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  • richardmitnick 4:40 pm on November 21, 2014 Permalink | Reply
    Tags: , , , , SLAC SSRL,   

    From SLAC: “Robotics Meet X-ray Lasers in Cutting-edge Biology Studies” 


    SLAC Lab

    November 21, 2014

    Platform Brings Speed, Precision in Determining 3-D Structure of Challenging Biological Molecules

    Scientists at the Department of Energy’s SLAC National Accelerator Laboratory are combining the speed and precision of robots with one of the brightest X-ray lasers on the planet for pioneering studies of proteins important to biology and drug discovery.

    The new system uses robotics and other automated components to precisely maneuver delicate samples for study with the X-ray laser pulses at SLAC’s Linac Coherent Light Source (LCLS). This will speed efforts to map the 3-D structures of nanoscale crystallized proteins, which are important for designing targeted drugs and synthesizing natural systems and processes.

    s
    This illustration shows an experimental setup used in crystallography experiments at SLAC’s Linac Coherent Light Source X-ray laser. The drum-shaped container at left stores supercooled crystal samples that are fetched by a robotic arm and delivered to another device, called a goniometer. The goniometer moves individual crystals through the X-ray beam, which travels from the pipe at upper left toward the lower right. A detector, right, captures X-ray diffraction patterns produced as the X-rays pass through the crystal samples. (SLAC National Accelerator Laboratory)

    i
    Equipment used in a highly automated X-ray crystallography system at SLAC’s Linac Coherent Light Source X-ray laser. The metal drum at lower left contains liquid nitrogen for cooling crystallized samples studied with LCLS’s intense X-ray pulses. (SLAC National Accelerator Laboratory)

    SLAC LCLS
    SLAC LCLS

    A New Way to Study Biology

    “This is an efficient, highly reliable and automated way to obtain high-resolution 3-D structural information from small sizes and volumes of samples, and from samples that are too delicate to study using other X-ray sources and techniques,” said Aina Cohen, who oversaw the development of the platform in collaboration with staff at LCLS and at SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL), both DOE Office of Science User Facilities.

    SLAC SSRL
    SLAC SSRL

    She is co-leader of the Macromolecular Crystallography group in the Structural Molecular Biology (SMB) program at SSRL, which has used robotic sample-handling systems to run remote-controlled experiments for a decade.

    The new setup at LCLS is described in the Oct. 31 edition of Proceedings of the National Academy of Sciences. It includes a modified version of a “goniometer,” a sample-handling device in use at SSRL and many other synchrotrons, as well as a custom version of an SSRL-designed software package that pinpoints the position of crystals in arrays of samples.

    LCLS, with X-ray pulses a billion times brighter than more conventional sources, has already allowed scientists to explore biological samples too small or fragile to study in detail with other tools. The new system provides added flexibility in the type of samples and sample-holders that can be used in experiments.

    Rather than injecting millions of tiny, randomly tumbling crystallized samples into the path of the pulses in a thin liquid stream – common in biology experiments at LCLS – the goniometer-based system places crystals one at a time into the X-ray pulses. This greatly reduces the number of crystals needed for structural studies on rare and important samples that require a more controlled approach.

    Early Successes

    “This system adapts common synchrotron techniques for use at LCLS, which is very important,” said Henrik Lemke, staff scientist at LCLS. “There is a large community of scientists who are familiar with the goniometer technique.”

    The system has already been used to provide a complete picture of a protein’s structure in about 30 minutes using only five crystallized samples of an enzyme, moved one at a time into the X-rays for a sequence of atomic-scale “snapshots.”

    It has also helped to determine the atomic-scale structures of an oxygen-binding protein found in muscles, and another protein that regulates heart and other muscle and organ functions.

    “We have shown that this system works, and we can further automate it,” Cohen said. “Our goal is to make it easy for everyone to use.”

    Many biological experiments at LCLS are conducted in air-tight chambers. The new setup is designed to work in the open air and can also be used to study room-temperature samples, although most of the samples used in the system so far have been deeply chilled to preserve their structure. One goal is to speed up the system so it delivers samples and measures the resulting diffraction patterns as fast as possible, ideally as fast as LCLS delivers pulses: 120 times a second.

    The goniometer setup is the latest addition to a large toolkit of systems that deliver a variety of samples to the LCLS beam, and a new experimental station called MFX that is planned at LCLS will incorporate a permanent version.

    Team Effort

    Developed through a collaboration of SSRL’s Structural Molecular Biology program and the Stanford University School of Medicine, the LCLS goniometer system reflects increasing cooperation in the science of SSRL and LCLS, Cohen said, drawing upon key areas of expertise for SSRL and the unique capabilities of LCLS. “The combined effort of staff at both experimental facilities was key in this success,” she said.

    In addition to staff at SLAC’s SSRL and LCLS and at Stanford University’s School of Medicine, researchers from SLAC’s Photon Science Directorate, the University of Pittsburgh School of Medicine, Howard Hughes Medical Institute, Montana State University, Lawrence Berkeley National Laboratory and the University of California, San Francisco also participated in this effort.

    The work was supported by the Department of Energy Office of Basic Energy Sciences, the SSRL Structural Molecular Biology Program via the DOE Office of Biological and Environmental Research, and the Biomedical Technology Research Resources program at the National Institute of General Medical Sciences, National Institutes of Health.

    See the full article here.

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    SLAC Campus
    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.
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  • richardmitnick 2:25 pm on November 12, 2014 Permalink | Reply
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    From SLAC: “Study at SLAC Explains Atomic Action in High-Temperature Superconductors “ 


    SLAC Lab

    November 12, 2014

    A study at the Department of Energy’s SLAC National Accelerator Laboratory suggests for the first time how scientists might deliberately engineer superconductors that work at higher temperatures.

    In their report, a team led by SLAC and Stanford University researchers explains why a thin layer of iron selenide superconducts — carries electricity with 100 percent efficiency — at much higher temperatures when placed atop another material, which is called STO for its main ingredients strontium, titanium and oxygen.

    bs
    In this illustration, a single layer of superconducting iron selenide (balls and sticks) has been placed stop another material known as STO for its main ingredients strontium, titanium and oxygen. The STO is shown as blue pyramids, which represent the arrangement of its atoms. A study at SLAC found that when natural vibrations (green glow) from the STO move up into the iron selenide film, electrons in the film (white spheres) can pair up and conduct electricity with 100 percent efficiency at much higher temperatures than before. The results suggest a way to deliberately engineer superconductors that work at even higher temperatures. (SLAC National Accelerator Laboratory)

    side
    This view from the side makes an important point: Putting iron selenide on top of STO enhances its superconductivity only if it’s applied in a single layer (left). When more than one layer is applied, the natural vibrations coming up from the STO layer don’t give electrons the boost of energy they need to pair up and superconduct (right). (SLAC National Accelerator Laboratory)

    These findings, described today in the journal Nature, open a new chapter in the 30-year quest to develop superconductors that operate at room temperature, which could revolutionize society by making virtually everything that runs on electricity much more efficient. Although today’s high-temperature superconductors operate at much warmer temperatures than conventional superconductors do, they still work only when chilled to minus 135 degrees Celsius or below.

    In the new study, the scientists concluded that natural trillion-times-per-second vibrations in the STO travel up into the iron selenide film in distinct packets, like volleys of water droplets shaken off by a wet dog. These vibrations give electrons the energy they need to pair up and superconduct at higher temperatures than they would on their own.

    “Our simulations indicate that this approach – using natural vibrations in one material to boost superconductivity in another – could be used to raise the operating temperature of iron-based superconductors by at least 50 percent,” said Zhi-Xun Shen, a professor at SLAC and Stanford University and senior author of the study.

    While that’s still nowhere close to room temperature, he added, “We now have the first example of a mechanism that could be used to engineer high-temperature superconductors with atom-by-atom control and make them better.”

    Spying on Electrons

    The study probed a happy combination of materials developed two years ago by scientists in China. They discovered that when a single layer of iron selenide film is placed atop STO, its maximum superconducting temperature shoots up from 8 degrees to nearly 77 degrees above absolute zero (minus 196 degrees Celsius).

    While this was a huge and welcome leap, it would be hard to build on this advance without understanding what, exactly, was going on.

    In the new study, SLAC Staff Scientist Rob Moore and Stanford graduate student J.J. Lee and postdoctoral researcher Felix Schmitt built a system for growing iron selenide films just one layer thick on a base of STO.

    The team examined the combined material at SLAC’s Stanford Synchrotron Radiation Lightsource, a DOE Office of Science User Facility. They used an exquisitely sensitive technique called ARPES to measure the energies and momenta of electrons ejected from samples hit with X-ray light. This tells scientists how the electrons inside the sample are behaving; in superconductors they pair up to conduct electricity without resistance. The researchers also got help from theorists who did simulations to help explain what they were seeing.

    SLAC SSRL
    SSRL at SLAC

    A Promising New Direction

    “This is a very impressive experiment, one that would have been very difficult to impossible to do anywhere else,” said Andrew Millis, a theoretical condensed matter physicist at Columbia University, who was not involved in the study. “And it’s clearly telling us something important about why putting one thin layer of iron selenide on this substrate, which everyone thought was inert and boring, changes things so dramatically. It opens lots of interesting questions, and it will definitely stimulate a lot of research.”

    Scientists still don’t know what holds electron pairs together so they can effortlessly carry current in high-temperature superconductors. With no way to deliberately invent new high-temperature superconductors or improve old ones, progress has been slow.

    The new results “point to a new direction that people have not considered before,” Moore said. “They have the potential to really break records in high-temperature superconductivity and give us a new understanding of things we’ve been struggling with for years.”

    He added that SLAC is developing a new X-ray beamline at SSRL with a more advanced ARPES system to create and study these and other exotic materials. “This paper predicts a new pathway to engineering superconductivity in these materials,” Moore said, “and we’re building the tools to do just that.”

    In addition to researchers from SLAC’s Materials Science Division and from Stanford, scientists from the University of British Columbia, the University of Tennessee, Lawrence Berkeley National Laboratory and the University of California, Berkeley contributed to this study. The work was funded by the DOE Office of Science.

    See the full article here.

    SLAC Campus
    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.
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  • richardmitnick 10:18 am on November 11, 2014 Permalink | Reply
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    From SLAC: “Researchers Take Snapshots of Potential ‘Kill Switch’ for Cancer” 


    SLAC Lab

    November 10, 2014

    X-ray Study Shows Protein Switch for Programmed Cell Death in Motion

    A study conducted in part at the Department of Energy’s SLAC National Accelerator Laboratory has revealed how a key human protein switches from a form that protects cells to a form that kills them – a property that scientists hope to exploit as a “kill switch” for cancer.

    The protein, called cIAP1, shields cells from programmed cell death, or apoptosis – a naturally occurring crackdown on unhealthy cells and tissues. When a cell is in trouble, a signal activates cIAP1, which rapidly transforms into a state that allows apoptosis to take place.

    cell
    The structure of cellular inhibitor-of-apoptosis protein 1 (cIAP1) in its “closed” state. The protein is a key switch for apoptosis, or programmed cell death, and is composed of four distinct domains (color coded) that rearrange depending on the position of the switch. (Allyn Schoeffler/Genentech)

    “Cancer cells produce excess amounts of cIAP1 in an attempt to shut down apoptosis and evade death,” says senior staff scientist Thomas Weiss from SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL), a DOE Office of Science User Facility, who participated in the study. “The search for drugs that would switch apoptosis back on to eradicate cancer is a very active research field.”

    The researchers used X-rays from SSRL to watch in real time how cIAP1 transitions from one state to another. The results are an important step towards becoming able to control the protein’s switching properties.

    “Our study closely ties cIAP1’s motions to its role as a switch,” says Allyn Schoeffler, a senior research associate at Genentech Inc. in South San Francisco and lead author of the study, published Nov. 10 in Nature Structural & Molecular Biology. “We now know why cIAP1 can act as a strictly controlled fail-safe for apoptosis and, at the same time, remain flexible enough to undergo rapid structural transitions.”

    Incomplete Static Model

    Earlier studies had given researchers a fairly good idea of cIAP1’s structure and general mechanism.

    In its “closed” state, which blocks apoptosis, the protein’s four parts, or domains, are tightly bound together in a rather rigid, compact structure.

    When a signal molecule binds to a specific site in cIAP1, the protein changes into its “open” state, in which the domains arrange in a more flexible, linear way. When two identical copies of this open structure partner up in what is known as a dimer, the assembly eventually self-destructs, removing the brake that blocks apoptosis and allowing cellular clean-up to carry on.

    “This model of cIAP1 action has largely been derived from static images of the protein,” Schoeffler says. “However, static pictures do not tell us the whole story.”

    Bringing Motion into the Equation

    To find out more, the research team first used a technique known as nuclear magnetic resonance spectroscopy, or NMR, to analyze how the protein domains move in the closed state, and followed up with studies at SSRL, where they observed how X-rays scatter off the transforming sample.

    scat
    Small-angle X-ray scattering models of different cIAP1 states. In its “closed” state, which blocks apoptosis, the domains are tightly bound together in a compact structure (left). Binding of a signal molecule for apoptosis switches the protein into its “open” state, in which the domains arrange in a more flexible linear way (center). When two identical copies of the open structure partner up in what is known as a dimer (right), the assembly eventually self-destructs, thereby allowing apoptosis to take place. (Allyn Schoeffler/Genentech)

    “The results showed that cIAP1 switches from ‘closed’ to ‘open’ extremely fast, within only 300 milliseconds, which we were able to determine using a technique called time-resolved small-angle X-ray scattering,” says Weiss. “The following dimer formation is even faster than that.”

    open
    Protein envelopes of cIAP1’s “open” and “closed” forms as determined by small-angle X-ray scattering (left) with detailed molecular structures modeled into them (right). For the first time, scientists have now monitored in real time how cIAP1 transitions from one state to another. (Allyn Schoeffler/Genentech)

    In addition, the scientists observed that the protein “breathes” rapidly in its closed form, with interfaces between domains opening and closing quickly.

    “The only region that is relatively rigid is the interaction site for the apoptosis signal,” says Schoeffler. “This well-defined site in the closed state allows nature to control cIAP1 very tightly. It is the critical latch that keeps the switch closed and makes sure that it does not open accidentally.”

    The rest of the protein, in contrast, is very flexible and allows cIAP1 to open instantaneously, like a spring-loaded trigger mechanism, when the proper signal is received. Once the trigger has been pulled, cell death becomes inevitable.

    Ties to Cancer Research

    The new insights could potentially benefit recent developments in cancer research. In fact, several studies are underway to explore the use of synthetic compounds that mimic nature’s signal molecules.

    “Natural and synthetic molecules are thought to interact with this protein the same way,” says Schoeffler. “Therefore, the mechanisms revealed by our study are likely to hold true in medically relevant molecules as well.”

    Research funding for the SSRL Structural Molecular Biology Program was provided by the DOE Office of Biological and Environmental Research and the National Institutes of Health, National Institute of General Medical Sciences.

    See the full article here.

    SLAC Campus
    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.
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  • richardmitnick 7:45 am on October 7, 2014 Permalink | Reply
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    From SLAC: “Study Reveals ‘Bellhops’ in Cell Walls Can Double as Hormones” 


    SLAC Lab

    October 6, 2014

    Discovery at SLAC’s Synchrotron Could Lead to New Drug Designs, Treatments

    Researchers have discovered that some common messenger molecules in human cells double as hormones when bound to a protein that interacts with DNA. The finding could bring to light a class of previously unknown hormones and lead to new ways to target diseases – including cancers and a host of hormone-related disorders.

    image
    In this rendering, the structure of the nuclear receptor transcription factor Steroidogenic Factor-1 (SF-1, shown in gray) is bound by the signaling phospholipid referred to as “PIP3″ (blue and red). (Raymond Blind/UCSF)

    Published in the Oct. 6 edition of Proceedings of the National Academy of Sciences, these results were made possible, in part, by X-ray experiments at the Department of Energy’s SLAC National Accelerator Laboratory.

    “This finding is comparable in its importance to the discovery of how the estrogen hormone triggers activity in human cells, which was key in the development of anti-breast cancer drugs and other hormone treatments,” Robert Fletterick, professor of biochemistry and biophysics at University of California, San Francisco, and one of the principal investigators in the study, said.

    Resolving a Cellular Mystery

    Researchers focused on messengers called signaling phospholipids that act like bellhops in cell walls, escorting proteins to compartments within a cell and activating their functions. The results could explain why these messengers had been observed linked to proteins in the nucleus of cells; their purpose there had been a mystery.

    pj
    Renderings of a signaling phospholipid, PIP3, which was studied while bound to a nuclear receptor, SF-1. The phospholipid was found to behave as a hormone. (Raymond Blind/UCSF)

    X-ray crystallography at SLAC’s Stanford Synchrotron Radiation Lightsource, a DOE Office of Science User Facility, provided the first detailed look at how this messenger acts as a hormone in binding to a specialized hormone-sensing protein called a nuclear receptor.

    SLAC SSRL
    SLAC SSRL

    These receptors are known to interact with DNA in the cell’s nucleus and directly regulate gene expression – a critical mechanism for carrying out the cell’s functions. The experiment focused on a well-studied receptor called SF-1 because its mutations are believed to be associated with infertility and other reproductive disorders, and diseases including colon and pancreatic cancers.

    In analyzing X-ray data measured at SSRL, researchers observed how the phospholipids act like hormones when docked into the SF-1 receptors. Hormones are key links in the communications chain between different types of cells and organs that turn on specific genes in cells and activate a broad range of responses.

    “The greatest impact of this work might be to prompt scientists to take a new view of phospholipids and what they do in the cell,” said Holly A. Ingraham, a UCSF professor who participated in the study.

    “The idea that a component of a cell membrane such as a phospholipid could work as a hormone, triggering gene expression, is quite novel,” she said. “People have not really known what their role is in the nucleus. Now we can say for the first time we know why they are there: Some of them might be acting like hormones.”

    New Details in Bound Biomolecule

    Ray Blind, a UCSF postdoctoral researcher who led the study, devoted years of effort to finding a way to prepare crystallized samples of two types of phospholipids that were separately bound to the SF-1 receptor. High-quality crystals were needed to capture high-resolution X-ray data of their contents and determine the structure of the biomolecular complexes.

    Debanu Das, a staff scientist at SSRL’s Structural Determination Core of the Joint Center for Structural Genomics, oversaw the experiments at SSRL. Based on highly automated X-ray data collection and analysis of about 250 crystal samples, scientists were able to fully map the 3-D atomic-scale structure of the biomolecules, revealing never-before-seen details.

    Well-known hormones like estrogen and testosterone bind to and activate receptors by changing their shape. The study found that the phospholipids bind with the receptor protein in a more complex way than classic hormones do, which potentially enables the phospholipids to manipulate the shape of receptors in more profound ways.

    The researchers said they hope to design synthetic molecules that can target the disease-associated structures in the receptor protein.

    The Joint Center for Structural Genomics is a research consortium that includes SLAC’s SSRL; The Scripps Research Institute; the Genomics Institute of the Novartis Research Foundation; the University of California, San Diego; and the Sanford-Burnham Medical Research Institute. The joint center is supported by the National Institute of General Medical Sciences’ Protein Structure Initiative (PSI) and the National Institutes of Health. The research was also supported by the PSI-Biology Partnership for Stem Cell Biology. Support for the SSRL Structural Molecular Biology Program, whose X-ray facilities enabled the structural work, is provided by the DOE Office of Biological and Environmental Research and by the National Institute of General Medical Sciences.

    See the full article, with video, here.

    SLAC Campus
    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.
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  • richardmitnick 3:46 pm on September 23, 2014 Permalink | Reply
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    From SLAC: “Research Pinpoints Role of ‘Helper’ Atoms in Oxygen Release” 


    SLAC Lab

    September 22, 2014

    System Studied at SLAC’s Synchrotron Mimics Steps in Photosynthesis

    Experiments at the Department of Energy’s SLAC National Accelerator Laboratory solve a long-standing mystery in the role calcium atoms serve in a chemical reaction that releases oxygen into the air we breathe. The results offer new clues about atomic-scale processes that drive the life-sustaining cycle of photosynthesis and could help forge a foundation for producing cleaner energy sources by synthesizing nature’s handiwork.

    The research is detailed in a paper published Sept. 14 in Nature Chemistry. X-ray experiments at SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL), a DOE Office of Science User Facility, played a key role in the study, led by Wonwoo Nam at Ewha Womans University in Korea in a joint collaboration with Riti Sarangi, an SSRL staff scientist.

    SLAC SSRL
    SLAC SSRL

    “For the first time, we show how calcium can actually tune this oxygen-releasing reaction in subtle but precise ways,” said Sarangi, who carried out the X-ray work and supporting computer simulations and calculations. “The study helps us resolve the question, ‘Why does nature choose calcium?’”

    Photosynthesis is one of many important biological processes that rely on proteins with metal-containing centers, such as iron or manganese. The chemistry carried out in such centers is integral to their function. Scientists have known that the presence of calcium is necessary for the oxygen-releasing stages of photosynthesis, but they didn’t know how or why.

    The SSRL experiment used a technique known as X-ray absorption spectroscopy to explore the chemical and structural details of sample systems that mimic of the oxygen-releasing steps in photosynthesis. The basic oxygen-releasing system contained calcium and was centered around an iron atom.

    Researchers found that charged atoms, or ions, of calcium and another element, strontium, bind to the oxygen atoms in a way that precisely tunes the chemical reaction at the iron center. This, in turn, facilitates the bond formation between two oxygen atoms. The study also revealed that calcium and strontium do not obstruct the release of these bound oxygen atoms into the air as an oxygen molecule — the final step in this reaction.

    “We saw that unless you use calcium or strontium, this sample system will not release oxygen,” Sarangi said. “Calcium and strontium bind at just the right strength to facilitate the oxygen release. Anything that binds too strongly would impede that step.”

    While the sample system studied is not biological, the chemistry at work is considered a very good analogue for the oxygen-releasing steps carried out in photosynthesis, she said, and could assist in constructing artificial systems that replicate these steps. The next step will be to study more complex samples that perform more closely to the actual chemistry in photosynthesis.

    Other participants in this research were from Osaka University in Japan and the Japan Science Technology Agency. The research was supported by the National Research Foundation of Korea and the Ministry of Education, Culture, Sports, Science and Technology in Japan. SSRL’s Structural Molecular Biology program is supported by the National Institutes of Health and the Office of Biological and Environmental Research of the U.S. Department of Energy.

    See the full article here.

    SLAC Campus
    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.
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  • richardmitnick 5:33 am on August 16, 2014 Permalink | Reply
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    From Brookhaven Lab: “Harnessing the Power of Bacteria’s Sophisticated Immune System” 

    Brookhaven Lab

    August 15, 2014
    Karen McNulty Walsh, (631) 344-8350 or Peter Genzer, (631) 344-3174

    Researchers Now Better Understand How Bacteria Can So Quickly Protect Itself From Harm, Could Help Unlock Clues About Antibiotic Resistance

    Bacteria’s ability to destroy viruses has long puzzled scientists, but researchers at the Johns Hopkins Bloomberg School of Public Health say they now have a clear picture of the bacterial immune system and say its unique shape is likely why bacteria can so quickly recognize and destroy their assailants.

    The researchers drew what they say is the first-ever picture of the molecular machinery, known as Cascade, which stands guard inside bacterial cells. To their surprise, they found it contains a two-strand, unencumbered structure that resembles a ladder, freeing it to do its work faster than a standard double-helix would allow.

    The findings, published online Aug. 14 in the journal Science, may also provide clues about the spread of antibiotic resistance, which occurs when bacteria adapt to the point where antibiotics no longer work in people who need them to treat infections, since similar processes are in play. The World Health Organization (WHO) considers antibiotic resistance a major threat to public health around the world.

    “If you understand what something looks like, you can figure out what it does,” says study leader Scott Bailey, PhD, an associate professor in the Bloomberg School’s Department of Biochemistry and Molecular Biology. “And here we found a structure that nobody’s ever seen before, a structure that could explain why Cascade is so good at what it does.”

    For their study, Bailey and his colleagues used something called X-ray crystallography to draw the picture of Cascade, a key component of bacteria’s sophisticated immune system known as CRISPR, an acronym for Clustered Regularly Interspaced Short Palindromic Repeats. Cascade uses the information housed in sequences of RNA as shorthand to identify foreign invaders and kill them.

    crispr
    Diagram of the possible mechanism for CRISPR

    Much of the human immune system is well understood, but until recently scientists didn’t realize the level of complexity associated with the immune system of single-cell life forms, including bacteria. Scientists first identified CRISPR several years ago when trying to understand why bacterial cultures used to make yogurt succumbed to viral infections. Researchers subsequently discovered they could harness the CRISPR bacterial immune system to edit DNA and repair damaged genes. One group, for example, was able to remove viral DNA from human cells infected with HIV.

    Bailey’s work is focused on how Cascade is able to help bacteria fight off viruses called bacteriophages. The Cascade system uses short strands of bacterial RNA to scan the bacteriophage DNA to see if it is foreign or self. If foreign, the cell launches an attack that chews up the invading bacteriophage.

    bac
    The structure of a typical myovirus bacteriophage

    To “see” how this happens, Bailey and his team converted Cascade into a crystalized form. Technicians at the National Synchrotron Light Source at Brookhaven National Laboratory in Upton, New York, and the Stanford Synchrotron Radiation Lightsource then trained high-powered X-rays on the crystals. The X-rays provided computational data to the Bloomberg School scientists allowing them to draw Cascade, an 11-protein machine that only operates if each part is in perfect working order.

    Brookhaven NSLS
    Brookhaven NSLS

    SLAC SSRL
    SLAC SSRL

    What they saw was unexpected. Instead of the RNA and DNA wrapping around each other to form what is known as a double-helix structure, in Cascade the DNA and RNA are more like parallel lines, forming something of a ladder. Bailey says that if RNA had to wrap itself around DNA to recognize an invader – and then unwrap itself to look at the next strand – the process would take too much time to ward off infection. With a ladder structure, RNA can quickly scan DNA.

    ah
    Annie Heroux at NSLS

    In the new study, Bailey says his team determined that the RNA scans the DNA in a manner similar to how humans scan text for a key word. They break long stretches of characters into smaller bite-sized segments, much like words themselves, so they can be spotted more easily.

    Since the CRISPR-Cas system naturally acts as a barrier to the exchange of genetic information between bacteria and bacteriophages, its function can offer clues to how antibiotic resistance develops and ideas for how to keep it from happening.

    “We’re finding more pieces to the puzzle,” Bailey says. “This gives us a better understanding of how these machines find their targets, which may help us harness the CRISPR system as a tool for therapy or manipulation of DNA in a lab setting. And it all started when someone wanted to make yogurt more cheaply.”

    “Crystal structure of a CRISPR RNA-guided surveillance complex bound to a ssDNA target” was written by Sabin Mulepati, Annie Heroux and Scott Bailey.

    This work was funded by a grant from the National Institute of Health’s National Institute of General Medical Sciences (GM097330).

    See the full article here.

    One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. The Laboratory’s almost 3,000 scientists, engineers, and support staff are joined each year by more than 5,000 visiting researchers from around the world.Brookhaven is operated and managed for DOE’s Office of Science by Brookhaven Science Associates, a limited-liability company founded by Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization.
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  • richardmitnick 2:51 pm on August 14, 2014 Permalink | Reply
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    From SLAC Lab: “SLAC Secures Role in Energy Frontier Research Center Focused on Next-generation Materials” 


    SLAC Lab

    August 14, 2014

    X-ray Studies will Explore Hybrid Materials for Solar Energy, Efficient Lighting and Other Uses

    he Department of Energy’s SLAC National Accelerator Laboratory will play a key role in a research consortium that seeks out new materials for next-generation solar panels, low-energy lighting and other uses.

    Collaborators in this effort will use SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL), a DOE Office of Science User Facility, to characterize these new materials as they are being discovered.

    tunnel
    SLAC SSRL Accelerator Tunnel

    strip
    A researcher at SLAC’s Stanford Synchrotron Radiation Lightsource holds up a thin strip of material printed with an ink (magenta) relevant to solar-energy conversion. SSRL will play a role in a new center, led by the National Renewable Energy Laboratory in Colorado, that will explore new materials for solar panels, energy-efficient lighting and other uses. (SLAC National Accelerator Laboratory)

    The collaboration will also aid in understanding their structure and performance as they operate. The work is made possible by a four-year, $14 million DOE award for an Energy Frontier Research Center (EFRC) distributed among several national labs and universities.

    “We are pushing the idea of ‘materials by design’ to the next step,” said Mike Toney, an SSRL senior staff scientist and head of the SSRL Materials Science Division. Toney will oversee SLAC’s contributions to this Center for Next Generation of Materials by Design: Incorporating Metastability, which is led by the National Renewable Energy Laboratory (NREL) in Colorado.

    “It’s a theory-centric center that aims to tell you what materials to make and how to make them,” Toney added. SLAC’s role will be purely experimental: investigating the novel materials with a slew of X-ray techniques. Watching materials as they’re being made and while they’re operating are already SSRL specialties, Toney said.

    “SLAC is a key partner on our EFRC team, bringing unique characterization tools to probe and understand new materials, including the processes that control their formation,” Bill Tumas, EFRC director and associate lab director for materials and chemistry at NREL, said.

    The center is one of 32 EFRCs approved by the DOE in June, which follow an initial batch of DOE research centers approved five years ago. According to Toney, SLAC played an important role in one of the earlier centers, the Center for Inverse Design, which was also led by NREL and laid the groundwork for the new round of research.

    In materials science it’s common to work from known materials and modify them to achieve desired properties. The Center for Inverse Design sought to flip this approach on its head by using theory integrated with experiment to discover new materials with desired properties.

    The new center stretches this idea to a realm where the sought-after material properties are complex and theory and computation are not fully developed. It will initially focus on creating new semiconductor materials that can be incorporated into solar energy conversion systems and solid-state lighting technologies that use less power than standard light bulbs.

    It also aims to tackle “multiple-property design” – tailoring materials with several enhanced properties. And it will explore lesser-understood “metastable” materials, which can have desirable traits but are not in their most stable state – they can fall back to a lower, more stable energy level when disturbed, for example.

    “These centers are bringing together different groups of people who normally would not converse,” Toney said, which makes for lively discussions and innovative approaches to scientific challenges.

    Other participants in the new research center, which starts up this summer, are from Oregon State University, Colorado School of Mines, the Massachusetts Institute of Technology, Lawrence Berkeley National Laboratory and Harvard University.

    See the full article here.

    SLAC Campus
    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.
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  • richardmitnick 2:15 pm on July 29, 2014 Permalink | Reply
    Tags: , , SLAC SSRL   

    From SLAC: “New Platinum Alloy Shows Promise as Fuel Cell Catalyst” 


    SLAC Lab

    July 21, 2014

    Highly Efficient Nanoparticles Could Bring Down the Cost of Fuel Cells

    Fuel cells are a promising, non-polluting way to power cars, but their platinum catalysts are so expensive that there’s no way current technology could be economically scaled up for widespread use. Now scientists at the Department of Energy’s SLAC National Accelerator Laboratory and the Technical University of Denmark have developed an alternative that would use just one-fifth as much of the pricey metal.

    The new catalyst is a mixture of platinum and a second, cheaper element, yttrium, formed into nanoparticles whose size can be precisely controlled. Electron microscopy and X-ray studies show that yttrium atoms leach out of the surface of these particles, leaving a thin, dense, sturdy crust of platinum atoms to enthusiastically promote a key reaction in the fuel cell that converts oxygen molecules into water.

    The results were published July 13 in Nature Chemistry.

    “We now have proof of principle that these nanoparticles work the way we had predicted,” said report co-author Daniel Friebel, an associate staff scientist at SUNCAT Center for Interface Science and Catalysis, which is jointly run by SLAC and Stanford University. “The next step is to find a more efficient way to make these nanoparticles so they can be mass-produced.”

    Wanted: Cheaper Fuel Cells

    car
    Scientists at SLAC National Accelerator Laboratory and Technical University of Denmark have developed a new fuel cell catalyst that uses much less pricey platinum and is five times more active than platinum alone. If developed commercially, the new catalyst could bring down the cost of fuel cells for vehicles. (iStockphoto.com/gchutka)

    All but a handful of today’s electric vehicles run on batteries, which are heavy and can only store so much energy; that’s why electric cars have a limited range. Fuel cells are an attractive alternative because they’re small and light and could run on a tank full of hydrogen replenished at a fueling station. In addition, the car’s exhaust would contain nothing but pure water.

    But the catalyst that breaks down oxygen molecules in a fuel cell requires five to 10 times more platinum than the catalytic converter that scrubs pollutants from conventional engine exhaust. With the price of platinum nearly $1,500 an ounce, running the world’s automotive fleet on fuel cells would be prohibitively expensive.

    “The number one goal is to minimize how much platinum you use, and you can only realize that goal with nanoparticles,” Friebel said. “That’s because the catalytic reaction happens only at the surface of the material; and the smaller the particle, the larger the surface area it has with respect to its interior volume.”

    But the smaller the particles, he said, the more unstable they become. Scientists have combined platinum with other elements, such as nickel, to make catalysts that initially outperformed pure platinum, but later fell behind as the non-platinum part of the alloy corroded away.

    About five years ago, SUNCAT Director Jens Nørskov, a theorist who was then at Technical University of Denmark (DTU), and his coworkers suggested that a mixture of platinum and yttrium might do the trick. This seemed like an odd choice; yttrium likes to react with oxygen, which does not bode well for its stability, and the alloy would prove difficult to synthesize. But initial samples made by a company in Germany turned out to be both stable and a decent catalyst.

    Testing an Unlikely Combo

    To turn the samples into nanoparticles, researchers at DTU bombarded the alloy with argon ions in a vacuum chamber. This knocked out atoms of platinum and yttrium, which cooled and stuck together to form nanoparticles. The scientists sorted the particles by size and discovered that some of the larger ones – about 9 nanometers in diameter – had the best catalytic activity, five times better than today’s pure platinum catalysts.

    Then the scientists examined the nanoparticles with X-ray beams at SLAC’s Stanford Synchrotron Radiation Lightsource, a DOE Office of Science user facility, to find out what made them so active. They found that the larger yttrium atoms had escaped from the surfaces of the particles, leaving a surface crust in which the smaller platinum atoms packed together more tightly than usual in a very stable configuration.

    For a commercial catalyst, Friebel said, the team will need to find a more efficient way to make the nanoparticles. They’ll also see if they can tune the density of the platinum crust so it will perform its tasks of bond-breaking and bond-making to convert oxygen into water even faster.

    The 15-member research team included Patricia Hernandez-Fernandez, Ifan E.L Stephens and Ib Chorkendorff at DTU and Anders Nilsson of SUNCAT. Support for this research came from the Danish Ministry of Science, the Danish National Research Foundation, the A.P. Møller and Chastine Mc-Kinney Møller Foundation, the Interdisciplinary Center for Electron Microscopy at EPFL and the DOE Office of Science.

    See the full article here.

    SLAC Campus
    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.
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  • richardmitnick 7:36 pm on July 22, 2014 Permalink | Reply
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    From SLAC: “Bringing High-energy X-rays into Better Focus” 


    SLAC Lab

    July 22, 2014
    SLAC-invented Etching Process Builds Custom Nanostructures for X-ray Optics

    Scientists at the Department of Energy’s SLAC National Accelerator Laboratory have invented a customizable chemical etching process that can be used to manufacture high-performance focusing devices for the brightest X-ray sources on the planet, as well as to make other nanoscale structures such as biosensors and battery electrodes.

    “The tools researchers use to manipulate X-rays today are very limited,” said Anne Sakdinawat, an associate staff scientist at SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL) who developed the new “V-MACE” process with Chieh Chang, an SSRL research associate.

    scan
    Scanning electron microscope image of a cleaved spiral zone plate, a type of X-ray optic, created using a chemical etching technique that was developed at SLAC. (Chieh Chang, Anne Sakdinawat)

    “Our new technique for fabricating high performance X-ray optics involves just a few chemicals in a simple, easy-to-implement, one-step technology,” Sakdinawat said. “It offers significant advantages in many far-ranging applications.” The patent-pending technique is detailed in the June 27 edition of Nature Communications.

    Focusing X-rays, particularly higher-energy or “hard” X-rays, is particularly challenging at the nanoscale, though it is key to the success of many scientific studies at two of SLAC’s DOE Office of Science user facilities, SSRL and the Linac Coherent Light Source (LCLS) X-ray laser.

    It is also of great interest for commercial applications such as X-ray microscopy, complex electronics, and biomedical devices and imaging tools.

    Existing tools for focusing hard X-rays, such as specialized mirrors and sequences of concave metal structures that form lenses, are generally limited in how they can shape the X-ray light. Focusing the highest-energy X-rays to produce crisp images remains a challenge, as the focusing tools themselves generally lack nanoscale precision and sap away much of the X-ray energy.

    “It’s been technologically very difficult to fabricate structures that offer both high resolution and high efficiency,” Sakdinawat said, and the effectiveness of the structures, which are examples of X-ray “diffractive optics,” is typically based on the height and precision of their features.

    The new fabrication technique is adapted from a process used to create hairlike silicon wires for research on advanced batteries and electronics. It can fabricate structures up to 100 times as tall as they are wide, with dimensions accurate to billionths of a meter. The technique reduces the need to stack multiple layers to create tall structures.

    The researchers used the etching technique to build tall, precise X-ray diffractive optics, called zone plates, whose thinly spaced lines, symmetric rings or spiral patterns alternately obstruct or phase-shift X-rays and allow them to pass through in a way that separates and refocuses them. This improves the focus and produces higher-quality images.

    zone
    Scanning electron microscope (SEM) image of a zone plate pattern produced using a chemical etching technique invented at SLAC. (Chieh Chang, Anne Sakdinawat)

    zone2
    This scanning electron microscope image shows a cross-sectional view of a zone plate produced using a patent-pending chemical etching technique called “V-MACE” developed at SLAC. (Chieh Chang, Anne Sakdinawat)

    “Basically, this is like an artificial crystal,” Sakdinawat said, diffracting the X-ray light in a predictable pattern, as a crystal would. “You can basically manipulate the light in whatever fashion you want – you can shape the light in different ways,” she said, based on the design of the optics and the needs of the experiment.

    Sakdinawat and Chang tested and imaged a sample zone plate at SSRL, and they hope to construct similar plates for use in experiments at SSRL and LCLS.

    The same technique can be used to build other types of precise silicon and metal-coated nanostructures, such as filtration devices, thermoelectric devices that can create electricity from heat and components for tiny bio-sensors that can be embedded in the body, and researchers are working to tailor the process to suit the needs of government agencies and corporate partners.

    “We’re trying to expand into other fields,” Sakdinawat said. “There are many different applications for this.”

    See the full article here.

    SLAC Campus
    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.
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  • richardmitnick 4:50 pm on May 22, 2014 Permalink | Reply
    Tags: , , , , SLAC SSRL,   

    From SLAC Lab: “Stanford Researchers Discover Immune System’s Rules of Engagement” 


    SLAC Lab

    May 22, 2014
    Media Contacts:
    K. Chris Garcia, Department of Molecular & Cellular Physiology, Stanford School of Medicine: (650) 498-7111, kcgarcia@stanford.edu
    Dan Stober, Stanford News Service: (650) 721-6965, dstober@stanford.edu
    Andy Freeberg, SLAC National Accelerator Laboratory: (650) 926-4359, afreeberg@slac.stanford.edu

    Study finds surprising similarities in the way immune system defenders bind to disease-causing invaders.

    A study led by researchers at Stanford’s School of Medicine reveals how T cells, the immune system’s foot soldiers, respond to an enormous number of potential health threats.

    t
    Stanford School of Medicine researchers, working with scientists at the SLAC National Accelerator Laboratory, have made discoveries about the ways in which T cell receptors (shown in bright red) recognize invaders in the body. (Eric Smith and K. Christopher Garcia / Stanford University)

    X-ray studies at the Department of Energy’s SLAC National Accelerator Laboratory, combined with Stanford biological studies and computational analysis, revealed remarkable similarities in the structure of binding sites, which allow a given T cell to recognize many different invaders that provoke an immune response.

    t3
    T-cells use their receptors (red) to recognize different peptides (blue and yellow) presented on the surface of cells, a key mechanism to detect and combat infection. (Eric Smith and K. Christopher Garcia/Stanford University)

    t2
    This illustration shows the binding sites of a T-cell receptor (highlighted red) and a peptide (orange). Similarities in binding sites allow T-cells to bind to many different peptides. (Eric Smith and K. Christopher Garcia, Stanford University)

    The research demonstrates a faster, more reliable way to identify large numbers of antigens, the targets of the immune response, which could speed the discovery of disease treatments. It also may lead to a better understanding of what T cells recognize when fighting cancers and why they are triggered to attack healthy cells in autoimmune diseases such as diabetes and multiple sclerosis.

    “Until now, it often has been a real mystery which antigens T cells are recognizing; there are whole classes of disease where we don’t have this information,” said Michael Birnbaum, a graduate student who led the research at the School of Medicine in the laboratory of K. Christopher Garcia, the study’s senior author and a professor of molecular and cellular physiology and of structural biology.

    “Now it’s far more feasible to take a T cell that is important in a disease or autoimmune disorder and figure out what antigens it will respond to,” Birnbaum said.

    T cells are triggered into action by protein fragments, called peptides, displayed on a cell’s surface. In the case of an infected cell, peptide antigens from a pathogen can trigger a T cell to kill the infected cell. The research provides a sort of rulebook that can be used with high success to track down antigens likely to activate a given T cell, easing a bottleneck that has constrained such studies.

    Combination Approach

    In the study, researchers exposed a handful of mouse and human T-cell receptors to hundreds of millions of peptides, and found hundreds of peptides that bound to each type. Then they compiled and compared the detailed sequence – the order of the chemical building blocks – of the peptides that bound to each T-cell receptor.

    From that sample set, which represents just a tiny fraction of all peptides, a detailed computational analysis identified other likely binding matches. Researchers compared the 3-D structures of T cells and their unique receptors bound to different peptides at SLAC’s Stanford Synchrotron Research Lightsource (SSRL).

    “The X-ray work at SSRL was a key breakthrough in the study,” Birnbaum said. “Very different peptides aligned almost perfectly with remarkably similar binding sites. It took us a while to figure out this structural similarity was a common feature, not an oddity – that a vast number of unique peptides could be recognized in the same way.”

    Researchers also checked the sequencing of the peptides that were known to bind with a given T cell and found striking similarities there, too.

    “T-cell receptors are ‘cross-reactive,’ but in fairly limited ways. Like a multilingual person who can speak Spanish and French but can’t understand Japanese, a receptor can engage with a broad set of peptides related to one another,” Birnbaum said.

    Impact on Biomedical Science

    Finding out whether a given peptide activates a specific T-cell receptor has been a historically piecemeal process with a 20 to 30 percent success rate, involving burdensome hit-and-miss studies of biological samples. “This latest research provides a framework that can improve the success rate to as high as 90 percent,” Birnbaum said.

    “This is an important illustration of how SSRL’s X-ray-imaging capabilities allow researchers to get detailed structural information on technically very challenging systems,” said Britt Hedman, professor of photon science and science director at SSRL. “To understand the factors behind T-cell-receptor binding to peptides will have major impact on biomedical developments, including vaccine design and immunotherapy.”

    Additional contributors included the laboratories of Mark Davis, the Burt and Marion Avery Family Professor at Stanford School of Medicine, and Kai Wucherpfennig at the Dana Farber Cancer Institute and Harvard University. The research was supported by the National Institutes of Health and the Howard Hughes Medical Institute. SSRL is a scientific user facility supported by DOE’s Office of Science.

    See the full article here.

    SLAC Campus
    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.
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