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    • 2018-05-09 12:05:10
    • Article ID: 694279

    SLAC's X-ray Laser Opens New View on Proteins Related to Alzheimer's Disease

    By placing the tiniest strands of proteins on one-atom-thick graphene, scientists capture promising X-ray laser images of these elusive biomolecules that play a key role in neurodegenerative diseases.

    • Credit: Greg Stewart/SLAC National Accelerator Laboratory

      Experiments at SLAC’s Linac Coherent Light Source show the promise of using X-ray free-electron lasers to better understand the structure and function of amyloid fibrils, tiny protein strands that play a role in diseases like Alzheimer’s and Parkinson’s. In this illustration, X-ray light penetrates a sample of amyloid fibrils placed on the honeycomb-like carbon lattice of graphene, a new method that produces cleaner data because the thin graphene virtually disappears from view.

    To learn more about diseases such as Alzheimer’s and Parkinson’s, scientists have zeroed in on invisibly small protein filaments that bunch up to form fibrous clusters called amyloids in the brain: How do these fibrils form and how do they lead to disease?

    Until now, the best tools for studying them have generated limited views, largely because the fibrils strands are so complex and tiny, just a few nanometers thick.

    Now an international research team has come up with a new method with potential for revealing the structure of individual amyloid fibrils with powerful beams of X-ray laser light. They describe it in a report published today in Nature Communications.

    In experiments conducted at the Linac Coherent Light Source (LCLS) at the Department of Energy’s SLAC National Accelerator Laboratory, the scientists placed up to 50 fibrils at a time on a layer of graphene, whose carbon atoms are arranged in a honeycomb-like pattern, and hit them with bursts of X-ray laser light. The graphene, it turned out, was almost transparent to the X-rays, and this allowed them to probe the structures of the delicate fibrils without picking up significant extraneous signals from the graphene layer in individual snapshots.

    While the team did not uncover the complete fibril structure, they said the innovative method they developed at LCLS opens up a promising path for amyloid studies using X-ray free-electron lasers, or XFELs, such as LCLS.

    Carolin Seuring, a scientist at the Center for Free-Electron Laser Science (CFEL) at DESY in Germany and principal author of the paper, said the results suggest this technique could even be used to determine the structure of individual fibrils.

    “There is a common consensus that it is not the amyloid fiber alone, but rather the protofilaments composing the fiber and the process of fibril formation that are toxic to the cell,” she said. “XFEL-based experiments have the potential to overcome the challenges we’ve faced in better understanding amyloid fibrils.”

    The Problem with Amyloids

    While amyloid fibrils are believed to play a major role in the development of neurodegenerative diseases, scientists have recently discovered that they also have other functions, Seuring said.

    “The ‘feel-good hormone’ endorphin, for example, can form amyloid fibrils in the pituitary gland,” she said. “They dissolve into individual molecules when the acidity of their surroundings changes, after which these molecules can fullfil their purpose in the body. Other amyloid proteins, such as those found in post-mortem brains of patients suffering from Alzheimer’s, accumulate as amyloid fibrils in the brain, and cannot be broken down and therefore impair brain function in the long term.”

    Accurate information about the structure of amyloid fibrils can inform scientists about their function, she added.

    “Our aim is to understand the role of the formation and structure of amyloid fibrils in the body and in the development of neurodegenerative diseases,” Seuring said.

    One barrier to studying amyloid fibrils is that they cannot be grown as crystals, which are the conventional targets for structural studies using X-rays. And because individual amyloid fibrils are so small, they don’t produce a measurable signal when exposed to X-rays. Scientists typically line up millions of fibrils parallel to each other to amplify the signal, but information about their individual differences is lost in the process.

    “A major part of our understanding about amyloid fibrils is derived from nuclear magnetic resonance and cryo-electron microscopy data,” Seuring said. But these methods are also of limited value for seeing individual differences between amyloid fibrils or observing their formation. “The structural analysis of amyloids is complex and examining them using existing methods is hampered by differences between the fibrils within a single sample,’” she said “Being able to look at the individual components of the sample would make it possible to determine the 3D structure of one type of fibril at a time.”

    The New Approach

    Earlier attempts to study fibrils at X-ray lasers delivered them into the path of the beam in jets of fluid. Switching to a solid graphene carrier gave the team two advantages, according to CFEL’s Henry Chapman, a professor at the University of Hamburg and a lead scientist at DESY.

    Because graphene is just one layer of atoms thick, it leaves hardly a trace in the diffraction patterns formed by X-rays scattering off the fibrils, which are used to determine their structures, he said. And the regular structure of the graphene encourages the fibrils to all line up in the same direction.

    This allows diffraction patterns to be obtained from fewer than 50 amyloid fibrils. Based on the results, the team hopes to eventually get patterns from single fibrils. To get to that goal, new methods of exposing a single fibril to the XFEL beam will need to be developed, according to Seuring: “With enough snapshots, a full 3D data set of a single fibril should be possible.”

    The exceptionally bright and narrowly focused beam at LCLS’s Coherent X-ray Imaging instrument was also key to the team’s success in taking data from such a small number of fibrils, according to SLAC staff scientist Mengning Liang.

    Intense X-ray pulses at XFELs limit the exposure of delicate samples to damaging X-rays. In this study, the fibrils were exposed for only a few femtoseconds, or millionths of a billionth of a second. Before the molecules are destroyed, information about their structure can be read by detectors.

    “Fibrils are a third category of samples that can be studied with the ‘diffract before destroy’ method at XFELs, in addition to single particles and crystals,” Liang said. “In some regards, fibrils fit between the other two: they have regular, recurring variations in structure like crystals, but without the rigid crystal structure.”

    The scientists tested their method on samples of well-studied tobacco mosaic virus filaments and smaller amyloid fibrils, some of which are associated with certain types of cancer. The tests produced structural data with a high degree of accuracy: The resolution in the diffraction images was almost on the scale of a single atom.

     “It is amazing that we are essentially carrying out the same experiments as Rosalind Franklin did on DNA in 1952, which led to the discovery of the double helix, but now we are reaching the level of single molecules,” says Chapman.

    LCLS is a DOE Office of Science user facility. Other researchers who contributed to this study came from the University of Zurich; Center for Cellular Imaging and Nano Analytics in Switzerland; DOE’s Lawrence Livermore National Laboratory; University of Canterbury; University of Gothenburg; University of Bordeaux; University of Copenhagen; ETH Zurich; University of Oxford; Diamond Light Source; and the University of Hamburg.

    This article is based in part on a DESY press release.

    Citation: Seuring, et alNature Communications, 9 May 2018 (10.1038/s41467-018-04116-9)


    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, Calif., SLAC is operated by Stanford University for the U.S. Department of Energy's Office of Science. For more information, please visit slac.stanford.edu.

    SLAC National Accelerator Laboratory is supported by the Office of Science of the U.S. Department of Energy. The Office of Science is the single largest supporter of basic research in the physical sciences in the United States, and is working to address some of the most pressing challenges of our time. For more information, please visit science.energy.gov.

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    Seeing a Salt Solution's Structure Supports One Hypothesis About How Minerals Form

    Oak Ridge National Laboratory scientists used neutrons, isotopes and simulations to "see" the atomic structure of a saturated solution and found evidence supporting one of two competing hypotheses about how ions come together to form minerals.

    New PMLD Technique Improves Tools to Form Organic Multilayers

    Researchers have developed a new class of molecular layer deposition chemistry that paves the way for a new photoactivated molecular layer deposition technique. They report that their new method will expand the tool kit for forming covalently bound organic multilayers at surfaces. These emerging deposition techniques have enabled engineers to produce organic thin films with improved conformality. Richard Closser, Stanford University, will present the findings at the AVS 65th International Symposium and Exhibition, Oct. 21-26, 2018.

    Spotlighting Differences in Closely-Related Species

    Aspergillus fungi play roles in fields including bioenergy, health, and biotechnology. In Nature Genetics, a team led by scientists at the Technical University of Denmark, the DOE Joint Genome Institute, and the Joint Bioenergy Institute, present the first large analysis of an Aspergillus fungal subgroup, section Nigri.

    Researchers switch material from one state to another with a single flash of light

    Scientists from the Department of Energy's SLAC National Accelerator Laboratory and the Massachusetts Institute of Technology have demonstrated a surprisingly simple way of flipping a material from one state into another, and then back again, with single flashes of laser light.

    The Stories Behind the Science: How Does the Ocean's Saltiness Affect Tropical Storms?

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    Surprise finding: Discovering a previously unknown role for a source of magnetic fields

    Feature describes unexpected discovery of a role the process that seeds magnetic fields plays in mediating a phenomenon that occurs throughout the universe and can disrupt cell phone service and knock out power grids on Earth.

    Genetic behavior reveals cause of death in poplars essential to ecosystems, industry

    Scientists studying a valuable, but vulnerable, species of poplar have identified the genetic mechanism responsible for the species' inability to resist a pervasive and deadly disease. Their finding could lead to more successful hybrid poplar varieties for increased biofuels and forestry production and protect native trees against infection.

    Pushing the (Extra Cold) Frontiers of Superconducting Science

    Ames Laboratory has developed a method to measure magnetic properties of superconducting and magnetic materials that exhibit unusual quantum behavior at very low temperatures in high magnetic fields.

    Scientists Find Unusual Behavior in Topological Material

    Argonne scientists have identified a new class of topological materials made by inserting transition metal atoms into the atomic lattice of a well-known two-dimensional material.

    Wind Farms and Reducing Hurricane Precipitation

    New research reveals an unexpected benefit of large-scale offshore wind farms: the ability to lessen precipitation from hurricanes.


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    Physicist Takes Cues from Artificial Intelligence

    In the world of computing, there's a groundswell of excitement for what is perceived as the impending revolution in artificial intelligence. Like the industrial revolution in the 19th century and the digital revolution in the 20th, the AI revolution is expected to change the way we live and work. Now, Cristiano Fanelli aims to bring the AI revolution to nuclear physics.

    Engineering professor receives Department of Energy grant

    New Mexico State University Department of Civil Engineering Assistant Professor Ehsan Dehghan Niri has received a United States Department of Energy grant. This is a three-year award for $400,000 and is a collaboration with Arizona State University.

    Argonne and Capstone receive funding to advance thermal energy storage technology

    The U.S. Department of Energy's (DOE) Argonne National Laboratory and Capstone Turbine Corp. have received $380,000 in DOE Technology Commercialization Funding to refine Argonne's high-efficiency, fast charging/discharging latent heat thermal energy storage system (TESS) for use in building applications and process/manufacturing industries.

    AVS and AIP Publishing Expand Partnership to Launch AVS Quantum Science

    AIP Publishing and AVS: Science and Technology of Materials, Interfaces, and Processing (AVS) today announced an agreement to publish AVS Quantum Science, a new online interdisciplinary journal. The announcement coincides with the AVS 65th International Symposium & Exhibition in Long Beach, California, from October 21-26, 2018.

    Prototype Solar Energy, Battery Systems to Fuel Commercialization

    Designing, building and testing prototype systems that show how renewable energy can power devices, such as a weather and soil sensor station, can help bridge the gap between basic science research and commercialization.

    Argonne to Advance High Performance Computing in Manufacturing

    Argonne awarded funding to partner with Industry to advance the use of high performance computing in manufacturing.

    "Invisible Glass" Wins 2018 Create the Future Design Contest Grand Prize

    Scientists from the Center for Functional Nanomaterials developed a technique for making nonreflecting glass, silicon, and plastic surfaces.

    Missouri S&T researchers win multimillion dollar grant to build fast-charging stations for electric cars

    Researchers from Missouri S&T and three private companies will combine their expertise to create charging stations for electric vehicles that could charge a car in less than 10 minutes - matching the time it takes to fill up a conventional vehicle with gasoline."The big problem with electric vehicles is range, and it's not so much range as range anxiety.

    Making batteries store more energy, last longer

    A new solid polymer electrolyte may help make cell phone batteries store more energy and last longer.

    Three Brookhaven Lab Scientists Named Fellows of American Physical Society

    The American Physical Society (APS), the world's largest physics organization, has elected three scientists from the U.S. Department of Energy's (DOE) Brookhaven National Laboratory as 2018 APS fellows.


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    Cryocooler Cools an Accelerator Cavity

    Researchers demonstrated cryogen-free operation of a superconducting radio-frequency cavity that might ease barriers to its use in societal applications.

    Shining Light on the Separation of Rare Earth Metals

    New studies identify key molecular characteristics to potentially separate rare earth metals cleanly and efficiently with light.

    Placing Atoms for Optimum Catalysts

    Precise positioning of oxygens could help engineer faster, more efficient energy-relevant chemical transformations.

    How to Make Soot and Stardust

    Scientists unlock mystery that could help reduce emissions of fine particles from combustion engines and other sources.

    Breaking the Symmetry Between Fundamental Forces

    Scientists improve our understanding of the relationship between fundamental forces by re-creating the earliest moments of the universe.

    Water Plays Unexpected Role in Forming Minerals

    Water molecules line up tiny particles to attach and form minerals; understanding how this happens impacts energy extraction and storage along with waste disposal.

    Heavy Particles Get Caught Up in the Flow

    First direct measurement show how heavy particles containing a charm quark get caught up in the flow of early universe particle soup.

    Seeing Between the Atoms

    New detector enables electron microscope imaging at record-breaking resolution.

    Scaling Up Single-Crystal Graphene

    New method can make films of atomically thin carbon that are over a foot long.

    Discovered: Optimal Magnetic Fields Suppress Instabilities in Tokamak Plasmas

    U.S. and Korean scientists show how to find and use beneficial 3-D field perturbations to stabilize dangerous edge-localized modes in plasma.


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