarct volume was significantly reduced (P < 0.01) following stroke in rats exercised on a treadmill. However, the amelioration of damage was not duplicated in voluntary exercise, even though running distance in the voluntary exercise group was significantly (P < 0.01) longer than that of the forced exercise group (4,828 vs. 900 m). Furthermore, rats in the electric shock group displayed a significantly increased (P < 0.01) infarct volume. Expression of both Hsp 27 and Hsp 70 mRNA was significantly increased (P < 0.01) in the treadmill exercise group as compared with that in the voluntary exercise group. These results suggest that exercise with a stressful component, rather than either voluntary exercise or stress alone, is better able to reduce infarct volume. This exercise-induced neuroprotection may be attributable to up-regulation of stress-induced heat shock proteins 27 and 70

Mechanism and Function of Excitable Cortical Waves in Cell Migration

Travelling waves of signaling and cytoskeletal events at the cell cortex have emerged as a common phenomenon in diverse cell types, yet the molecular mechanisms and cellular functions are poorly understood. Here I use the model system Dictyostelium to elucidate principles underlying wave self-organization and illuminate the roles of cortical waves in cell migration. We found that the formation of cortical waves is controlled by two coordinated networks of different time scales: a slow network including Rap/Ras small GTPases, PI3K, and PKB, and a fast one containing Rac small GTPase, F-actin, RacGEF1, and Coronin. These networks displayed hallmarks of excitable media. To illustrate the molecular basis of excitability, I adopted the FKBP-FRB dimerization system for rapid perturbation of wave properties. Acute lowering PIP2 levels or activating Rap/Ras increased the speed and range of waves, elevating PKB activity hindered wave propagation, whereas activating Rac generated unorganized patches of actin polymerization. Linking these observations to a theoretical framework, we mapped the feedback loops within and between the Ras/Rap- and Rac/F-actin- centric networks which together control wave generation. The same perturbations that shifted wave properties also transformed types of cellular protrusion and modes of cell migration. Innate pseudopodia and macropinosomes of Dictyostelium cells were promptly switched to lamellipodia-like protrusions, once the speed and range of waves were elevated. As a result, amoeboid migratory modes transitioned to gliding keratocyte-like or oscillatory mode. On the other hand, filopodia-like protrusions appeared after actin wave propagation was acutely hindered. Taken together, a causal chain of events is revealed: The thresholds of excitable networks control the speed and range of waves, which organize the size and dynamics of cellular protrusions, which determine different cell migratory modes. These suggest that various types of protrusion are on a continuum and the overall state of the excitable networks determines cell morphology. We advance a unifying theory that wave propagation serves as a higher order organizer of cellular protrusions, which might explain migratory transitions found in development and pathological conditions

Mechanism and Function of Excitable Cortical Waves in Cell Migration

Travelling waves of signaling and cytoskeletal events at the cell cortex have emerged as a common phenomenon in diverse cell types, yet the molecular mechanisms and cellular functions are poorly understood. Here I use the model system Dictyostelium to elucidate principles underlying wave self-organization and illuminate the roles of cortical waves in cell migration. We found that the formation of cortical waves is controlled by two coordinated networks of different time scales: a slow network including Rap/Ras small GTPases, PI3K, and PKB, and a fast one containing Rac small GTPase, F-actin, RacGEF1, and Coronin. These networks displayed hallmarks of excitable media. To illustrate the molecular basis of excitability, I adopted the FKBP-FRB dimerization system for rapid perturbation of wave properties. Acute lowering PIP2 levels or activating Rap/Ras increased the speed and range of waves, elevating PKB activity hindered wave propagation, whereas activating Rac generated unorganized patches of actin polymerization. Linking these observations to a theoretical framework, we mapped the feedback loops within and between the Ras/Rap- and Rac/F-actin- centric networks which together control wave generation. The same perturbations that shifted wave properties also transformed types of cellular protrusion and modes of cell migration. Innate pseudopodia and macropinosomes of Dictyostelium cells were promptly switched to lamellipodia-like protrusions, once the speed and range of waves were elevated. As a result, amoeboid migratory modes transitioned to gliding keratocyte-like or oscillatory mode. On the other hand, filopodia-like protrusions appeared after actin wave propagation was acutely hindered. Taken together, a causal chain of events is revealed: The thresholds of excitable networks control the speed and range of waves, which organize the size and dynamics of cellular protrusions, which determine different cell migratory modes. These suggest that various types of protrusion are on a continuum and the overall state of the excitable networks determines cell morphology. We advance a unifying theory that wave propagation serves as a higher order organizer of cellular protrusions, which might explain migratory transitions found in development and pathological conditions

Coupling traction force patterns and actomyosin wave dynamics reveals mechanics of cell motion.

Motile cells can use and switch between different modes of migration. Here, we use traction force microscopy and fluorescent labeling of actin and myosin to quantify and correlate traction force patterns and cytoskeletal distributions in Dictyostelium discoideum cells that move and switch between keratocyte-like fan-shaped, oscillatory, and amoeboid modes. We find that the wave dynamics of the cytoskeletal components critically determine the traction force pattern, cell morphology, and migration mode. Furthermore, we find that fan-shaped cells can exhibit two different propulsion mechanisms, each with a distinct traction force pattern. Finally, the traction force patterns can be recapitulated using a computational model, which uses the experimentally determined spatiotemporal distributions of actin and myosin forces and a viscous cytoskeletal network. Our results suggest that cell motion can be generated by friction between the flow of this network and the substrate

A minimal computational model for three-dimensional cell migration.

During migration, eukaryotic cells can continuously change their three-dimensional morphology, resulting in a highly dynamic and complex process. Further complicating this process is the observation that the same cell type can rapidly switch between different modes of migration. Modelling this complexity necessitates models that are able to track deforming membranes and that can capture the intracellular dynamics responsible for changes in migration modes. Here we develop an efficient three-dimensional computational model for cell migration, which couples cell mechanics to a simple intracellular activator-inhibitor signalling system. We compare the computational results to quantitative experiments using the social amoeba Dictyostelium discoideum. The model can reproduce the observed migration modes generated by varying either mechanical or biochemical model parameters and suggests a coupling between the substrate and the biomechanics of the cell

Thin-film semiconductor perspective of organometal trihalide perovskite materials for high-efficiency solar cells

Organometal trihalide perovskites (OTPs) are arising as a new generation of low-cost active materials for solar cells with efficiency rocketing from 3.5% to over 20% within only five years. From "dye" in dye sensitized solar cells (DSSCs) to "hole conductors" and "electron conductors" in mesoscopic heterojunction solar cells, there has been a dramatic conceptual evolution on the function of OTPs in photovoltaic devices. OTPs were originally used as dyes in Gratzel cells, achieving a high efficiency above 15% which, however, did not manifest the excellent charge transport properties of OTPs. An analogy of OTPs to traditional semiconductors. was drawn after the demonstration of highly efficient planar heterojunction structure OTP devices and the observation of their excellent bipolar transport properties with a large diffusion length exceeding 100 nm in CH3NH3PbI3 (MAPbI(3)) polycrystalline thin films. This review aims to provide the most recent advances in the understanding of the origin of the high OTP device efficiency. Specifically, we will focus on reviewing the progress in understanding (1) the characterization of fantastic optoelectronic property of OTPs, (2) the unusual defect physics that originate the optoelectronic property, (3) morphology control of the perovskite film from fabrication process and film post-treatment, (4) device interface and charge transport layers that dramatically impact device efficiency in the OTP thin-film devices, (5) photocurrent hysteresis, (6) tandem solar cells and (7) stability of the perovskite materials and solar cell devices. (C) 2016 Elsevier B.V. All rights reserved

A dynamic partitioning mechanism polarizes membrane protein distribution

Abstract The plasma membrane is widely regarded as the hub of the numerous signal transduction activities. Yet, the fundamental biophysical mechanisms that spatiotemporally compartmentalize different classes of membrane proteins remain unclear. Using multimodal live-cell imaging, here we first show that several lipid-anchored membrane proteins are consistently depleted from the membrane regions where the Ras/PI3K/Akt/F-actin network is activated. The dynamic polarization of these proteins does not depend upon the F-actin-based cytoskeletal structures, recurring shuttling between membrane and cytosol, or directed vesicular trafficking. Photoconversion microscopy and single-molecule measurements demonstrate that these lipid-anchored molecules have substantially dissimilar diffusion profiles in different regions of the membrane which enable their selective segregation. When these diffusion coefficients are incorporated into an excitable network-based stochastic reaction-diffusion model, simulations reveal that the altered affinity mediated selective partitioning is sufficient to drive familiar propagating wave patterns. Furthermore, normally uniform integral and lipid-anchored membrane proteins partition successfully when membrane domain-specific peptides are optogenetically recruited to them. We propose “dynamic partitioning” as a new mechanism that can account for large-scale compartmentalization of a wide array of lipid-anchored and integral membrane proteins during various physiological processes where membrane polarizes