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"Edwards, Brian"
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Amyloid accelerator polyphosphate fits as the mystery density in α-synuclein fibrils
Aberrant aggregation of α-Synuclein is the pathological hallmark of a set of neurodegenerative diseases termed synucleinopathies. Recent advances in cryo-electron microscopy have led to the structural determination of the first synucleinopathy-derived α-Synuclein fibrils, which contain a non-proteinaceous, “mystery density” at the core of the protofilaments, hypothesized to be highly negatively charged. Guided by previous studies that demonstrated that polyphosphate (polyP), a universally conserved polyanion, significantly accelerates α-Synuclein fibril formation, we conducted blind docking and molecular dynamics simulation experiments to model the polyP binding site in α-Synuclein fibrils. Here, we demonstrate that our models uniformly place polyP into the lysine-rich pocket, which coordinates the mystery density in patient-derived fibrils. Subsequent in vitro studies and experiments in cells revealed that substitution of the 2 critical lysine residues K43 and K45 with alanine residues leads to a loss of all previously reported effects of polyP binding on α-Synuclein, including stimulation of fibril formation, change in filament conformation and stability as well as alleviation of cytotoxicity. In summary, our study demonstrates that polyP fits the unknown electron density present in in vivo α-Synuclein fibrils and suggests that polyP exerts its functions by neutralizing charge repulsion between neighboring lysine residues.
Journal Article
Phosphorylations and Acetylations of Cytochrome c Control Mitochondrial Respiration, Mitochondrial Membrane Potential, Energy, ROS, and Apoptosis
Cytochrome c (Cytc) has both life-sustaining and cellular death-related functions, depending on subcellular localization. Within mitochondria, Cytc acts as a single electron carrier as part of the electron transport chain (ETC). When released into the cytosol after cellular insult, Cytc triggers the assembly of the apoptosome, committing the cell to intrinsic apoptosis. Due to these dual natures, Cytc requires strong regulation by the cell, including post-translational modifications, such as phosphorylation and acetylation. Six phosphorylation sites and three acetylation sites have been detected on Cytc in vivo. Phosphorylations at T28, S47, Y48, T49, T58, and Y97 tend to be present under basal conditions in a tissue-specific manner. In contrast, the acetylations at K8, K39, and K53 tend to be present in specific pathophysiological conditions. All of the phosphorylation sites and two of the three acetylation sites partially inhibit respiration, which we propose serves to maintain an optimal, intermediate mitochondrial membrane potential (ΔΨm) to minimize reactive oxygen species (ROS) production. Cytc phosphorylations are lost during ischemia, which drives ETC hyperactivity and ΔΨm hyperpolarization, resulting in exponential ROS production thus causing reperfusion injury following ischemia. One of the acetylation sites, K39, shows a unique behavior in that it is gained during ischemia, stimulating respiration while blocking apoptosis, demonstrating that skeletal muscle, which is particularly resilient to ischemia-reperfusion injury compared to other organs, possesses a different metabolic strategy to handle ischemic stress. The regulation of Cytc by these post-translational modifications underscores the importance of Cytc for the ETC, ΔΨm, ROS production, apoptosis, and the cell as a whole.
Journal Article
After the American century : the ends of U.S. culture in the Middle East
\"When Henry Luce announced in 1941 that we were living in the 'American century,' he believed that the international popularity of American culture made the world favorable to U.S. interests. Now, in the digital twenty-first century, the American century has been superseded, as American movies, music, video games, and television shows are received, understood, and transformed in unexpected ways. How do we make sense of this shift? Building on a decade of fieldwork in Cairo, Casablanca, and Tehran, Brian T. Edwards maps new routes of cultural exchange that are innovative, accelerated, and full of diversions. Shaped by the digital revolution, these paths are entwined with the growing fragility of American 'soft' power. They indicate an era after the American century, in which popular American products and phenomena--such as comic books, teen romances, social-networking sites, and ways of expressing sexuality--are stripped of their associations with the United States and recast in very different forms. Arguing against those who talk about a world in which American culture is merely replicated or appropriated, Edwards focuses on creative moments of uptake, in which Arabs and Iranians make something unpredicted. He argues that these products do more than extend the reach of the original. They reflect a world in which culture endlessly circulates and gathers new meanings\"--From publisher's website.
Book
A single inverse-designed photonic structure that performs parallel computing
In the search for improved computational capabilities, conventional microelectronic computers are facing various problems arising from the miniaturization and concentration of active electronics. Therefore, researchers have explored wave systems, such as photonic or quantum devices, for solving mathematical problems at higher speeds and larger capacities. However, previous devices have not fully exploited the linearity of the wave equation, which as we show here, allows for the simultaneous parallel solution of several independent mathematical problems within the same device. Here we demonstrate that a transmissive cavity filled with a judiciously tailored dielectric distribution and embedded in a multi-frequency feedback loop can calculate the solutions of a number of mathematical problems simultaneously. We design, build, and test a computing structure at microwave frequencies that solves two independent integral equations with any two arbitrary inputs and also provide numerical results for the calculation of the inverse of four 5 x 5 matrices.
Optical analog computing has so far been mostly limited to solving a single instance of a mathematical problem at a time. Here, the authors show that the linearity of the wave equation allows to solve several problems simultaneously, and demonstrate it using an MW transmissive cavity.
Journal Article
A hat for Mrs. Goldman : a story about knitting and love
Sophia knits a special hat for her elderly neighbor and knitting teacher, Mrs. Goldman.
Book
Achieving asymmetry and trapping in diffusion with spatiotemporal metamaterials
The process of diffusion is central to the ever increasing entropic state of the universe and is fundamental in many branches of science and engineering. Although non-reciprocal metamaterials are well developed for wave systems, the studies of diffusive metamaterials have been limited by their characteristic spatial inversion symmetry and time inversion antisymmetry. Here, we achieve large spatial asymmetric diffusion characteristics inside a metamaterial whose material parameters are space- and time-modulated. Inside such a spatiotemporal metamaterial, diffusion occurs as if the material had an intrinsic flow velocity, whose direction is dictated by the relative phase between the modulations of the conductivity and capacity. This creates dramatic out-of-equilibrium concentrations and depletions, which we demonstrate experimentally for the diffusion of electric charges in a one-dimensional electrical system composed of an array of space-time-modulated variable capacitors and switches. These results may offer exciting possibilities in various fields, including electronics, thermal management, chemical mixing, etc.
Being able to manipulate the temporal evolution and spatial distribution of diffusive quantities would provide exciting possibilities for applications. Here, the authors show that one can achieve large spatial asymmetric diffusion characteristics inside a metamaterial whose material parameters are space- and time-modulated.
Journal Article
Cardiac Tyrosine 97 Phosphorylation of Cytochrome c Regulates Respiration and Apoptosis
It was previously reported that tyrosine 97 (Y97) of cytochrome c is phosphorylated in cow heart tissue under physiological conditions. Y97 phosphorylation was shown to partially inhibit respiration in vitro in the reaction with purified cytochrome c oxidase. Here, we use phosphomimetic Y97E Cytc to further characterize the functional effects of this modification both in vitro and in cell culture models. In vitro, phosphomimetic Y97E Cytc showed lower activity in the reaction with purified cow heart cytochrome c oxidase (COX), decreased caspase-3 activity, and reduced rate of reduction. Additionally, the phosphomimetic Y97E Cytc tended to be resistant to heme degradation and showed an increased rate of oxidation. Intact mouse Cytc double knockout fibroblasts were transfected with plasmids coding for phosphomimetic Y97E Cytc and other variants. Compared to cells expressing wild-type Cytc, the cells expressing phosphomimetic Y97E Cytc showed reduced respiration, mitochondrial membrane potential, and reactive oxygen species production, and protection from apoptosis. In an oxygen–glucose deprivation/reoxygenation cell culture model of ischemia/reperfusion injury, mitochondrial membrane potential and reactive oxygen species production were decreased. These data show that Cytc phosphorylation controls the overall flux through the electron transport chain by maintaining optimal intermediate ΔΨm potentials for efficient ATP production while minimizing reactive oxygen species production, thus protecting the cell from apoptosis.
Journal Article