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  • richardmitnick 6:49 pm on October 20, 2014 Permalink | Reply
    Tags: Applied Research & Technology, ,   

    From NYT: “25 Years Ago, NASA Envisioned Its Own ‘Orient Express’” 

    New York Times

    The New York Times

    OCT. 20, 2014
    KENNETH CHANG

    The National Aero-Space Plane was to be a revolutionary advance beyond the space shuttle.

    plane

    In his 1986 State of the Union address, President Ronald Reagan promised “a new Orient Express that could, by the end of the next decade, take off from Dulles Airport and accelerate up to 25 times the speed of sound, attaining low-earth orbit or flying to Tokyo within two hours.”

    On Oct. 3, 1989, an article in Science Times, Designing a Plane for the Leap of Space (and Back), reported frenetic activity at NASA and the Defense Department.

    “Scientists and engineers are making rapid progress in developing technologies needed to build a 17,000-mile-an-hour ‘space plane’ that could escape earth’s gravity and circle the globe in 90 minutes,” the article began.

    “Their goal,” it continued, “is a space plane that could take off and land from virtually any airport in the world, carry satellites and other space cargo into orbit cheaply, shuttle between the earth and an orbiting space station, or carry a load of bombs deep into enemy territory as fast as an intercontinental missile.”

    Proponents contended the space plane would be far cheaper to operate than the shuttle.

    Others were dubious. The Air Force, which was providing most of the financing, had already tried to back out, but the National Space Council, headed by Vice President Dan Quayle, recommended continuing work at a slower pace.

    The target for the first flight of the first experimental version, known as the X-30, was originally 1993 but was pushed back to 1997.

    25 YEARS LATER The space plane, able to fly by itself to orbit, never took off. The X-30 died in 1994. Smaller-scale hypersonic programs came and went.

    Was the X-30 technologically feasible?

    “No, and it’s still not,” said Jess Sponable, a program manager in the tactical technology office at Darpa, the Defense Advanced Research Projects Agency. For X-30 to succeed, infant ideas would have had to have been developed into robust, reliable technologies — materials that could survive intense temperatures, air-breathing engines that could fly faster and higher.

    Nonetheless, “absolutely, it was worthwhile,” Mr. Sponable said, although he added perhaps not worth the more than $1.6 billion spent. “We learned a lot.”

    The pendulum for spacecraft design has since swung away from the cutting edge to the tried and true. The Orion craft, which NASA is building for deep-space missions, is a capsule, just like the one used for the Apollo moon missions but bigger. The two private company designs that NASA chose to take future astronauts to the space station are also capsules. (The loser in that competition was a mini-shuttle offering.)

    NASA Orion Spacecraft
    NASA/Orion

    But the dream of hypersonic space planes continues.

    At Darpa, Mr. Sponable heads the XS-1 space plane project. It is not a do-it-all-at-once effort like the 1980s space plane but a much simpler, unmanned vehicle that would serve as a reusable first stage.

    Mr. Sponable is eager to figure out how to send it up many times, quickly and cheaply; the goal is 10 flights in 10 days.

    “We want operability No. 1,” he said. With the quick launches, the issue of cost “just disappears, because we can’t spend a lot of money from Day 1 to Day 2 to Day 3.”

    Darpa has awarded contracts to three industry teams to develop preliminary designs. Mr. Sponable said the decision of a next step would come next spring.

    The space plane episode illustrates the recurring money woes that have bedeviled NASA for decades: A grandiose plan is announced with fanfare and a burst of financing that fades as delays and cost overruns undercut the optimistic plans. Then a new president or a new NASA administrator changes course.

    Most recently, the Obama administration canceled plans started under President George W. Bush to send astronauts back to the moon and told NASA to consider an asteroid instead.

    If the pattern continues, NASA priorities could zig again after the next president moves into the White House in 2017.

    See the full article here.

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  • richardmitnick 3:04 pm on October 20, 2014 Permalink | Reply
    Tags: Applied Research & Technology, , ,   

    From LLNL: “Supercomputers link proteins to drug side effects” 


    Lawrence Livermore National Laboratory

    10/20/2014
    Kenneth K Ma, LLNL, (925) 423-7602, ma28@llnl.gov

    New medications created by pharmaceutical companies have helped millions of Americans alleviate pain and suffering from their medical conditions. However, the drug creation process often misses many side effects that kill at least 100,000 patients a year, according to the journal Nature.

    Lawrence Livermore National Laboratory researchers have discovered a high-tech method of using supercomputers to identify proteins that cause medications to have certain adverse drug reactions (ADR) or side effects. They are using high-performance computers (HPC) to process proteins and drug compounds in an algorithm that produces reliable data outside of a laboratory setting for drug discovery.

    The team recently published its findings in the journal PLOS ONE, titled Adverse Drug Reaction Prediction Using Scores Produced by Large-Scale Drug-Protein Target Docking on High-Performance Computer Machines.

    “We need to do something to identify these side effects earlier in the drug development cycle to save lives and reduce costs,” said Monte LaBute, a researcher from LLNL’s Computational Engineering Division and the paper’s lead author.

    It takes pharmaceutical companies roughly 15 years to bring a new drug to the market, at an average cost of $2 billion. A new drug compound entering Phase I (early stage) testing is estimated to have an 8 percent chance of reaching the market, according to the Food and Drug Administration (FDA).

    A typical drug discovery process begins with identifying which proteins are associated with a specific disease. Candidate drug compounds are combined with target proteins in a process known as binding to determine the drug’s effectiveness (efficacy) and/or harmful side effects (toxicity). Target proteins are proteins known to bind with drug compounds in order for the pharmaceutical to work.

    While this method is able to identify side effects with many target proteins, there are myriad unknown “off-target” proteins that may bind to the candidate drug and could cause unanticipated side effects.

    Because it is cost prohibitive to experimentally test a drug candidate against a potentially large set of proteins — and the list of possible off-targets is not known ahead of time — pharmaceutical companies usually only test a minimal set of off-target proteins during the early stages of drug discovery. This results in ADRs remaining undetected through the later stages of drug development, such as clinical trials, and possibly making it to the marketplace.

    There have been several highly publicized medications with off-target protein side effects that have reached the marketplace. For example, Avandia, an anti-diabetic drug, caused heart attacks in some patients; and Vioxx, an anti-inflammatory medication, caused heart attacks and strokes among certain patient populations. Both therapeutics were recalled because of their side effects.

    “There were no indications of side effects of these medications in early testing or clinical trials,” LaBute said. “We need a way to determine the safety of such therapeutics before they reach patients. Our work can help direct such drugs to patients who will benefit the most from them with the least amount of side effects.”

    LaBute and the LLNL research team tackled the problem by using supercomputers and information from public databases of drug compounds and proteins. The latter included protein databases of DrugBank, UniProt and Protein Data Bank (PDB), along with drug databases from the FDA and SIDER, which contain FDA-approved drugs with ADRs.

    The team examined 4,020 off-target proteins from DrugBank and UniProt. Those proteins were indexed against the PDB, which whittled the number down to 409 off-proteins that have high-quality 3D crystallographic X-ray diffraction structures essential for analysis in a computational setting.

    mp

    The 409 off-target proteins were fed into a Livermore HPC software known as VinaLC along with 906 FDA-approved drug compounds. VinaLC used a molecular docking matrix that bound the drugs to the proteins. A score was given to each combination to assess whether effective binding occurred.

    The binding scores were fed into another computer program and combined with 560 FDA-approved drugs with known side effects. An algorithm was used to determine which proteins were associated with certain side effects.

    The Lab team showed that in two categories of disorders — vascular disorders and neoplasms — their computational model of predicting side effects in the early stages of drug discovery using off-target proteins was more predictive than current statistical methods that do not include binding scores.

    In addition to LLNL ADR prediction methods performing better than current prediction methods, the team’s calculations also predicted new potential side effects. For example, they predicted a connection between a protein normally associated with cancer metastasis to vascular disorders like aneurysms. Their ADR predictions were validated by a thorough review of existing scientific data.

    “We have discovered a very viable way to find off-target proteins that are important for side effects,” LaBute said. “This approach using HPC and molecular docking to find ADRs never really existed before.”

    The team’s findings provide drug companies with a cost-effective and reliable method to screen for side effects, according to LaBute. Their goal is to expand their computational pharmaceutical research to include more off-target proteins for testing and eventually screen every protein in the body.

    “If we can do that, the drugs of tomorrow will have less side effects that can potentially lead to fatalities,” Labute said. “Optimistically, we could be a decade away from our ultimate goal. However, we need help from pharmaceutical companies, health care providers and the FDA to provide us with patient and therapeutic data.”

    two
    LLNL researchers Monte LaBute (left) and Felice Lightstone (right) were part of a Lab team that recently published an article in PLOS ONE detailing the use of supercomputers to link proteins to drug side effects. Photo by Julie Russell/LLNL

    The LLNL team also includes Felice Lightstone, Xiaohua Zhang, Jason Lenderman, Brian Bennion and Sergio Wong.

    See the full article here.

    LLNL Campus

    Operated by Lawrence Livermore National Security, LLC, for the Department of Energy’s National Nuclear Security
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  • richardmitnick 1:41 pm on October 19, 2014 Permalink | Reply
    Tags: Applied Research & Technology, , livescience   

    From livescience: “Bronze Warrior Chariot Discovery Is ‘Find of a Lifetime'” 

    Livescience

    October 14, 2014
    Stephanie Pappas

    More than 2,000 years ago, pieces of an Iron Age chariot were burnt and buried, perhaps as a religious offering. Now, archaeologists have discovered the bronze remains of this sacrifice.

    Digging near Melton Mowbray in Leicestershire, England, an archaeology team discovered a trove of bronze chariot fittings dating back to the second or third century B.C. The remains were discovered at the Burrough Hill Iron Age Hillfort, a fortified hilltop structure that was once surrounded by farms and settlements. Though humans lived in the area beginning around 4000 B.C., it was used most heavily between about 100 B.C. and A.D. 50, according to the University of Leicester.

    stuff
    A linch pin (shown from three angles) from an Iron Age chariot that were discovered at the Burrough Hill Iron Age Hillfort in Leicestershire, England
    Credit: University of Leicester

    hill
    Maiden Castle in England is one of the largest hill forts in Europe.[1][2] Photograph taken in 1935 by Major George Allen (1891–1940).

    “This is the most remarkable discovery of material we made at Burrough Hill in the five years we worked on the site,” University of Leicester archaeologist Jeremy Taylor said in a statement. “This is a very rare discovery and a strong sign of the prestige of the site.” [See Images of the Iron Age Chariot's Remains]

    Burnt offering

    Taylor co-directs the field project at Burrough Hill, which is used to train archaeology students. It was four of these archaeology students who first found a piece of bronze near an Iron Age house within the Burrough Hill fort. More bronze pieces were found nearby.

    The pieces are the metal remains of a chariot that once belonged to a warrior or noble, according to university archaeologists. They include linchpins with decorated end caps, as well as rings and fittings that would have held harnesses. One linchpin is decorated with three wavy lines radiating from a single point, almost like the modern flag for the Isle of Man, a British dependency in the Irish Sea. The Isle of Man’s flag is decorated with an odd symbol called a triskelion, or three half-bent legs converging at the thigh.

    tris
    The flag of the Isle of Man, is composed solely of a triskele against a red background

    “The atmosphere at the dig on the day was a mix of ‘tremendously excited’ and ‘slightly shell-shocked,'” Taylor said. “I have been excavating for 25 years, and I have never found one of these pieces — let alone a whole set. It is a once-in-a-career discovery.”

    The pieces were found upon a layer of chaff, which may have provided fuel for the burning ritual. The chariot pieces were put into a box and then covered with cinder and slag after being set on fire. This may have been a ritual marking the dismantling or closing of a home at the fort, or it could have honored the change of seasons, University of Leicester archaeologists suspect.

    Bronze and iron

    Alongside the chariot pieces, the researchers found a set of iron tools, which were placed around the parts before they were burned.

    “The function of the iron tools is a bit of a mystery, but given the equestrian nature of the hoard, it is possible that they were associated with horse grooming,” Burrough Hill project co-director John Thomas said in a statement. “One piece, in particular, has characteristics of a modern curry comb, while two curved blades may have been used to maintain horses’ hooves or manufacture harness parts.”

    The pieces will be on display temporarily at the Melton Carnegie Museum in Melton Mowbray from Oct. 18 to Dec. 13.

    “Realizing that I was actually uncovering a hoard that was carefully placed there hundreds of years ago made it the find of a lifetime,” University of Leicester student Nora Battermann, who was one of the four students to make the find, said in a statement. “Looking at the objects now that they have been cleaned makes me even more proud, and I can’t wait for them to go on display.”

    See the full article here.

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  • richardmitnick 1:18 pm on October 19, 2014 Permalink | Reply
    Tags: Applied Research & Technology, ,   

    From Huff Post: “Ancient Cult Complex Discovered In Israel Dates Back 3,300 Years, May Be Temple Of Baal” 

    Huffington Post
    The Huffington Post

    10/15/2014
    Dominique Mosbergen

    Archaeologists working in Israel have discovered an “ancient cult complex,” where people who lived thousands of years ago might have worshipped a Canaanite “storm god” known as Baal.

    baal
    Bronze figurine of a Baal, ca. 14th–12th century BC, found at Ras Shamra (ancient Ugarit) near the Phoenician coast. Musée du Louvre.

    site
    Inside the massive cult complex, archaeologists found facemasks, human-size containers and burnt animal bones possibly related to sacrificial practices. The Canaanite storm god may have been worshiped

    The complex was unearthed at the archaeological site of Tel Burna, located near the Israeli city of Kiryat Gat. It’s believed to date back 3,300 years.

    tel
    Aerial view of Tel Burna

    tel

    site2
    Tel Burna Archaeological Project

    Though more excavation needs to be conducted, the archaeologists said the site is believed to be quite large, with the courtyard of the complex measuring more than 50 feet on one side.

    Researchers said the site has already yielded artifacts that seem to confirm the complex’s cultic past. These include enormous jars that may have been used to store tithes, masks that might have been used in ceremonial processions, and burnt animal bones that hint at sacrificial rituals.

    Itzhaq Shai, director of the Tel Burna Excavation Project, told Live Science that it wasn’t entirely clear which god the complex was dedicated to. But he called Baal — which ancient Middle Eastern cultures worshipped as a fertility god — the “most likely candidate.” Another possibility, according to UPI, is that members of the cult worshipped a female god, like the ancient war goddess Anat.

    anat

    Excavation work at Tel Burna has been going on since 2009, and members of the public have a standing invitation to help out.
    “Unlike most excavations, we are looking for people come to participate for even just a few hours,” Shai told Fox News in 2013. ” Hopefully they will be captivated and come back.”

    See the full article here.

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  • richardmitnick 2:46 pm on October 17, 2014 Permalink | Reply
    Tags: Applied Research & Technology, ,   

    From NOVA: “Insulin-Producing Stem Cells Could Provide Lasting Diabetes Treatments” 

    PBS NOVA

    NOVA

    Fri, 17 Oct 2014
    Sarah Schwartz

    Researchers have crafted what may be a powerful weapon in the fight against diabetes: A new line of insulin-producing cells that has been shown to reverse diabetes in mice within forty days. Scientists hope that these cells may someday do the same in humans.

    The new cells, called “Stage 7” or “S7” for their seven-step production process, are the product of a study by researchers at the University of British Columbia and the pharmaceutical company Janssen. S7 cells are made to mimic human beta cells, which are damaged or destroyed in patients with diabetes. Healthy beta cells produce insulin and help regulate blood sugar; S7 cells are grown from human embryonic stem cells and are programmed to do the same.

    cells
    A microscopic view of beta cells derived from stem cells

    “The advance that they have made is that they’ve got better cells in the test tube, cells that have more insulin and can secrete insulin in response to glucose,” said Dr. Gordon Weir, a physician and researcher at Joslin Diabetes Center and Harvard Medical School. “People haven’t been able to do that before.”

    Human embryonic stem cells, like those used to produce the S7 line, show great promise for producing beta cell replacements. Just last week, another team of researchers led by Dr. Douglas Melton at Harvard University announced their own line of insulin-producing cells, also produced from human embryonic stem cells. Like S7 cells, the Harvard team’s cells produce insulin in response to high blood sugar and can reverse diabetes symptoms in mice.

    The hope is that cells like these could be injected into diabetic patients, restoring normal beta cell function. Timothy Kieffer, head of the diabetes research group at University of British Columbia and a co-author of the S7 cell study, said that treatment with these cells could be curative, though other researchers caution that additional work has to be done before that’s the case.

    Cellular transplantation has already been shown to effectively combat diabetes. Since the late 1980s, beta cells extracted from cadaver pancreases have been used to normalize blood sugar in diabetics. But these treatments are not an option for many patients. In addition to the challenges of establishing a treatment program, Weir said, “there aren’t enough pancreatic donors to even scratch the surface.” These transplanted cells also tend to stop working over time, said Dr. David Nathan, the director of the Diabetes Center and Clinical Research Center at Massachusetts General Hospital. Whole organ pancreatic transplants usually last longer and have been increasingly successful in recent years, Nathan says. But both organ and cell transplants from cadavers require immunosuppressive treatments, which can cause tumors, skin cancers, and weakened immune systems.

    Beta cells grown from stem cells could solve some of these problems. It is possible that stem cells could be developed to reduce or eliminate the need for immunosuppression, Nathan said. Plus, their supply is theoretically unlimited. “If you can make them in a test tube, in a dish, whatever—well, that gets rid of the problem of donor pancreases,” Nathan said. While S7 cells are most efficient when made from human embryonic stem cells, they can also be made using induced pluripotent stem cells, which are reprogrammed adult cells. This, Weir noted, could eliminate “ethical issues” involved with embryonic stem cell use.

    Kieffer believes that a stem cell-based treatment would also be superior to insulin supplementation, the current standard of treatment for type 1 diabetes. In type 1 diabetes, which Kieffer’s research targets, beta cells are destroyed by an autoimmune attack, and patients require external insulin to survive. Even with advanced treatment options like insulin pumps, Weir said, it is challenging to keep blood sugar in a normal range. “And if you push hard enough to drive the blood sugar down, you end up getting into trouble with insulin reactions,” Weir said. “The blood sugar goes too low and that’s dangerous.”

    But S7 cells have some challenges to overcome before they can replace current treatments. For one, it can be difficult to control the development of stem cells, Nathan pointed out. Kieffer agreed that more research is needed to mature the cells, which are still not identical to human beta cells because they react more slowly to sugar and don’t release as much insulin. Kieffer’s collaborators are also working to scale up production of the S7 line. Meanwhile, the Harvard study uses a protocol that already seems to allow relatively large-scale development of insulin-producing cells.

    There are also other challenges to treating type 1 diabetes with cells like S7 because of the autoimmune nature of the disease. If beta cell transplants are injected into type 1 diabetics, Weir said, “those cells are still going to be subject to the immune problem that killed the cells in the first place.” Kieffer said that the “next hurdle” for his team is to see if S7 cells will work inside devices that prevent immune attack.

    These “immunobarrier” devices are essentially capsules that contain implanted stem cells, allowing the exchange of nutrients and insulin while blocking attacking immune cells. Nathan and Weir expressed reservations about these devices. Nathan wondered if they can be designed to allow sufficient blood flow and nutrients to all the cells inside, while Weir questioned whether there could be a device large enough to hold the number of cells needed to control the disease. Still, in August, the company Viacyte started clinical trials with such a device, using a line of cells less developed than S7. “We’ll have to wait and see,” Weir said.

    Because of the autoimmunity problem inherent in type 1 diabetes, Weir says that it may be easier to use beta cell transplantations to treat type 2 diabetes instead. Up to 95% of diabetic patients have this form of the disease, which involves no autoimmunity. Instead, in type 2, beta cells “wear out” such that the body stops responding to insulin.

    “You can take a type 2 diabetic and give them insulin injections and normalize the sugar if you do it carefully,” Weir said. “So, a beta cell transplant is just the same thing as giving an insulin injection.” He feels the effects of such treatment could be profound. “You can put cells in and normalize the blood sugar for years,” he said. “So if you want to call that a cure, I’d go along with that.” Nathan disagrees: because type 2 diabetics have some pancreatic function, it can be simpler and easier to treat their symptoms. Because of this, he believes that cellular transplantations will mostly be useful to combat type 1 diabetes.

    Nathan doesn’t think that beta cell transplantations are an “appropriate clinical option”—yet. “The balance between risk and benefit isn’t quite right,” he says. Still, he hopes that someday, a cellular treatment will be advanced enough to safely and effectively treat this disease. “To cure type 1 diabetes would be a godsend,” he says. “To actually do a single procedure that essentially takes away the disease at low risk would be great.”

    Though several questions must be answered before they start curing patients, S7 cells are a promising step in the fight against a disease that affects 347 million people worldwide. The field is moving quickly towards its goal; as Kieffer writes, “I am very optimistic that we are narrowing down on a cure for diabetes.”

    See the full article here.

    NOVA is the highest rated science series on television and the most watched documentary series on public television. It is also one of television’s most acclaimed series, having won every major television award, most of them many times over.

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  • richardmitnick 1:45 pm on October 17, 2014 Permalink | Reply
    Tags: Applied Research & Technology, ,   

    From AAAS: “Would-be drug mimics ‘good’ cholesterol” 

    AAAS

    AAAS

    16 October 2014
    Robert F. Service

    A new drug candidate designed to mimic the body’s “good” cholesterol shows a striking ability in mice to lower cholesterol levels in the blood and dissolve artery-clogging plaques. What’s more, the compound works when given orally, rather than as an injection. If the results hold true in humans—a big if, given past failures at transferring promising treatments from mice—it could provide a new way to combat atherosclerosis, the biggest killer in developed countries.

    Although doctors already have effective cholesterol-lowering agents, such as statins, at their disposal, there’s room for improvement. Statins have significant side effects in some people and don’t always reduce cholesterol enough in others. “There is still plenty of heart disease out there even among people who take statins,” says Godfrey Getz, an experimental pathologist at the University of Chicago in Illinois.

    For that reason, researchers around the globe are searching for novel drugs that affect cholesterol levels in one of two ways. The first has been to reduce levels of low-density lipoprotein (LDL), commonly known as bad cholesterol, which has been associated with higher heart disease risk. This is the goal of statins, which block an enzyme involved in cholesterol production. The second strategy is to increase levels of good cholesterol, or high-density lipoprotein (HDL), which seems to boost heart health in people who have a lot of it. But producing HDL-raising drugs that prevent heart disease has proven difficult. In the body, a large protein called apolipoprotein A-I (apoA-I) wraps around fatty lipid molecules to create HDL particles that sop up LDL and ferry it to the liver where it is eliminated. So for several decades researchers have been designing and testing small protein fragments called peptides to see if they could mimic the behavior of apoA-I. One such peptide, known as 4F, did not reduce serum cholesterol levels, but it did shrink arterial plaques in mice, rabbits, and monkeys. And in an early clinical trial by researchers at Bruin Pharma Inc. in Beverly Hills, California, that was designed only to measure its safety in people, 4F didn’t appear to show any beneficial effect.

    pro
    Multiple copies of a four-armed peptide wrap around lipids to create particles that mimic the behavior of HDL, the “good” cholesterol.
    Y.Zhao et al., J. Am. Chem. Soc

    M. Reza Ghadiri, a chemist at the Scripps Research Institute in San Diego, California, and his colleagues took a slightly different tack, creating a peptide that mimics another part of the apoA-I protein than 4F does. Initial in vitro studies suggested the peptide formed HDL-like particles and sopped up LDL, an encouraging result that prompted them to push it further. Ghadiri and his Scripps colleagues have now tested their compound in mice that develop artery clogging plaques when fed a Western-style high-fat diet. One group of animals received the peptide intravenously. For another group, the researchers simply added the compound to the animals’ water, a strategy they considered unlikely to work, because the gut contains high amounts of proteases designed to chop proteins apart. To their surprise, in both groups, serum cholesterol levels dropped 40% from their previous levels within 2 weeks of starting to take the drug. And by 10 weeks, the number of artery-clogging lesions had been reduced by half, the team reports in the October issue of the Journal of Lipid Research. What remains puzzling, however, is that Ghadiri and his colleagues did not detect their peptides in the blood of their test animal. Ghadiri says this suggests that the new peptide may work by removing cholesterol precursors in the gut before they enter the bloodstream.

    “It’s a very interesting result,” Getz says. But he cautions that the work has been tested only in animals, and many therapies—including the closely related 4F peptide—fail to transfer to humans. That said, Getz notes that some of the initial promising results with this peptide and other apoA-I mimics offer hope that researchers may soon come up with novel drugs capable of dissolving artery-clogging plaques before they can wreak their havoc.

    See the full article here.

    The American Association for the Advancement of Science is an international non-profit organization dedicated to advancing science for the benefit of all people.

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  • richardmitnick 9:02 am on October 17, 2014 Permalink | Reply
    Tags: Applied Research & Technology, , ,   

    From MIT: “Nanoparticles get a magnetic handle” 


    MIT News

    October 9, 2014
    David L. Chandler | MIT News Office

    A long-sought goal of creating particles that can emit a colorful fluorescent glow in a biological environment, and that could be precisely manipulated into position within living cells, has been achieved by a team of researchers at MIT and several other institutions. The finding is reported this week in the journal Nature Communications.

    4
    Elemental mapping of the location of iron atoms (blue) in the magnetic nanoparticles and cadmium (red) in the fluorescent quantum dots provide a clear visualization of the way the two kinds of particles naturally separate themselves into a core-and-shell structure. Image courtesy of the researchers

    The new technology could make it possible to track the position of the nanoparticles as they move within the body or inside a cell. At the same time, the nanoparticles could be manipulated precisely by applying a magnetic field to pull them along. And finally, the particles could have a coating of a bioreactive substance that could seek out and bind with particular molecules within the body, such as markers for tumor cells or other disease agents.

    “It’s been a dream of mine for many years to have a nanomaterial that incorporates both fluorescence and magnetism in a single compact object,” says Moungi Bawendi, the Lester Wolfe Professor of Chemistry at MIT and senior author of the new paper. While other groups have achieved some combination of these two properties, Bawendi says that he “was never very satisfied” with results previously achieved by his own team or others.

    For one thing, he says, such particles have been too large to make practical probes of living tissue: “They’ve tended to have a lot of wasted volume,” Bawendi says. “Compactness is critical for biological and a lot of other applications.”

    In addition, previous efforts were unable to produce particles of uniform and predictable size, which could also be an essential property for diagnostic or therapeutic applications.

    Moreover, Bawendi says, “We wanted to be able to manipulate these structures inside the cells with magnetic fields, but also know exactly what it is we’re moving.” All of these goals are achieved by the new nanoparticles, which can be identified with great precision by the wavelength of their fluorescent emissions.

    The new method produces the combination of desired properties “in as small a package as possible,” Bawendi says — which could help pave the way for particles with other useful properties, such as the ability to bind with a specific type of bioreceptor, or another molecule of interest.

    In the technique developed by Bawendi’s team, led by lead author and postdoc Ou Chen, the nanoparticles crystallize such that they self-assemble in exactly the way that leads to the most useful outcome: The magnetic particles cluster at the center, while fluorescent particles form a uniform coating around them. That puts the fluorescent molecules in the most visible location for allowing the nanoparticles to be tracked optically through a microscope.

    “These are beautiful structures, they’re so clean,” Bawendi says. That uniformity arises, in part, because the starting material, fluorescent nanoparticles that Bawendi and his group have been perfecting for years, are themselves perfectly uniform in size. “You have to use very uniform material to produce such a uniform construction,” Chen says.

    Initially, at least, the particles might be used to probe basic biological functions within cells, Bawendi suggests. As the work continues, later experiments may add additional materials to the particles’ coating so that they interact in specific ways with molecules or structures within the cell, either for diagnosis or treatment.

    The ability to manipulate the particles with electromagnets is key to using them in biological research, Bawendi explains: The tiny particles could otherwise get lost in the jumble of molecules circulating within a cell. “Without a magnetic ‘handle,’ it’s like a needle in a haystack,” he says. “But with the magnetism, you can find it easily.”

    A silica coating on the particles allows additional molecules to attach, causing the particles to bind with specific structures within the cell. “Silica makes it completely flexible; it’s a well developed material that can bind to almost anything,” Bawendi says.

    For example, the coating could have a molecule that binds to a specific type of tumor cells; then, “You could use them to enhance the contrast of an MRI, so you could see the spatial macroscopic outlines of a tumor,” he says.

    The next step for the team is to test the new nanoparticles in a variety of biological settings. “We’ve made the material,” Chen says. “Now we’ve got to use it, and we’re working with a number of groups around the world for a variety of applications.”

    Christopher Murray, a professor of chemistry and materials science and engineering at the University of Pennsylvania who was not connected with this research, says, “This work exemplifies the power of using nanocrystals as building blocks for multiscale and multifunctional structures. We often use the term ‘artificial atoms’ in the community to describe how we are exploiting a new periodic table of fundamental building blocks to design materials, and this is a very elegant example.”

    The study included researchers at MIT; Massachusetts General Hospital; Institut Curie in Paris; the Heinrich-Pette Institute and the Bernhard-Nocht Institute for Tropical Medicine in Hamburg, Germany; Children’s Hospital Boston; and Cornell University. The work was supported by the National Institutes of Health, the Army Research Office through MIT’s Institute for Soldier Nanotechnologies, and the Department of Energy.

    See the full article, with video, here.

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  • richardmitnick 8:38 am on October 17, 2014 Permalink | Reply
    Tags: Applied Research & Technology, , , ,   

    From UC Berkeley: “New front in war on Alzheimer’s, other protein-folding diseases” 

    UC Berkeley

    UC Berkeley

    October 16, 2014
    Robert Sanders

    A surprise discovery that overturns decades of thinking about how the body fixes proteins that come unraveled greatly expands opportunities for therapies to prevent diseases such as Alzheimer’s and Parkinson’s, which have been linked to the accumulation of improperly folded proteins in the brain.

    “This finding provides a whole other outlook on protein-folding diseases; a new way to go after them,” said Andrew Dillin, the Thomas and Stacey Siebel Distinguished Chair of Stem Cell Research in the Department of Molecular and Cell Biology and Howard Hughes Medical Institute investigator at the University of California, Berkeley.

    br
    A cell suffering heat shock is like a country besieged, where attackers first sever lines of communications. The pat-10 gene helps repair communication to allow chaperones to treat misfolded proteins. (Andrew Dillin graphic)

    Dillin, UC Berkeley postdoctoral fellows Nathan A. Baird and Peter M. Douglas and their colleagues at the University of Michigan, The Scripps Research Institute and Genentech Inc., will publish their results in the Oct. 17 issue of the journal Science.

    Cells put a lot of effort into preventing proteins – which are like a string of beads arranged in a precise three-dimensional shape – from unraveling, since a protein’s activity as an enzyme or structural component depends on being properly shaped and folded. There are at least 350 separate molecular chaperones constantly patrolling the cell to refold misfolded proteins. Heat is one of the major threats to proteins, as can be demonstrated when frying an egg – the clear white albumen turns opaque as the proteins unfold and then tangle like spaghetti.

    Heat shock

    For 35 years, researchers have worked under the assumption that when cells undergo heat shock, as with a fever, they produce a protein that triggers a cascade of events that field even more chaperones to refold unraveling proteins that could kill the cell. The protein, HSF-1 (heat shock factor-1), does this by binding to promoters upstream of the 350-plus chaperone genes, upping the genes’ activity and launching the army of chaperones, which originally were called “heat shock proteins.”

    Injecting animals with HSF-1 has been shown not only to increase their tolerance of heat stress, but to increase lifespan.

    Because an accumulation of misfolded proteins has been implicated in aging and in neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases, scientists have sought ways to artificially boost HSF-1 in order to reduce the protein plaques and tangles that eventually kill brain cells. To date, such boosters have extended lifespan in lab animals, including mice, but greatly increased the incidence of cancer.

    Dillin’s team found in experiments on the nematode worm C. elegans that HSF-1 does a whole lot more than trigger release of chaperones. An equal if not more important function is to stabilize the cell’s cytoskeleton, which is the highway that transports essential supplies – healing chaperones included – around the cell.

    “We are suggesting that, rather than making more of HSF-1 to prevent diseases like Huntington’s, we should be looking for ways to make the actin cytoskeleton better,” Dillin said. Such tactics might avoid the carcinogenic side effects of upping HSF-1.

    Dillin is codirector of the Paul F. Glenn Center for Aging Research, a new collaboration between UC Berkeley and UC San Francisco supported by the Glenn Foundation for Medical Research. Center investigators will study the many ways that proteins malfunction within cells, ideally paving the way for novel treatments for neurodegenerative diseases.

    A cell at war

    Dillin compares a cell experiencing heat shock to a country under attack. In a war, an aggressor first cuts off all communications, such as roads, train and bridges, which prevents the doctors from treating the wounded. Similarly, heat shock disrupts the cytoskeletal highway, preventing the chaperone “doctors” from reaching the patients, the misfolded proteins.

    chap
    Chaperones help newborn proteins (polypeptides) fold properly, but also fix misfolded proteins.

    “We think HSF-1 not only makes more chaperones, more doctors, but also insures that the roadways stay intact to keep everything functional and make sure the chaperones can get to the sick and wounded warriors,” he said.

    The researchers found specifically that HSF-1 up-regulates another gene, pat-10, that produces a protein that stabilizes actin, the building blocks of the cytoskeleton.

    By boosting pat-10 activity, they were able to cure worms that had been altered to express the Huntington’s disease gene, and also extend the lifespan of normal worms.

    Dillin suspects that HSF-1’s main function is, in fact, to protect the actin cytoskeleton. He and his team mutated HSF-1 so that it no longer boosted chaperones, demonstrating, he said, that “you can survive heat shock with the normal level of heat shock proteins, as long as you make your cytoskeleton work better.”

    He noted that the team’s results – that boosting chaperones is not essential to surviving heat stress – were so contradictory to current thinking that “I made my post-docs’ lives hell for three years” insisting on more experiments to rule out errors. Yet, when Dillin presented the results recently to members of the protein-folding community, he said the first reaction of many was, “That makes perfect sense.”

    Dillin’s colleagues include Milos S. Simic and Suzanne C. Wolff of UC Berkeley, Ana R. Grant of the University of Michigan in Ann Arbor, James J. Moresco and John R. Yates III of Scripps in La Jolla, Calif., and Gerard Manning of Genentech, South San Francisco, Calif. The work is funded by the Howard Hughes Medical Institute as well as by the National Institute of General Medical Sciences (8 P41 GM103533-17) and National Institute on Aging (R01AG027463-04) of the National Institutes of Health.

    See the full article here.

    Founded in the wake of the gold rush by leaders of the newly established 31st state, the University of California’s flagship campus at Berkeley has become one of the preeminent universities in the world. Its early guiding lights, charged with providing education (both “practical” and “classical”) for the state’s people, gradually established a distinguished faculty (with 22 Nobel laureates to date), a stellar research library, and more than 350 academic programs.

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  • richardmitnick 8:20 am on October 17, 2014 Permalink | Reply
    Tags: Applied Research & Technology, , ,   

    From MIT: “Superconducting circuits, simplified” 


    MIT News

    October 17, 2014
    Larry Hardesty | MIT News Office

    Computer chips with superconducting circuits — circuits with zero electrical resistance — would be 50 to 100 times as energy-efficient as today’s chips, an attractive trait given the increasing power consumption of the massive data centers that power the Internet’s most popular sites.

    chip
    Shown here is a square-centimeter chip containing the nTron adder, which performed the first computation using the researchers’ new superconducting circuit. Photo: Adam N. McCaughan

    Superconducting chips also promise greater processing power: Superconducting circuits that use so-called Josephson junctions have been clocked at 770 gigahertz, or 500 times the speed of the chip in the iPhone 6.

    But Josephson-junction chips are big and hard to make; most problematic of all, they use such minute currents that the results of their computations are difficult to detect. For the most part, they’ve been relegated to a few custom-engineered signal-detection applications.

    In the latest issue of the journal Nano Letters, MIT researchers present a new circuit design that could make simple superconducting devices much cheaper to manufacture. And while the circuits’ speed probably wouldn’t top that of today’s chips, they could solve the problem of reading out the results of calculations performed with Josephson junctions.

    The MIT researchers — Adam McCaughan, a graduate student in electrical engineering, and his advisor, professor of electrical engineering and computer science Karl Berggren — call their device the nanocryotron, after the cryotron, an experimental computing circuit developed in the 1950s by MIT professor Dudley Buck. The cryotron was briefly the object of a great deal of interest — and federal funding — as the possible basis for a new generation of computers, but it was eclipsed by the integrated circuit.

    “The superconducting-electronics community has seen a lot of devices come and go, without any real-world application,” McCaughan says. “But in our paper, we have already applied our device to applications that will be highly relevant to future work in superconducting computing and quantum communications.”

    Superconducting circuits are used in light detectors that can register the arrival of a single light particle, or photon; that’s one of the applications in which the researchers tested the nanocryotron. McCaughan also wired together several of the circuits to produce a fundamental digital-arithmetic component called a half-adder.

    Resistance is futile

    Superconductors have no electrical resistance, meaning that electrons can travel through them completely unimpeded. Even the best standard conductors — like the copper wires in phone lines or conventional computer chips — have some resistance; overcoming it requires operational voltages much higher than those that can induce current in a superconductor. Once electrons start moving through an ordinary conductor, they still collide occasionally with its atoms, releasing energy as heat.

    Superconductors are ordinary materials cooled to extremely low temperatures, which damps the vibrations of their atoms, letting electrons zip past without collision. Berggren’s lab focuses on superconducting circuits made from niobium nitride, which has the relatively high operating temperature of 16 Kelvin, or minus 257 degrees Celsius. That’s achievable with liquid helium, which, in a superconducting chip, would probably circulate through a system of pipes inside an insulated housing, like Freon in a refrigerator.

    A liquid-helium cooling system would of course increase the power consumption of a superconducting chip. But given that the starting point is about 1 percent of the energy required by a conventional chip, the savings could still be enormous. Moreover, superconducting computation would let data centers dispense with the cooling systems they currently use to keep their banks of servers from overheating.

    Cheap superconducting circuits could also make it much more cost-effective to build single-photon detectors, an essential component of any information system that exploits the computational speedups promised by quantum computing.

    Engineered to a T

    The nanocryotron — or nTron — consists of a single layer of niobium nitride deposited on an insulator in a pattern that looks roughly like a capital “T.” But where the base of the T joins the crossbar, it tapers to only about one-tenth its width. Electrons sailing unimpeded through the base of the T are suddenly crushed together, producing heat, which radiates out into the crossbar and destroys the niobium nitride’s superconductivity.

    A current applied to the base of the T can thus turn off a current flowing through the crossbar. That makes the circuit a switch, the basic component of a digital computer.

    After the current in the base is turned off, the current in the crossbar will resume only after the junction cools back down. Since the superconductor is cooled by liquid helium, that doesn’t take long. But the circuits are unlikely to top the 1 gigahertz typical of today’s chips. Still, they could be useful for some lower-end applications where speed isn’t as important as energy efficiency.

    Their most promising application, however, could be in making calculations performed by Josephson junctions accessible to the outside world. Josephson junctions use tiny currents that until now have required sensitive lab equipment to detect. They’re not strong enough to move data to a local memory chip, let alone to send a visual signal to a computer monitor.

    In experiments, McCaughan demonstrated that currents even smaller than those found in Josephson-junction devices were adequate to switch the nTron from a conductive to a nonconductive state. And while the current in the base of the T can be small, the current passing through the crossbar could be much larger — large enough to carry information to other devices on a computer motherboard.

    “I think this is a great device,” says Oleg Mukhanov, chief technology officer of Hypres, a superconducting-electronics company whose products rely on Josephson junctions. “We are currently looking very seriously at the nTron for use in memory.”

    “There are several attractions of this device,” Mukhanov says. “First, it’s very compact, because after all, it’s a nanowire. One of the problems with Josephson junctions is that they are big. If you compare them with CMOS transistors, they’re just physically bigger. The second is that Josephson junctions are two-terminal devices. Semiconductor transistors are three-terminal, and that’s a big advantage. Similarly, nTrons are three-terminal devices.”

    “As far as memory is concerned,” Mukhanov adds, “one of the features that also attracts us is that we plan to integrate it with magnetoresistive spintronic devices, mRAM, magnetic random-access memories, at room temperature. And one of the features of these devices is that they are high-impedance. They are in the kilo-ohms range, and if you look at Josephson junctions, they are just a few ohms. So there is a big mismatch, which makes it very difficult from an electrical-engineering standpoint to match these two devices. NTrons are nanowire devices, so they’re high-impedance, too. They’re naturally compatible with the magnetoresistive elements.”

    McCaughan and Berggren’s research was funded by the National Science Foundation and by the Director of National Intelligence’s Intelligence Advanced Research Projects Activity.

    See the full article here.

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  • richardmitnick 9:04 pm on October 16, 2014 Permalink | Reply
    Tags: Applied Research & Technology, , , ,   

    From LLNL: “Lab, UC Davis partner to personalize cancer medications” 


    Lawrence Livermore National Laboratory

    10/16/2014
    Stephen P Wampler, LLNL, (925) 423-3107, wampler1@llnl.gov

    Buoyed by several dramatic advances, Lawrence Livermore National Laboratory scientists think they can tackle biological science in a way that couldn’t be done before.

    Over the past two years, Lab researchers have expedited accelerator mass spectrometer sample preparation and analysis time from days to minutes and moved a complex scientific process requiring accelerator physicists into routine laboratory usage.

    Ken Turteltaub, the leader of the Lab’s Biosciences and Biotechnology Division, sees the bio AMS advances as allowing researchers to undertake quantitative assessments of complex biological pathways.

    “We are hopeful that we’ll be able to quantify the individual steps in a metabolic pathway and be able to measure indicators of disease processes and factors important to why people differ in responses to therapeutics, to diet and other factors,” Turteltaub said.

    Graham Bench, the director of the Lab’s Center for Accelerator Mass Spectrometry, anticipates the upgrades will enable Lab researchers “to produce high-density data sets and tackle novel biomedical problems that in the past couldn’t be addressed.”

    Ted Ognibene, a chemist who has worked on AMS for 15 years and who co-developed the technique that accommodates liquid samples, also envisions new scientific work coming forth.

    two
    Ted Ognibene (left), a chemist who co-developed the technique that accommodates liquid samples for accelerator mass spectrometry, peers with biomedical scientist Mike Malfatti at the new biological AMS instrument that has been installed in the Laboratory’s biomedical building. Photo by George Kitrinos

    “We previously had the capability to detect metabolites, but now with the ability to see our results almost immediately for a fraction of the cost, it’s going to enable a lot more fundamental and new science to be done,” Ognibene said.

    Biological AMS is a technique in which carbon-14 is used as a tag to study with extreme precision and sensitivity complex biological processes, such as cancer, molecular damage, drug and toxin behavior, nutrition and other areas.

    Among the biomedical studies that will be funded through the five-year, $7.8 million National Institutes of Health grant for biological AMS work is one to try to develop a test to predict how people will respond to chemotherapeutic drugs.

    Another research project seeks to create an assay that is so sensitive that it can detect one cancer cell among one million healthy cells. If this work is successful, it could be possible to evaluate the metastasis potential of different primary human cancer cells.

    Lab biomedical scientist Mike Malfatti and two researchers - Paul Henderson, an associate professor, and Chong-Xian Pan, a medical oncologist — from the University of California, Davis Comprehensive Cancer Center, are using the AMS in a human trial with 50 patients to see how cancer patients respond or don’t respond to the chemotherapeutic drug carboplatin. This drug kills cancer cells by binding to DNA, and is toxic to rapidly dividing cells.

    The three researchers have the patients take a microdose of carboplatin — about 1/100th of a therapeutic dose — that has no toxicity or therapeutic value to evaluate how effectively the drug will bind to a person’s DNA during full dose treatment.

    Within a few days of patients receiving the microdose, the degree of drug binding is checked by blood sample, in which the DNA is isolated from white blood cells, or by tumor biopsy, in which the DNA is isolated from the tumor cells.

    The carboplatin dose is prepared with a carbon-14 tag. The DNA sample is analyzed using AMS and the instrument quantifies the carbon-14 level, with a high level of carbon-14 indicating a high level of drug binding to the DNA.

    “A high degree of binding indicates that you have a high probability of a favorable response to the drug,” Malfatti said. “Conversely, a low degree of binding means it is likely the person’s body won’t respond to the treatment.

    “If we can identify which people will respond to which chemotherapeutic drug, we can tailor the treatment to the individual.

    “There are many negative side effects associated with chemotherapy, such as nausea, loss of appetite, loss of hair and even death. We don’t want someone to receive chemotherapy that’s not going to help them, yet leave them with these negative side effects,” he added.

    Malfatti, Henderson and Pan also are using the AMS in pre-clinical studies to investigate the resistance or receptivity of other commonly used chemotherapeutic agents such as cisplatin, oxaliplatin and gemcitabine.

    Another team of researchers, led by Gaby Loots, a Lab biomedical scientist and an associate professor at the University of California, Merced, wants to use AMS to measure cancer cells labeled with carbon-14 to study the cancer cells’ migration to healthy tissues to determine how likely they are to form metastatic tumors.

    While today’s standard methods can detect tumors that are comprised of thousands of cells, the team would like to develop an assay with a thousand-fold better resolution – to detect one cancer cell among one million healthy ones.

    “The sensitivity of AMS allows us to develop more accurate, quantitative assays with single-cell resolution. Is the cancer completely gone, or do we see one cell worth of cancer DNA?” Loots noted.

    Some of the questions the team would like to answer are: 1) why certain cells metastasize? 2) how do cells metastasize? 3) what new methods can be developed to prevent metastasis?

    “Tumors shed cells all the time that enter our circulation. We would like to find ways to prevent the circulating tumor cells from forming metastatic tumors,” Loots continued.

    As a part of their research, the team members hope to determine whether cancer cells with stem-cell-like properties form more aggressive tumors.

    “We’re going to separate the cancer cells into stem-cell-like and non-stem-cell-like populations and seek to determine if they behave differently,” said Loots, who is working with fellow Lab biomedical scientists Nick Hum and Nicole Collette.

    See the full article here.

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