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  • richardmitnick 8:40 pm on August 25, 2016 Permalink | Reply
    Tags: Applied Research & Technology, , , Scientists have finally figured out how cancer spreads through the bloodstream   

    From Science Alert: “Scientists have finally figured out how cancer spreads through the bloodstream…” 

    ScienceAlert

    Science Alert

    24 AUG 2016
    DAVID NIELD

    1
    K. Hodivala-Dilke, M. Stone/Wellcome Images

    …And that means we might be able to stop it.

    In what could be a major step forward in our understanding of how cancer moves around the body, researchers have observed the spread of cancer cells from the initial tumour to the bloodstream.

    The findings suggest that secondary growths called metastases ‘punch’ their way through the walls of small blood vessels by targeting a molecule known as Death Receptor 6 (no, really, that’s what it’s called). This then sets off a self-destruct process in the blood vessels, allowing the cancer to spread.

    According to the team from Goethe University Frankfurt and the Max Planck Institute in Germany, disabling Death Receptor 6 (DR6) may effectively block the spread of cancerous cells – so long as there aren’t alternative ways for the cancer to access the bloodstream.

    “This mechanism could be a promising starting point for treatments to prevent the formation of metastases,” said lead researcher Stefan Offermanns.

    Catching these secondary growths is incredibly important, because most cancer deaths are caused not by the original tumour, but by the cancer spreading.

    To break through the walls of blood vessels, cancer cells target the body’s endothelial cells, which line the interior surface of blood and lymphatic vessels. They do this via a process known as necroptosis – or ‘programmed cell death’ – which is prompted by cellular damage.

    According to the researchers, this programmed death is triggered by the DR6 receptor molecule. Once the molecule is targeted, cancer cells can either travel through the gap in the vascular wall, or take advantage of weakening cells in the surrounding area.

    2
    MPI for Heart and Lung Research

    The team observed the same behaviour in both lab-grown cells and mice. In genetically modified mice where DR6 was disabled, less necroptosis and less metastasis was recorded.

    The scientists have reported their findings in Nature.

    The next step is to look for potential side effects caused by the disabling of DR6, and to figure out if the same benefits can be seen in humans. If so – and there’s no guarantee of that – this has the potential to be a seriously effective way of slowing down the spread of cancer.

    There are other hypotheses on how some metastases get around the body to cause secondary growths, though. Scientists at the University of California, Los Angeles (UCLA) are currently investigating the idea that tumour cells could also spread through the body outside blood vessels and the bloodstream.

    The researchers suggest that a mechanism known as angiotropism could be used by some melanoma cancers to cling to the outside of blood vessels, rather than penetrating them. If this is confirmed, they would escape the effects of disabled DR6 and chemotherapy alike.

    “If tumour cells can spread by continuous migration along the surfaces of blood vessels and other anatomical structures such as nerves, they now have an escape route outside the bloodstream,” explained researcher Laurent Bentolila from UCLA.

    The findings from that research, also conducted on mice, have been published in Nature Scientific Reports.

    As the two studies show, not all cancers behave in the same way, which makes figuring out how they operate doubly difficult. But the more we come to appreciate how complex and varied this disease can be, the better chance we have of fighting it.

    See the full article here .

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  • richardmitnick 5:25 pm on August 25, 2016 Permalink | Reply
    Tags: Applied Research & Technology, ,   

    From Salk: “Salk scientists map brain’s action center” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    August 25, 2016
    No writer credit found

    New work dispels long-held notions about area involved in Parkinson’s and addiction

    1
    Salk Institute researchers employed novel genetic tools to map the connectivity of neurons within a part of the brain, called the striatum, that controls movement toward a goal or reward. The matrix neurons, highlighted in green, appear to avoid the patch neurons (in red), which are smaller clusters of neurons in the striatum. Credit: Salk Institute

    When you reach for that pan of brownies, a ball-shaped brain structure called the striatum is critical for controlling your movement toward the reward. A healthy striatum also helps you stop yourself when you’ve had enough.

    But when the striatum doesn’t function properly, it can lead to disorders such as Parkinson’s disease, obsessive-compulsive disorder or addiction.

    In fact, the exact functions of the striatum are by no means resolved, and it’s also a mystery how the structure can coordinate many diverse functions. Now, a new study published August 25, 2016 by Salk Institute researchers and their colleagues in the journal Neuron, delves into the anatomy and function of the striatum by employing cutting-edge strategies to comprehensively map one of the brain’s lesser-known forms of organization.

    “The most exciting result from this research is that we now have a new avenue to study long-standing questions about how the striatum controls movement in both healthy and diseased brains,” says the study’s senior investigator Xin Jin, an assistant professor in the Molecular Neurobiology Laboratory at Salk.

    Forty years ago, researchers discovered a unique way that the striatum is organized. It is dotted with patch neurons, which under the microscope look like tiny islands of cells. The ocean surrounding them is made up of neurons scientists collectively refer to as “matrix” cells.

    Over the course of four decades, scientists hypothesized about the role of patch and matrix neurons in neurodegenerative diseases. One idea was that patch cells were fed by the brain’s higher thought centers, suggesting they could play a role in cognition, whereas the matrix cells seemed to play a role in sensing and movement.

    2
    Using genetic engineering, cutting-edge neuronal tracing and electrophysiology, researchers decipher a lesser known form of organization in a deep, ball-shaped brain area that helps control movement toward a goal. In this artistic interpretation, patch neurons (red) sit as separate, small islands amid matrix neurons (green), but each cell type is well connected with the rest of the brain. Credit: Salk Institute

    In contrast, the new study dispels that idea, showing that both types of information are sent to the patch and matrix neurons, though patch cells tend to receive slightly more information from the brain’s emotion centers (these are included in the higher thought centers). But those results could help explain why, in the brains of patients with neurological disorders like Huntington’s disease (a progressive neurodegenerative disease affecting movement and other functions), patch cells and matrix cells are both affected, Jin says.

    “This is an elegant example demonstrating that we are in a new era of studying brain circuits in ever more refined detail,” said Daofen Chen, Ph.D., program director at the NIH’s National Institute of Neurological Disorders and Stroke. “As a result of emerging technologies and novel tools, we are gaining new insights into mechanisms of brain disorders.”

    Jin, together with the paper’s first authors Jared Smith, Jason Klug and Danica Ross, drew upon several technologies to uncover these new findings. The first was genetic engineering to selectively and precisely target the patch versus matrix neurons; traditionally, researchers used staining methods that were not as exact. Secondly, new neural tracing methods, including one generated by collaborator Edward Callaway and his group at Salk, allowed Jin’s team to chart the entire brain’s input to the patch and matrix cells and the output of each of the cell types as well. A third major approach, from the field of electrophysiology, enabled the scientists to confirm the connections they had mapped and to understand their strength.

    “Much of the previous work on patch and matrix cells inferred their functions based on connectivity with the rest of the brain, but most of those hypotheses were incorrect,” Smith says. “With a more precise map of the input and output of patch and matrix cells, we can now make more informed hypotheses.”

    Patch and matrix neurons are not the only way that neuroscientists understand the striatum. The striatum also contains cells that take two opposing routes—the direct and indirect pathways—that are thought to provide the gas and brakes on movement, so to speak. Those indirect and direct pathways are also crucial for certain behaviors, such as the formation of new habits.

    Interestingly, both patch and matrix groups contain both indirect and direct pathway cells. That makes the story of the striatum more complicated, Jin says, but in future studies his team can study the intersection of these two types of organization in the context of how the striatum controls actions in health and disease.

    Other authors on the study are Jason Klug, Danica Ross, Christopher Howard, Nick Hollon, Vivian Ko, Hilary Hoffman and Edward Callaway of the Salk Institute; and Charles Gerfen of the National Institute of Mental Health in Bethesda, Maryland.

    The research was supported by grants from the National Institutes of Health, the Dana Foundation, the Ellison Medical Foundation, and the Whitehall Foundation.

    See the full article here .

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    Salk Institute Campus

    Every cure has a starting point. Like Dr. Jonas Salk when he conquered polio, Salk scientists are dedicated to innovative biological research. Exploring the molecular basis of diseases makes curing them more likely. In an outstanding and unique environment we gather the foremost scientific minds in the world and give them the freedom to work collaboratively and think creatively. For over 50 years this wide-ranging scientific inquiry has yielded life-changing discoveries impacting human health. We are home to Nobel Laureates and members of the National Academy of Sciences who train and mentor the next generation of international scientists. We lead biological research. We prize discovery. Salk is where cures begin.

     
  • richardmitnick 3:29 pm on August 25, 2016 Permalink | Reply
    Tags: Applied Research & Technology, ,   

    From NOVA: “The ‘Quantum Theory’ of Cancer Treatment” 

    PBS NOVA

    NOVA

    20 Jul 2016 [This just appeared in social media.]
    Amanda B. Keener

    In April 2011, Christopher Barker, a radiation oncologist at Memorial Sloan Kettering Cancer Center in New York, received some unusual news about a participant in a clinical trial. The patient was battling a second recurrence of melanoma that had spread to several areas of her body. After more than a year on the experimental drug, her tumors had only gotten bigger, and after one near her spine started causing back pain, her doctors arranged for local radiation therapy to shrink the tumor and give her some relief.

    But the tumor near her spine was not the only one that shrank. “From one set of images to another, the radiologist noticed that there was a dramatic change in the extent of the melanoma,” Barker says. Although only one tumor was exposed to radiation, two others had started shrinking, too.

    The striking regression was a very rare effect of radiation therapy, Barker and his colleagues concluded, called an abscopal response. “It’s not common,” says Barker. “But we see it, and it’s pretty remarkable when it happens.”

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    A woman prepares to receive radiation treatment for cancer. Photo credit: Mark Kostich/iStockphoto.

    Although the abscopal response was first recognized back in 1953, and a smattering of case reports similar to Barker’s appeared in the literature throughout the 1960s, ’70s, and ’80s, the mystery behind the abscopal response largely went unsolved until a medical student named Silvia Formenti dusted it off.

    While studying radiation therapy in Milan during the 1980s, Formenti couldn’t shake the idea that local radiotherapy must have some effect on the rest of the body. “When you burn yourself, the burn is very localized, yet you can get really systemic effects,” says Formenti, now chair of the department of radiation oncology at Weill Cornell Medical College in New York. “It seemed that applying radiotherapy to one part of the body should be sensed by the rest of the body as well.”

    The primary goal of therapy with ionizing radiation—the type used to shrink tumors—is to damage the DNA of fast-growing cancer cells so they self-destruct. But like burns, radiation also causes inflammation, a sign of the immune system preparing for action. For a long time, it was unclear what effect inflammation might have on the success of radiation therapy, though there were some hints buried in the scientific literature. For example, a 1979 study showed that mice lacking immune cells called T cells had poorer responses to radiation therapy than normal mice. But exactly what those T cells had to do with radiation therapy was anyone’s guess.

    Better Together

    In 2001, shortly after arriving in New York, Formenti attended a talk by Sandra Demaria, a pathologist also at Weill Cornell. Demaria was studying slivers of breast tumors removed from patients who had received chemotherapy and had found that in some patients, chemotherapy caused immune cells to flood the tumors. This made Formenti wonder if the same thing could happen after radiation therapy.

    In addition to fighting off illness-causing pathogens, part of the immune system’s job is to keep tabs on cells that could become cancerous. For example, cytotoxic T cells kill off any cells that display signs of cancer-related mutations. Cancer cells become troublesome when they find ways to hide these signs or release proteins that dull T cells’ senses. “Cancer is really a failure of the immune system to reject [cancer-forming] cells,” Formenti says.

    Formenti and Demaria, a fellow Italian native, quickly joined forces to determine whether the immune system was driving the abscopal response. To test their idea, their team injected breast cancer cells into mice at two separate locations, causing individual tumors to grow on either side of the animals’ bodies. Then they irradiated just one of the tumors on each mouse. Radiation alone prevented the primary tumor from growing, but didn’t do much else. Yet when the researchers also injected a protein called GM-CSF into the mice, the size of the second tumor was also controlled.

    GM-CSF expands the numbers of dendritic cells, which act as T cells’ commanding officers, providing instructions about where to attack. But the attack couldn’t happen unless one of the tumors was irradiated. “Somehow radiation inflames the tumor and makes it interesting to the immune system,” Formenti says.

    Formenti and Demaria knew that if their findings held up in human studies, then it could be possible to harness the abscopal effect to treat cancer that has metastasized throughout the body.

    Although radiation therapy is great at shrinking primary tumors, once a cancer has spread, the treatment is typically reserved for tumors that are causing patients pain. “Radiation is considered local therapy,” says Michael Lim, a neurosurgeon at Johns Hopkins University in Baltimore who is studying ways to combine radiotherapy with immunotherapy to treat brain tumors. But, he adds, “if you could use radiation to kindle a systemic response, it becomes a whole different paradigm.”

    When Demaria and Formenti first published their results in 2004, the concept of using radiation to activate immunity was a hard sell. At the time, research into how radiation affected the immune system focused on using high doses of whole-body irradiation to knock out the immune systems of animal models. It was counterintuitive to think the same treatment used locally could activate immunity throughout the body.

    That perspective, however, would soon change. In 2003 and 2004, James Hodge, an immunologist at the National Cancer Institute and his colleagues published two mouse studies showing that after radiation, tumor cells displayed higher levels of proteins that attract and activate cancer-killing T cells. It was clear radiation doesn’t just kill cancer cells, it can also make those that don’t die more attractive to immune attack, Hodge says.

    This idea received another boost in 2007 when a research team from Gustave Roussy Institute of Oncology near Paris reported that damage from radiation caused mouse and human cancer cells to release a protein that activates dendritic cells called HMGB1. They additionally found that women with breast cancer who also carried a mutation preventing their dendritic cells from sensing HMGB1 were more likely to have metastases in the two years following radiotherapy. In addition to making tumors more attractive to the immune system, Hodge says, the damage caused by radiation also releases bits of cancer cells called antigens, which then prime immune cells against the cancer, much like a vaccine.

    In some ways, Barker says, oncologists have always sensed that radiation works hand-in-hand with the immune system. For example, when his patients ask him where their tumors go after they’ve been irradiated, he tells them that immune cells mop up the dead cell debris. “The immune system acts like the garbage man,” he says.

    Now, immunologists had evidence that the garbage men do more than clean up debris: they are also part of the demolition team, and if they could coordinate at different worksites, they could generate abscopal responses. With radiation alone, this only happened very rarely. “Radiation does some of this trick,” Formenti says. “But you really need to help radiation a bit.”

    Formenti and Demaria had already shown in mice that such assistance could come in the form of immunotherapy with GM-CSF, and in 2003 they set out to test their theory in patients. They treated 26 metastatic cancer patients who were undergoing radiation treatment with GM-CSF. The researchers then used CT scans to track the sizes of non-irradiated tumors over time. Last June, they reported that the treatment generated abscopal responses in 20% of the patients. Patients with abscopal responses tended to survive longer, though none of the patients were completely cured.

    As the Weill Cornell team was conducting their GM-CSF study, a new generation of immunotherapeutic drugs arrived on the scene. Some, like imiquimod, activate dendritic cells in a more targeted way than GM-CSF does. Another group, the checkpoint inhibitors, release the brakes on the immune system and T cells in particular, freeing the T cells to attack tumors.

    In 2005, Formenti and her team found that a particular checkpoint inhibitor worked better with radiotherapy than alone and later reported that the same combination produces abscopal responses in a mouse model of breast cancer.

    Off-target, Spot-on

    In 2012, Formenti had an unexpected chance to test this treatment in the clinic when one of her patients who had read about her research requested that she try the combination on him. The patient had run out of options, so Formenti’s team obtained an exception to use the immunotherapy ipilimumab, which she had used in her 2005 study and had only been approved for melanoma, and proceeded to irradiate tumors in the patient’s liver. After five months, all but one of his tumors had disappeared. “We were ecstatic,” Formenti says. “He’s still alive and well.”

    The availability of checkpoint inhibitors seems to have opened the floodgates. Since the US Food and Drug Administration approved ipilimumab in 2011, there have been at least seven reports of suspected or confirmed abscopal responses in patients on checkpoint inhibitors, including the one Barker witnessed. Contrast that with the previous three decades, where less than one per year was reported, according to one review. Almost all of the recent cases involving checkpoint inhibitors have been in patients with melanoma, since that’s where the drugs have mainly been tested. But, abscopal responses with or without immunotherapy have been reported in patients with cancers of the liver, kidney, blood, and lung.

    There are now dozens of clinical trials combining radiation with a range of immunotherapies, including cancer vaccines and oncolytic viruses. “There’s quite a nice critical mass of people working on this,” Formenti says. She and Demaria are now finishing up a clinical trial in lung cancer patients using a protocol similar to the one that worked so well in their original patient.

    “I think we know that people who respond to checkpoint inhibitors already have more immune-activating tumors,” Demaria says. The question now, she says, is whether radiation can expand the 20% of people who respond to the combination therapy.

    One solution might be to match combinations to particular patients or tumor types. Demaria’s team is collecting blood and tissue samples from patients in a Weill Cornell lung cancer trial to look for differences in the immune responses of those who do and don’t generate abscopal responses. Such changes in the number or status of a cell type associated with particular outcomes are known as biomarkers.

    So far, there is little data about how the two types of responses differ. Barker and his team did publish measurements of a broad range of immune markers from their patient who experienced an abscopal response. “We didn’t really have a lot of clues in terms of what we should look at,” he says. They observed a bump in activated T cells and antibodies specific to tumor proteins following radiation, followed by steady declines of both as the tumors regressed. But, he says, there was no “smoking gun” that could explain why this particular patient responded the way she did.

    Understanding how the immune system responds to immunotherapy and radiation will be key to optimizing the combination of the two. “One needs to do these combinations to try and improve the outcome on both sides of the equation,” says William McBride, a radiation oncologist at the University of California, Los Angeles. There’s still controversy, for example, over whether the immune system responds better to high doses of radiation over short periods or low doses over longer periods. “We think we know the best sequence of therapy based on the pre-clinical studies, but that hasn’t been confirmed in clinical studies yet,” Barker says. “If we had a biomarker that would tell us in what way you should give the radiation, that would be enormously valuable.”

    Demaria says her research suggests that more tumor damage is not always better and that high radiation doses may be counterproductive, activating feedback responses that suppress immunity. She’s currently comparing immune signatures of different radiation regimens in mice. So far she says regimens that make the cancer look and act like virally-infected cells tend to elicit the best immune responses, but there is a long way to go in translating that work into humans.

    “Things are moving faster than they have for a long time, but at this point there are still a lot of unanswered questions,” she says.

    Fortunately, she and Formenti have plenty of motivation to work on those questions. Demaria says she still remembers examining a bit of tumor that was left behind after that first lung cancer patient received treatment. It was full of T cells which had presumably destroyed the cancer. “It’s the picture you never forget,” she says. “It is probably the biggest satisfaction to see somebody’s fate turned around by what you can do.”

    See the full article here .

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    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.

     
  • richardmitnick 3:08 pm on August 25, 2016 Permalink | Reply
    Tags: Applied Research & Technology, ,   

    From EPFL: “An effective and low-cost solution for storing solar energy” 

    EPFL bloc

    École Polytechnique Fédérale de Lausanne EPFL

    25.08.16
    Laure-Anne Pessina

    1
    An effective and low-cost solution for storing solar energy © Infini Lab / 2016 EPFL

    Solar energy can be stored by converting it into hydrogen. But current methods are too expensive and don’t last long. Using commercially available solar cells and none of the usual rare metals, researchers at EPFL and CSEM have now designed a device that outperforms in stability, efficiency and cost.

    How can we store solar energy for period when the sun doesn’t shine? One solution is to convert it into hydrogen through water electrolysis. The idea is to use the electrical current produced by a solar panel to ‘split’ water molecules into hydrogen and oxygen. Clean hydrogen can then be stored away for future use to produce electricity on demand, or even as a fuel.

    But this is where things get complicated. Even though different hydrogen-production technologies have given us promising results in the lab, they are still too unstable or expensive and need to be further developed to use on a commercial and large scale.

    The approach taken by EPFL and CSEM researchers is to combine components that have already proven effective in industry in order to develop a robust and effective system. Their prototype is made up of three interconnected, new-generation, crystalline silicon solar cells attached to an electrolysis system that does not rely on rare metals. The device is able to convert solar energy into hydrogen at a rate of 14.2%, and has already been run for more than 100 hours straight under test conditions. The method, which surpasses previous efforts in terms of stability, performance, lifespan and cost efficiency, is published in the Journal of The Electrochemical Society.

    Enough to power a fuel cell car over 10,000km every year

    “A 12-14 m2 system installed in Switzerland would allow the generation and storage of enough hydrogen to power a fuel cell car over 10,000 km every year”, says Christophe Ballif, who co-authored the paper. In terms of performance, this is a world record for silicon solar cells and for hydrogen production without using rare metals. It also offers a high level of stability.

    High voltage cells have an edge

    The key here is making the most of existing components, and using a ‘hybrid’ type of crystalline-silicon solar cell based on heterojunction technology. The researchers’ sandwich structure – using layers of crystalline silicon and amorphous silicon – allows for higher voltages. And this means that just three of these cells, interconnected, can already generate an almost ideal voltage for electrolysis to occur. The electrochemical part of the process requires a catalyst made from nickel, which is widely available.

    “With conventional crystalline silicon cells, we would have to link up four cells to get the same voltage,” says co-author Miguel Modestino at EPFL.“So that’s the strength of this method.”

    A stable and economically viable method

    The new system is unique when it comes to cost, performance and lifespan. “We wanted to develop a high performance system that can work under current conditions,” says Jan-Willem Schüttauf, a researcher at CSEM and co-author of the paper. “The heterojunction cells that we use belong to the family of crystalline silicon cells, which alone account for about 90% of the solar panel market. It is a well-known and robust technology whose lifespan exceeds 25 years. And it also happens to cover the south side of the CSEM building in Neuchâtel.”

    The researchers used standard heterojunction cells to prove the concept; by using the best cells of that type, they would expect to achieve a performance above 16%.

    The research is part of the nano-tera SHINE project.

    See the full article here .

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    EPFL campus

    EPFL is Europe’s most cosmopolitan technical university with students, professors and staff from over 120 nations. A dynamic environment, open to Switzerland and the world, EPFL is centered on its three missions: teaching, research and technology transfer. EPFL works together with an extensive network of partners including other universities and institutes of technology, developing and emerging countries, secondary schools and colleges, industry and economy, political circles and the general public, to bring about real impact for society.

     
  • richardmitnick 2:08 pm on August 25, 2016 Permalink | Reply
    Tags: Applied Research & Technology, , ,   

    From PPPL: “How to keep the superhot plasma inside tokamaks from chirping” 


    PPPL

    August 19, 2016
    Raphael Rosen

    1
    Graduate student Vinícius Duarte. (Photo by Elle Starkman)

    Chirp, chirp, chirp.” The familiar sound of birds is also what researchers call a wave in plasma that breaks from a single note into rapidly changing notes. This behavior can cause heat in the form of high energy particles — or fast ions — to leak from the core of plasma inside tokamaks — doughnut-shaped facilities that house fusion reactions.

    PPPL NSTXII
    NSTX tokamak at PPPL

    Physicists want to prevent these waves from chirping because they may cause too many fast ions to escape, cooling the plasma. As the plasma cools, the atomic nuclei in the tokamak are less likely to come together and release energy and the fusion reactions will sputter to a halt.

    “Chirping modes can be very harmful because they can steal energy from the fast ions in an extended region of the plasma,” said Vinícius Duarte, a graduate student from the University of São Paulo. Duarte is at the U.S. Department of Energy’s (DOE) Princeton Plasma Physics Laboratory (PPPL) conducting research for his dissertation. Support for this work comes from the DOE Office of Science.

    Chirping modes often have frequencies far above what the human ear can hear. The name — “chirping” — stems from the change in the waves’ frequency over time. Typically, the modes start with a high frequency and drop down in frequency very rapidly. The chirping of modes has been studied for decades as physicists seek to understand and eliminate them.

    In a recent theoretical study, Duarte discovered some conditions within plasma that can make the chirping of modes more likely. A paper he is preparing on this topic explains the phenomenon and may help to optimize the design of fusion energy plants in the future. Collaborating on the research were physicists at PPPL, General Atomics, the University of California-Irvine, and the University of Texas at Austin. Physicist Nikolai Gorelenkov, Duarte’s PPPL advisor, introduced him to the software code that enabled this work, Prof. Herbert Berk of the University of Texas co-advised on the project and researchers from the DIII-D National Fusion Facility that General Atomics operates for the DOE provided the data for comparison with the theory.

    The researchers began by noting that the chirping of modes seems to occur in some tokamaks more often than in others. They are rare in the DIII-D tokamak, for example, but were common in the National Spherical Torus Experiment (NSTX), PPPL’s former flagship fusion device, which has recently been upgraded.

    By running simulations on PPPL computers, Duarte and the team found that plasma turbulence — or random fluctuation — was a factor that helped explain the chirping of modes. Chirping can occur when there is a strong concentration of fast ions bunched together, while other particles are widely spaced.

    The surprise is that substantial turbulence can break up concentrations of fast ions, and therefore help to extinguish the chirping of modes.

    The simulations matched the data from experiments. In NSTX, the turbulence has little effect on fast ions and chirping modes are common, whereas DIII-D has relatively high interaction between turbulence and fast ions and chirping modes are rare. In DIII-D, chirping starts only when the interaction between the turbulence and fast-ions markedly decreases.

    These findings could lead to fusion facilities that leak less heat than current machines and could improve the efficiency of ITER, the international tokamak under construction in France to demonstrate the feasibility of fusion power.

    ITER Tokamak
    ITER Tokamak, France

    “In ITER, where fast ions from fusion reactions are expected to sustain a burning plasma, the good confinement of these particles is a crucial issue,” said Duarte.

    See the full article here .

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    Princeton Plasma Physics Laboratory is a U.S. Department of Energy national laboratory managed by Princeton University. PPPL, on Princeton University’s Forrestal Campus in Plainsboro, N.J., is devoted to creating new knowledge about the physics of plasmas — ultra-hot, charged gases — and to developing practical solutions for the creation of fusion energy. Results of PPPL research have ranged from a portable nuclear materials detector for anti-terrorist use to universally employed computer codes for analyzing and predicting the outcome of fusion experiments. The Laboratory is managed by the University for the U.S. Department of Energy’s Office of Science, which is the largest single supporter of basic research in the physical sciences in the United States, and is working to address some of the most pressing challenges of our time. For more information, please visit science.energy.gov.

     
  • richardmitnick 1:38 pm on August 25, 2016 Permalink | Reply
    Tags: Applied Research & Technology, , Neuregulin-1,   

    From Salk: “Elevating brain protein allays symptoms of Alzheimer’s and improves memory” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    August 25, 2016
    No writer credit found

    Salk Institute tests drug that could boost levels of critical protective protein in brain

    1
    In a mouse model of Alzheimer’s disease, Salk Institute researchers show that raising levels of neuregulin-1 (right) lowers a marker of disease pathology in a part of the brain that controls memory compared with controls (left). Credit: Salk Institute

    LA JOLLA—Boosting levels of a specific protein in the brain alleviates hallmark features of Alzheimer’s disease in a mouse model of the disorder, according to new research published online August 25, 2016 in Scientific Reports.

    The protein, called neuregulin-1, has many forms and functions across the brain and is already a potential target for brain disorders such as Parkinson’s disease, amyotrophic lateral sclerosis and schizophrenia.

    “Neuregulin-1 has broad therapeutic potential, but mechanistically, we are still learning about how it works,” says the study’s senior investigator Kuo-Fen Lee, a professor in the Salk Institute’s Clayton Foundation Laboratories for Peptide Biology and holder of the Helen McLoraine Chair in Molecular Neurobiology. “We’ve shown that it promotes metabolism of the brain plaques that are characteristic of Alzheimer’s disease.”

    Previously, researchers have shown that treating cells with neuregulin-1, for example, dampens levels of amyloid precursor protein, a molecule that generates amyloid beta, which aggregate and form plaques in the brains of Alzheimer’s patients. Other studies suggest that neuregulin-1 could protect neurons from damage caused by blockage of blood flow.

    In the new study, Lee’s team tested this idea in a mouse model of Alzheimer’s disease by raising the levels of one of two forms of neuregulin-1 in the hippocampus, an area of the brain responsible for learning and memory. Both forms of the protein seemed to improve performance on a test of spatial memory in the models.

    What’s more, the levels of cellular markers of disease—including the levels of amyloid beta and plaques—were noticeably lower in mice with more neuregulin-1 compared to controls.

    The group’s experiments suggest that neuregulin-1 breaks up plaques by raising levels of an enzyme called neprilysin, shown to degrade amyloid-beta. But that is probably not the only route through which neuregulin-1 confers its benefits, and the group is exploring other possible mechanisms—such as whether the protein improves signaling between neurons, which is impaired in Alzheimer’s—says the study’s first author Jiqing Xu, a research associate in Lee’s group

    A neuregulin-1 treatment is not available on the market, though it is being explored in clinical trials as a potential treatment for chronic heart failure and Parkinson’s disease. One advantage of neuregulin-1 as a potential drug is that it can cross the blood brain barrier, which means that it could be administered relatively noninvasively even though the efficiency is not clear. On the other hand, other research suggests too much of the protein impairs brain function. Working with chemists at Salk, Lee’s team has come up with a small molecule that can raise levels of existing neuregulin-1 (rather than administering it directly) and are testing it in cells. This alternative therapy could be a better way to prevent plaques from forming because small molecules more readily cross the blood brain barrier.

    The group is also interested in neuregulin-1 for its ties to schizophrenia. An alteration in the neuregulin-1 gene—a single change in one letter of the DNA code for the protein—has been found in families with schizophrenia and linked to late-onset Alzheimer’s disease with psychosis. The protein may be a way to understand the overlap between Alzheimer’s and other brain disorders, Lee says.

    An important caveat is that the new research was conducted in a single type of mouse model of Alzheimer’s. Lee’s group is testing neuregulin-1’s affects across other models. “There’s much more work ahead before neuregulin-1 could become a treatment, but we are excited about its potential, possibly in combination with other therapeutics for Alzheimer’s disease,” Lee says.

    Other authors on the study are Fred DeWinter, Catherine Farrokhi, Jonathan Cook and Xin Jin of Salk’s Clayton Foundation for Peptide Biology Laboratories; and Edward Rockenstein, Michael Mante, Anthony Adame and Eliezer Masliah of the University of California, San Diego.

    The research was supported by the National Institutes of Health, the Clayton Foundation, The Albert G. and Olive H. Schlink Foundation, the Gemcon Family Foundation and the Brown Foundation.

    See the full article here .

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    Salk Institute Campus

    Every cure has a starting point. Like Dr. Jonas Salk when he conquered polio, Salk scientists are dedicated to innovative biological research. Exploring the molecular basis of diseases makes curing them more likely. In an outstanding and unique environment we gather the foremost scientific minds in the world and give them the freedom to work collaboratively and think creatively. For over 50 years this wide-ranging scientific inquiry has yielded life-changing discoveries impacting human health. We are home to Nobel Laureates and members of the National Academy of Sciences who train and mentor the next generation of international scientists. We lead biological research. We prize discovery. Salk is where cures begin.

     
  • richardmitnick 9:38 am on August 25, 2016 Permalink | Reply
    Tags: Applied Research & Technology, , Fight Aids at Home - Phase 2,   

    From FightAIDS@Home – Phase 2 at WCG: “AIDS is constantly evolving. So are the tools to fight it.” 

    New WCG Logo

    WCGLarge

    World Community Grid (WCG)

    Since 2005, the volunteers behind FightAIDS@Home have helped scientists advance HIV research. The next phase of that effort is just beginning, and you can play a key role in helping the millions of people afflicted by this deadly virus.

    FightAIDS@Home – Phase 2

    Even with the advances in treating people infected with HIV, there are still about two million new infections and one million HIV-related deaths each year. HIV continues to be a challenge because it quickly mutates in ways that make existing drug treatments ineffective. FightAIDS@Home joined World Community Grid 10 years ago with the simple – but challenging – goal of finding new treatments for HIV. Since then, the project has made some incredible advances in understanding the virus, developing better drug search tools, and identifying chemical compounds that might be able to bind to the virus and disrupt its lifecycle.

    The computing power donated by World Community Grid volunteers has allowed the FightAIDS@Home research team to significantly expand their research beyond what they originally planned. Phase 1 of this project is considered to be the biggest docking experiment ever conducted with more than 20 billion drug-target comparisons performed. The research team was able to computationally evaluate millions of chemical compounds against many different regions of the entire viral machinery, rather than restricting the search to only certain compounds or certain binding sites.

    Although the researchers expect to run additional Phase 1 screenings in the future, they will now focus on identifying the most valuable results from Phase 1. While the team has already identified thousands of potentially promising candidates to be confirmed experimentally in the lab, it would be cost and time prohibitive to lab test all of the potential candidates. The virtual docking techniques used in Phase 1 are only an approximation of the potential effectiveness of these promising compounds. They can be evaluated in the lab, but this is expensive and slow, because each chemical must be either synthesized or purchased, and then thoroughly tested. Therefore, results from Phase 1 will be filtered to prioritize computationally-selected candidate compounds, evaluating them using more accurate methods in Phase 2.

    This is necessary for two related reasons. First, Phase 1 generated a significant number of “false positives,” compounds that looked promising in Phase 1 screening but would not actually be effective as HIV drugs. Second, the large number of results is likely to contain other candidates, “false negatives,” which scored lower but merit further investigation.

    Phase 2 of FightAIDS@Home uses a different simulation method to double-check and further refine the virtual screening results that were generated in Phase 1. The technique is called BEDAM (Binding Energy Distribution Analysis Method), which has proven effective in computational contests, but has been limited to evaluating just a few dozen molecules. It has not yet been used on such a large scale because of the much larger amount of processing time required. With World Community Grid, it will be possible to more thoroughly evaluate the top candidates from the vast number of results generated in Phase 1.

    So Phase 2 has two main goals: increase the success rate by reducing false positives and false negatives from the Phase 1 docking data, and prove the BEDAM analysis techniques on a large scale. This should save enormous amounts of time and money in the lab testing stage of drug development.

    This new phase is another chapter in a long and well-established collaboration between World Community Grid and The Scripps Research Institute, a world-renowned research organization. Our teams have already collaborated on other research efforts including the search for treatments against Ebola and malaria. The relationship has been beneficial for all involved. For the researchers, the enormous amount of computing power available through World Community Grid has enabled them to run larger experiments and explore greater numbers of chemicals than they ever thought possible. Furthermore, the virtual screening tools they have developed and refined (AutoDock and AutoDock Vina) are the world’s most widely used and cited molecular docking programs and have benefited other World Community Grid research projects searching for drug candidates for other diseases. Once BEDAM is validated on a large scale, it could prove equally useful to these other research efforts as well.

    Please continue to support the FightAIDS@Home project as it establishes a new front in the fight against the world’s deadliest virus.

    Learn more

    Follow this project:
    Project forum
    Project website

    See the full article here.

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    Stem Education Coalition

    World Community Grid (WCG) brings people together from across the globe to create the largest non-profit computing grid benefiting humanity. It does this by pooling surplus computer processing power. We believe that innovation combined with visionary scientific research and large-scale volunteerism can help make the planet smarter. Our success depends on like-minded individuals – like you.”

    WCG projects run on BOINC software from UC Berkeley.
    BOINCLarge

    BOINC is a leader in the field(s) of Distributed Computing, Grid Computing and Citizen Cyberscience.BOINC is more properly the Berkeley Open Infrastructure for Network Computing.

    BOINC WallPaper

    CAN ONE PERSON MAKE A DIFFERENCE? YOU BET!!

    MyBOINC

    “Download and install secure, free software that captures your computer’s spare power when it is on, but idle. You will then be a World Community Grid volunteer. It’s that simple!” You can download the software at either WCG or BOINC.

    Please visit the project pages-

    FightAIDS@home Phase II

    FAAH Phase II
    OpenZika

    Rutgers Open Zika

    Help Stop TB
    WCG Help Stop TB
    Outsmart Ebola together

    Outsmart Ebola Together

    Mapping Cancer Markers
    mappingcancermarkers2

    Uncovering Genome Mysteries
    Uncovering Genome Mysteries

    Say No to Schistosoma

    GO Fight Against Malaria

    Drug Search for Leishmaniasis

    Computing for Clean Water

    The Clean Energy Project

    Discovering Dengue Drugs – Together

    Help Cure Muscular Dystrophy

    Help Fight Childhood Cancer

    Help Conquer Cancer

    Human Proteome Folding

    FightAIDS@Home

    World Community Grid is a social initiative of IBM Corporation
    IBM Corporation
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    IBM – Smarter Planet
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  • richardmitnick 8:46 am on August 25, 2016 Permalink | Reply
    Tags: ALS-Lou Gehrig’s disease, Applied Research & Technology, , , Necrostatin-1 restored the myelin sheath and stopped axonal damage, RIPK1 as a key regulator of inflammation and cell death   

    From Harvard: “Harvard researchers pinpoint enzyme that triggers cell demise in ALS” 

    Harvard University

    Harvard University

    August 24, 2016
    Ekaterina Pesheva

    1
    Therapies already in development aim to block the activity of a particular enzyme in order to halt the stripping of axons and prevent neuronal dysfunction in people with amyotrophic lateral sclerosis, or ALS. Credit: iStock

    Scientists from Harvard Medical School (HMS) have identified a key instigator of nerve cell damage in people with amyotrophic lateral sclerosis, or ALS, a progressive and incurable neurodegenerative disorder.

    Researchers say the findings of their study, published Aug. 5 in the journal Science, may lead to new therapies to halt the progression of the uniformly fatal disease that affects more than 30,000 Americans. One such treatment is already under development for testing in humans after the current study showed it stopped nerve cell damage in mice with ALS.

    The onset of ALS, also known as Lou Gehrig’s disease, is marked by the gradual degradation and eventual death of neuronal axons, the slender projections on nerve cells that transmit signals from one cell to the next. The HMS study reveals that the aberrant behavior of an enzyme called RIPK1 damages neuronal axons by disrupting the production of myelin, the soft, gel-like substance that envelopes axons to insulate them from injury.

    “Our study not only elucidates the mechanism of axonal injury and death but also identifies a possible protective strategy to counter it by inhibiting the activity of RIPK1,” said the study’s senior investigator, Junying Yuan, the Elizabeth D. Hay Professor of Cell Biology at HMS.

    The new findings come on the heels of a series of pivotal discoveries Yuan and colleagues made over the last decade, which revealed RIPK1 as a key regulator of inflammation and cell death. But until now, scientists were unaware of its role in axonal demise and ALS. Experiments conducted in mice and in human ALS cells reveal that when RIPK1 is out of control, it can spark axonal damage by setting off a chemical chain reaction that culminates in stripping the protective myelin off axons and triggering axonal degeneration — the hallmark of ALS. RIPK1, the researchers found, inflicts damage by directly attacking the body’s myelin production plants — nerve cells known as oligodendrocytes, which secrete the soft substance, rich in fat and protein, that wraps around axons to support their function and shield them from damage. Building on previous work from Yuan’s lab showing that RIPK1’s activity could be blocked by a chemical called necrostatin-1, the research team tested how ALS cells in lab dishes would respond to the same treatment. Indeed, necrostatin-1 tamed the activity of RIPK1 in cells of mice genetically altered to develop ALS.

    In a final set of experiments, the researchers used necrostatin-1 to treat mice with axonal damage and hind leg weakness, a telltale sign of axonal demise similar to the muscle weakness that occurs in the early stages of ALS in humans. Necrostatin-1 not only restored the myelin sheath and stopped axonal damage, but also prevented limb weakness in animals treated with it.

    See the full article here .

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    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 8:36 am on August 25, 2016 Permalink | Reply
    Tags: Amlodipine, Applied Research & Technology, Heart arrhythmias, , Two classes of calcium channel blockers, Verapamil   

    From U Washington: “Calcium channel blockers caught in the act at atomic level” 

    U Washington

    University of Washington

    08.24.2016
    Leila Gray

    1
    Catterall and Zheng labs

    An atomic level analysis has revealed how two classes of calcium channel blockers, widely prescribed for heart disease patients, produce separate therapeutic effects through their actions at different sites on the calcium channel molecule.

    Millions of Americans, and an even larger number of patients worldwide, take calcium channel blockers to control cardiovascular problems.

    In a study published Aug. 24 in the advanced online edition of Nature, researchers describe how the fundamental mode of action of two distinct chemical classes of these drugs differs. The knowledge was gleaned by analyzing the atomic structure of their binding sites. Read the Nature paper here.

    UW Medicine researchers Dr. William A. Catterall, University of Washington professor and chair of pharmacology, and Ning Zheng, UW professor of pharmacology and investigator of the Howard Hughes Medical Institute, headed the project. The first author on the Nature report was Lin Tang, UW postdoctoral research scientist in pharmacology.

    Calcium channel blockers were first identified and approved as medications in the previous half-century, and have emerged as major therapies for cardiovascular disorders. These latest findings could inform the design of better, safer versions of calcium channel blockers for managing heart beat irregularities, chest pain, and high blood pressure.

    The researchers compared calcium channel blockers that treat heart arrhythmias, such as verapamil, with those taken for hypertension or angina, such as amlodipine. A third class of calcium channel blockers, including diltiazem, both slow the heart rate and dilate the blood vessels. Those drugs were not part of this study.

    The team wanted to learn how calcium channel blocker molecules interact with calcium channels, the molecular pores that govern the flow of calcium ions across a cell membrane. When these pores open in heart muscle cells or in the smooth muscle cells in arteries and veins, the rush of calcium entering the cells triggers contraction of the heart to pump blood and contraction of the arteries to narrow their diameter and thereby increase blood pressure. By interfering with these molecular pores, calcium channel blockers can subdue a too-powerful cardiovascular response that can cause an irregular heart beat or high blood pressure.

    Pharmacologists had thought that verapamil-like drugs physically blocked calcium channel pores to prevent calcium entry into the cell, and thereby restore a normal heart rhythm, whereas amlodipine-like drugs (called dihydropyridines) were thought to indirectly prevent calcium channel activation and pore opening, and thereby prevent high blood pressure and angina. However, the specific structures behind these different mechanisms of action remained uncharted.

    Advances in X-ray crystallography – a way to determine the arrangement of atoms within a large protein molecule – and in the functional analyses of ion channels have now enabled researchers to probe the submolecular depths of the drugs’ actions. Researchers looked at where the drug molecules bound to calcium channels, and how this binding changes the workings of the channels.

    The binding site for the blood pressure and angina medication, amlodipine, was discovered to be on the outside edge of the calcium channel molecule. The central pore has voltage sensors around it which are sensitive to electrical potential. The binding site is positioned on the outside edge of the central pore structure between two of the four subunits of the calcium channel molecule. The binding shuts down the channel by distorting its shape and lodging a calcium ion permanently within it.

    “The amlodipine subtly remodels the pore so that the calcium ion is pulled to one side and just sticks there the whole time, as if it were locked up, “ said Ning Zheng.

    In contrast, the verapamil molecule plugs the central cavity of a calcium channel and by itself directly barricades the calcium ion-conducting pathway.

    Verapamil also takes advantage of the frequent openings of the calcium channels when the heart is palpitating, as it does during atrial fibrillation or atrial flutter. The more often the pore opens, the greater the odds that the verapamil molecule can slip into the central cavity and seal off the pore.

    “Verapamil appears to bind better to calcium channels in the rapidly beating parts of the heart and slows them down,” Catterall said. He noted that his UW colleague, Bertil Hille, professor of physiology and biophysics, and his associates earlier had demonstrated the effects of rapid firing frequency on sodium channel blockade in their studies of local anesthetic drugs like lidocaine that prevent pain in dentistry and surgery.

    3
    Certain calcium channel blockers, like verapamil, correct irregular heart beats and restore a normal rhythm

    On the other hand, in their resting state, calcium channels in blood vessel cells are usually closed. Amlodipine molecules modulate the voltage-dependent activation of calcium channels, and do not need to rely on frequent openings of the channel to enter the pore. That is why amlodipine-like drugs, which relax the blood vessels, can treat certain causes of high blood pressure and the tight, squeezing pain of angina without major effects on the heart itself. This sets them apart from the verapamil-like drugs, which favor calcium channels in cells active in the electrical circuitry of the heart.

    Understanding details of the two binding sites might lead to the development of calcium channel blockers that fit more exactly in place. A more precise shape might also prevent next-generation versions of the blockers from inadvertently aligning with the wrong binding sites and causing unwanted side effects.

    “Calcium channel blockers are relatively safe drugs,” Catterall explained, “but toxicity can arise from overdoses that can lead to ventricular arrhythmias or to too strong depression of the contraction of the heart or smooth muscle cells.” Structure-based, improved drug design, he said, might allow for smaller, yet still effective, drug doses that are more specific and safer. Fine-tuning the drug design, he added, might prevent another possible contributor to unwanted side effects: the off-target blocking of sodium channels by calcium channel blockers.

    The new research was conducted on bacterial ion channels, which are the ancestors of sodium and calcium channels in other life forms, including worms, flies, fish and humans.

    “These ancient channels in bacteria still recognize the drugs designed for people,” Catterall said. “The experiments done by our second author Tamer Gamal El-Din, acting assistant professor of pharmacology, showed that these drugs act in the same way on bacterial channels as they do on those in mammals. It’s remarkable that the most basic bacterial channels respond to these modern medicines for treating arrhythmias and certain other cardiovascular diseases. ”

    The study benefited from the federally sponsored Advanced Light Source at the Lawrence Berkeley National Laboratory, where the minute structures of the bound and unbound calcium channels could be analyzed. Amazingly, Zheng explained that the experimental procedures carried out at the synchrotron beam line in California could be managed long-distance from the UW in Seattle via a simple laptop computer operated by Lin Tang and other investigators in this study.

    Other researchers on this project were Teresa M. Swanson, UW pharmacology Ph.D. candidate; David C. Pryde, Pfizer Research Unit at Worldwide Medicinal Chemistry in the United Kingdom; and Todd Scheuer, UW research professor of pharmacology.

    The project reported in this week’s Nature was supported by the National Heart, Lung and Blood Institute of the National Institutes of Health (grant R01 HL112808), a National Research Service Award (grant T32GM008268) and the Howard Hughes Medical Institute.

    See the full article here .

    Please help promote STEM in your local schools.

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    Stem Education Coalition

    The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.

    So what defines us — the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
  • richardmitnick 4:36 pm on August 24, 2016 Permalink | Reply
    Tags: Applied Research & Technology, , , In unstable times the brain reduces cell production to help cope   

    From Princeton: “In unstable times, the brain reduces cell production to help cope” 

    Princeton University
    Princeton University

    August 24, 2016
    Morgan Kelly

    People who experience job loss, divorce, death of a loved one or any number of life’s upheavals often adopt coping mechanisms to make the situation less traumatic.

    While these strategies manifest as behaviors, a Princeton University and National Institutes of Health study suggests that our response to stressful situations originates from structural changes in our brain that allow us to adapt to turmoil.

    A study conducted with adult rats showed that the brains of animals faced with disruptions in their social hierarchy produced far fewer new neurons in the hippocampus, the part of the brain responsible for certain types of memory and stress regulation. Rats exhibiting this lack of brain-cell growth, or neurogenesis, reacted to the surrounding upheaval by favoring the company of familiar rats over that of unknown rats, according to a paper published in The Journal of Neuroscience.

    1
    A Princeton University and National Institutes of Health study suggests that our response to stressful situations originates from structural changes in our brain that allows us to adapt to turmoil. Adult rats with disruptions in their social hierarchy produced far fewer new neurons in the hippocampus, the part of the brain responsible for certain types of memory and stress regulation. They also reacted to the disruption by favoring the company of familiar rats. Their behavior manifested six weeks after social disruption, during which time brain-cell growth, or neurogenesis, had decreased by 50 percent. The photo shows adult hippocampal neurons that are less than two weeks old. (Image courtesy of Maya Opendak, New York University)

    The research is among the first to show that adult neurogenesis — or the lack thereof — has an active role in shaping social behavior and adaptation, said first author Maya Opendak, who received her Ph.D. in neuroscience from Princeton in 2015 and conducted the research as a graduate student. The preference for familiar rats may be an adaptive behavior triggered by the reduction in neuron production, she said.

    “Adult-born neurons are thought to have a role in responding to novelty, and the hippocampus participates in resolving conflicts between different goals for use in decision-making,” said Opendak, who is now a postdoctoral research fellow of child and adolescent psychology at the New York University School of Medicine.

    “Data from this study suggest that the reward of social novelty may be altered,” she said. “Indeed, sticking with a known partner rather than approaching a stranger may be beneficial in some circumstances.”

    The findings also show that behavioral responses to instability may be more measured than scientists have come to expect, explained senior author Elizabeth Gould, Princeton’s Dorman T. Warren Professor of Psychology and department chair. Gould and her co-authors were surprised that the disrupted rats did not display any of the stereotypical signs of mental distress such as anxiety or memory loss, she said.

    “Even in the face of what appears to be a very disruptive situation, there was not a negative pathological response but a change that could be viewed as adaptive and beneficial,” said Gould, who also is a professor of neuroscience in the Princeton Neuroscience Institute (PNI).

    “We thought the animals would be more anxious, but we were making our prediction based on all the bias in the field that social disruption is always negative,” she said. “This research highlights the fact that organisms, including humans, are typically resilient in response to disruption and social instability.”

    Co-authors on the paper include: Lily Offit, who received her bachelor’s degree in psychology and neuroscience from Princeton in 2015 and is now a research assistant at Columbia University Medical Center; Patrick Monari, a research specialist in PNI; Timothy Schoenfeld, a postdoctoral researcher at the National Institutes of Health (NIH) who received his Ph.D. in psychology and neuroscience from Princeton in 2012; Anup Sonti, an NIH researcher; and Heather Cameron, an NIH principal investigator of neuroplasticity.

    The study is unusual for mimicking the true social structure of rats, Gould said. Rats live in structured societies that contain a single dominant male. The researchers placed rats into several groups consisting of four males and two females in to a large enclosure known as a visible burrow system. They then monitored the groups until the dominant rat in each one emerged and was identified. After a few days, the alpha rats of two communities were swapped, which reignited the contest for dominance in each group.

    The rats from disrupted hierarchies displayed their preference for familiar fellows six weeks after those turbulent times, during which time neurogenesis had decreased by 50 percent, Opendak said. (Any neurons generated during the time of instability would take four to six weeks to be incorporated into the hippocampus’ circuitry, she said.)

    When the researchers chemically restored adult neurogenesis in these rats, however, the animals’ interest in unknown rats returned to pre-disruption levels. At the same time, the researchers inhibited neuron growth in “naïve” transgenic rats that had not experienced social disruption. They found that the mere cessation of neurogenesis produced the same results as social disruption, particularly a preference for spending time with familiar rats.

    “These results show that the reduction in new neurons is directly responsible for social behavior, something that hasn’t been shown before,” Gould said. The exact mechanism behind how lower neuron growth led to the behavior change is not yet clear, she said.

    Bruce McEwen, professor of neuroendocrinology at The Rockefeller University, said that the research is a “major step forward” in efforts to explore the role of the dentate gyrus — a part of the hippocampus — in social behavior and antidepressant efficacy.

    “The ventral dentate gyrus, where they found these effects, is now implicated in mood-related behaviors and the response to antidepressants,” said McEwen, who is familiar with the research but had no role in it.

    “The connection to social behavior shown here is an important addition because social withdrawal is a key aspect of depression in humans, and the anterior hippocampus in humans is the homolog of the ventral hippocampus in rodents,” McEwen said. “Although there is no ‘animal model’ of human depression, the individual behaviors such as social avoidance, and brain changes such as neurogenesis, have been very useful in elucidating brain mechanisms in human depression.”

    At this point, the extent to which the exact mechanism and behavioral changes the researchers observed in the rats would apply to humans is unknown, Gould and Opendak said. The study’s overall conclusion, however, that social disruption and instability lead to neurological changes that help us to better cope is likely universal, they said.

    “Most people do experience some disruption in their lives, and resilience is the most typical response,” Gould said. “After all, if organisms always responded to stress with depression and anxiety, it’s unlikely early humans would have made it because life in the wild is very stressful.”

    “For people who are exposed to social disruption frequently, our animal model suggests that these life events may be accompanied by long-term changes in brain function and social behavior,” Opendak said. “Although we hope that our findings may guide research on the mechanisms of resilience in humans, it is important as always to exercise caution when extrapolating these data across species.”

    The paper, Lasting Adaptations In Social Behavior Produced By Social Disruption And Inhibition of Adult Neurogenesis, was published June 29 in The Journal of Neuroscience. This work was supported by the National Institute for Mental Health (NIMH).

    See the full article here .

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    Princeton University Campus

    About Princeton: Overview

    Princeton University is a vibrant community of scholarship and learning that stands in the nation’s service and in the service of all nations. Chartered in 1746, Princeton is the fourth-oldest college in the United States. Princeton is an independent, coeducational, nondenominational institution that provides undergraduate and graduate instruction in the humanities, social sciences, natural sciences and engineering.

    As a world-renowned research university, Princeton seeks to achieve the highest levels of distinction in the discovery and transmission of knowledge and understanding. At the same time, Princeton is distinctive among research universities in its commitment to undergraduate teaching.

    Today, more than 1,100 faculty members instruct approximately 5,200 undergraduate students and 2,600 graduate students. The University’s generous financial aid program ensures that talented students from all economic backgrounds can afford a Princeton education.

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