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  • richardmitnick 3:22 pm on November 18, 2014 Permalink | Reply
    Tags: , , , FightAIDs@home,   

    From NOVA: “Why There’s No HIV Cure Yet” 

    [After the NOVA article, I tell you how you and your family, friends, and colleagues can help to find a cure for AIDS and other diseases]

    PBS NOVA

    NOVA

    27 Aug 2014
    Alison Hill

    Over the past two years, the phrase “HIV cure” has flashed repeatedly across newspaper headlines. In March 2013, doctors from Mississippi reported that the disease had vanished in a toddler who was infected at birth. Four months later, researchers in Boston reported a similar finding in two previously HIV-positive men. All three were no longer required to take any drug treatments. The media heralded the breakthrough, and there was anxious optimism among HIV researchers. Millions of dollars of grant funds were earmarked to bring this work to more patients.

    But in December 2013, the optimism evaporated. HIV had returned in both of the Boston men. Then, just this summer, researchers announced the same grim results for the child from Mississippi. The inevitable questions mounted from the baffled public. Will there ever be a cure for this disease? As a scientist researching HIV/AIDS, I can tell you there’s no straightforward answer. HIV is a notoriously tricky virus, one that’s eluded promising treatments before. But perhaps just as problematic is the word “cure” itself.

    Science has its fair share of trigger words. Biologists prickle at the words “vegetable” and “fruit”—culinary terms which are used without a botanical basis—chemists wrinkle their noses at “chemical free,” and physicists dislike calling “centrifugal” a force—it’s not; it only feels like one. If you ask an HIV researcher about a cure for the disease, you’ll almost certainly be chastised. What makes “cure” such a heated word?

    t
    HIV hijacks the body’s immune system by attacking T cells.

    It all started with a promise. In the early 1980s, doctors and public health officials noticed large clusters of previously healthy people whose immune systems were completely failing. The new condition became known as AIDS, for “acquired immunodeficiency syndrome.” A few years later, in 1984, researchers discovered the cause—the human immunodeficiency virus, now known commonly as HIV. On the day this breakthrough was announced, health officials assured the public that a vaccine to protect against the dreaded infection was only two years away. Yet here we are, 30 years later, and there’s still no vaccine. This turned out to be the first of many overzealous predictions about controlling the HIV epidemic or curing infected patients.

    The progression from HIV infection to AIDS and eventual death occurs in over 99% of untreated cases—making it more deadly than Ebola or the plague. Despite being identified only a few decades ago, AIDS has already killed 25 million people and currently infects another 35 million, and the World Health Organization lists it as the sixth leading cause of death worldwide.

    HIV disrupts the body’s natural disease-fighting mechanisms, which makes it particularly deadly and complicates efforts to develop a vaccine against it. Like all viruses, HIV gets inside individual cells in the body and highjacks their machinery to make thousands of copies of itself. HIV replication is especially hard for the body to control because the white blood cells it infects, and eventually kills, are a critical part of the immune system. Additionally, when HIV copies its genes, it does so sloppily. This causes it to quickly mutate into many different strains. As a result, the virus easily outwits the body’s immune defenses, eventually throwing the immune system into disarray. That gives other obscure or otherwise innocuous infections a chance to flourish in the body—a defining feature of AIDS.

    Early Hope

    In 1987, the FDA approved AZT as the first drug to treat HIV. With only two years between when the drug was identified in the lab and when it was available for doctors to prescribe, it was—and remains—the fastest approval process in the history of the FDA. AZT was widely heralded as a breakthrough. But as the movie The Dallas Buyer’s Club poignantly retells, AZT was not the miracle drug many hoped. Early prescriptions often elicited toxic side-effects and only offered a temporary benefit, as the virus quickly mutated to become resistant to the treatment. (Today, the toxicity problems have been significantly reduced, thanks to lower doses.) AZT remains a shining example of scientific bravura and is still an important tool to slow the infection, but it is far from the cure the world had hoped for.

    In three decades, over 25 highly-potent drugs have been developed and FDA-approved to treat HIV.

    Then, in the mid-1990s, some mathematicians began probing the data. Together with HIV scientists, they suggested that by taking three drugs together, we could avoid the problem of drug resistance. The chance that the virus would have enough mutations to allow it to avoid all drugs at once, they calculated, would simply be too low to worry about. When the first clinical trials of these “drug cocktails” began, both mathematical and laboratory researchers watched the levels of virus drop steadily in patients until they were undetectable. They extrapolated this decline downwards and calculated that, after two to three years of treatment, all traces of the virus should be gone from a patient’s body. When that happened, scientists believed, drugs could be withdrawn, and finally, a cure achieved. But when the time came for the first patients to stop their drugs, the virus again seemed to outwit modern medicine. Within a few weeks of the last pill, virus levels in patients’ blood sprang up to pre-treatment levels—and stayed there.

    In the three decades since, over 25 more highly-potent drugs have been developed and FDA-approved to treat HIV. When two to five of them are combined into a drug cocktail, the mixture can shut down the virus’s replication, prevent the onset of AIDS, and return life expectancy to a normal level. However, patients must continue taking these treatments for their entire lives. Though better than the alternative, drug regimens are still inconvenient and expensive, especially for patients living in the developing world.

    Given modern medicine’s success in curing other diseases, what makes HIV different? By definition, an infection is cured if treatment can be stopped without the risk of it resurfacing. When you take a week-long course of antibiotics for strep throat, for example, you can rest assured that the infection is on track to be cleared out of your body. But not with HIV.

    A Bad Memory

    The secret to why HIV is so hard to cure lies in a quirk of the type of cell it infects. Our immune system is designed to store information about infections we have had in the past; this property is called “immunologic memory.” That’s why you’re unlikely to be infected with chickenpox a second time or catch a disease you were vaccinated against. When an infection grows in the body, the white blood cells that are best able to fight it multiply repeatedly, perfecting their infection-fighting properties with each new generation. After the infection is cleared, most of these cells will die off, since they are no longer needed. However, to speed the counter-attack if the same infection returns, some white blood cells will transition to a hibernation state. They don’t do much in this state but can live for an extremely long time, thereby storing the “memory” of past infections. If provoked by a recurrence, these dormant cells will reactivate quickly.

    This near-immortal, sleep-like state allows HIV to persist in white blood cells in a patient’s body for decades. White blood cells infected with HIV will occasionally transition to the dormant state before the virus kills them. In the process, the virus also goes temporarily inactive. By the time drugs are started, a typical infected person contains millions of these cells with this “latent” HIV in them. Drug cocktails can prevent the virus from replicating, but they do nothing to the latent virus. Every day, some of the dormant white blood cells wake up. If drug treatment is halted, the latent virus particles can restart the infection.

    Latent HIV’s near-immortal, sleep-like state allows it to persist in white blood cells in a patient’s body for decades.

    HIV researchers call this huge pool of latent virus the “barrier to a cure.” Everyone’s looking for ways to get rid of it. It’s a daunting task, because although a million HIV-infected cells may seem like a lot, there are around a million times that many dormant white blood cells in the whole body. Finding the ones that contain HIV is a true needle-in-a-haystack problem. All that remains of a latent virus is its DNA, which is extremely tiny compared to the entire human genome inside every cell (about 0.001% of the size).
    Defining a Cure

    Around a decade ago, scientists began to talk amongst themselves about what a hypothetical cure could look like. They settled on two approaches. The first would involve purging the body of latent virus so that if drugs were stopped, there would be nothing left to restart the infection. This was often called a “sterilizing cure.” It would have to be done in a more targeted and less toxic way than previous attempts of the late 1990s, which, because they attempted to “wake up” all of the body’s dormant white blood cells, pushed the immune system into a self-destructive overdrive. The second approach would instead equip the body with the ability to control the virus on its own. In this case, even if treatment was stopped and latent virus reemerged, it would be unable to produce a self-sustaining, high-level infection. This approach was referred to as a “functional cure.”

    The functional cure approach acknowledged that latency alone was not the barrier to a cure for HIV. There are other common viruses that have a long-lived latent state, such as the Epstein-Barr virus that causes infectious mononucleosis (“mono”), but they rarely cause full-blown disease when reactivated. HIV is, of course, different because the immune system in most people is unable to control the infection.

    The first hint that a cure for HIV might be more than a pipe-dream came in 2008 in a fortuitous human experiment later known as the “Berlin patient.” The Berlin patient was an HIV-positive man who had also developed leukemia, a blood cancer to which HIV patients are susceptible. His cancer was advanced, so in a last-ditch effort, doctors completely cleared his bone marrow of all cells, cancerous and healthy. They then transplanted new bone marrow cells from a donor.

    Fortunately for the Berlin patient, doctors were able to find a compatible bone marrow donor who carried a unique HIV-resistance mutation in a gene known as CCR5. They completed the transplant with these cells and waited.

    For the last five years, the Berlin patient has remained off treatment without any sign of infection. Doctors still cannot detect any HIV in his body. While the Berlin patient may be cured, this approach cannot be used for most HIV-infected patients. Bone marrow transplants are extremely risky and expensive, and they would never be conducted in someone who wasn’t terminally ill—especially since current anti-HIV drugs are so good at keeping the infection in check.

    Still, the Berlin patient was an important proof-of-principle case. Most of the latent virus was likely cleared out during the transplant, and even if the virus remained, most strains couldn’t replicate efficiently given the new cells with the CCR5 mutation. The Berlin patient case provides evidence that at least one of the two cure methods (sterilizing or functional), or perhaps a combination of them, is effective.

    Researchers have continued to try to find more practical ways to rid patients of the latent virus in safe and targeted ways. In the past five years, they have identified multiple anti-latency drug candidates in the lab. Many have already begun clinical trials. Each time, people grow optimistic that a cure will be found. But so far, the results have been disappointing. None of the drugs have been able to significantly lower levels of latent virus.

    In the meantime, doctors in Boston have attempted to tease out which of the two cure methods was at work in the Berlin patient. They conducted bone marrow transplants on two HIV-infected men with cancer—but this time, since HIV-resistant donor cells were not available, they just used typical cells. Both patients continued their drug cocktails during and after the transplant in the hopes that the new cells would remain HIV-free. After the transplants, no HIV was detectable, but the real test came when these patients volunteered to stop their drug regimens. When they remained HIV-free a few months later, the results were presented at the International AIDS Society meeting in July 2013. News outlets around the world declared that two more individuals had been cured of HIV.

    Latent virus had likely escaped the detection methods available.

    It quickly became clear that everyone had spoken too soon. Six months later, researchers reported that the virus had suddenly and rapidly returned in both individuals. Latent virus had likely escaped the detection methods available—which are not sensitive enough—and persisted at low, but significant levels. Disappointment was widespread. The findings showed that even very small amounts of latent virus could restart an infection. It also meant meant that the anti-latency drugs in development would need to be extremely potent to give any hope of a cure.

    But there was one more hope—the “Mississippi baby.” A baby was born to an HIV-infected mother who had not received any routine prenatal testing or treatment. Tests revealed high levels of HIV in the baby’s blood, so doctors immediately started the infant on a drug cocktail, to be continued for life.

    The mother and child soon lost touch with their health care providers. When they were relocated a few years later, doctors learned that the mother had stopped giving drugs to the child several months prior. The doctors administered all possible tests to look for signs of the virus, both latent and active, but they didn’t find any evidence. They chose not to re-administer drugs, and a year later, when the virus was still nowhere to be found, they presented the findings to the public. It was once again heralded as a cure.

    Again, it was not to be. Just last month, the child’s doctors announced that the virus had sprung back unexpectedly. It seemed that even starting drugs as soon as infection was detected in the newborn could not prevent the infection from returning over two years later.
    Hope Remains

    Despite our grim track record with the disease, HIV is probably not incurable. Although we don’t have a cure yet, we’ve learned many lessons along the way. Most importantly, we should be extremely careful about using the word “cure,” because for now, we’ll never know if a person is cured until they’re not cured.

    Clearing out latent virus may still be a feasible approach to a cure, but the purge will have to be extremely thorough. We need drugs that can carefully reactivate or remove latent HIV, leaving minimal surviving virus while avoiding the problems that befell earlier tests that reactivated the entire immune system. Scientists have proposed multiple, cutting-edge techniques to engineer “smart” drugs for this purpose, but we don’t yet know how to deliver this type of treatment safely or effectively.

    As a result, most investigations focus on traditional types of drugs. Researchers have developed ways to rapidly scan huge repositories of existing medicines for their ability to target latent HIV. These methods have already identified compounds that were previously used to treat alcoholism, cancer, and epilepsy, and researchers are repurposing them to be tested in HIV-infected patients.
    The less latent virus that remains, the less chance there is that the virus will win the game of chance.

    Mathematicians are also helping HIV researchers evaluate new treatments. My colleagues and I use math to take data collected from just a few individuals and fill in the gaps. One question we’re focusing on is exactly how much latent virus must be removed to cure a patient, or at least to let them stop their drug cocktails for a few years. Each cell harboring latent virus is a potential spark that could restart the infection. But we don’t know when the virus will reactivate. Even once a single latent virus awakens, there are still many barriers it must overcome to restart a full-blown infection. The less latent virus that remains, the less chance there is that the virus will win this game of chance. Math allows us to work out these odds very precisely.

    Our calculations show that “apparent cures”—where patients with latent virus levels low enough to escape detection for months or years without treatment—are not a medical anomaly. In fact, math tells us that they are an expected result of these chance dynamics. It can also help researchers determine how good an anti-latency drug should be before it’s worth testing in a clinical trial.

    Many researchers are working to augment the body’s ability to control the infection, providing a functional cure rather than a sterilizing one. Studies are underway to render anyone’s immune cells resistant to HIV, mimicking the CCR5 mutation that gives some people natural resistance. Vaccines that could be given after infection, to boost the immune response or protect the body from the virus’s ill effects, are also in development.

    In the meantime, treating all HIV-infected individuals—which has the added benefit of preventing new transmissions—remains the best way to control the epidemic and reduce mortality. But the promise of “universal treatment” has also not materialized. Currently, even in the U.S., only 25% of HIV-positive people have their viral levels adequately suppressed by treatment. Worldwide, for every two individuals starting treatment, three are newly infected. While there’s no doubt that we’ve made tremendous progress in fighting the virus, we have a long way to go before the word “cure” is not taboo when it comes to HIV/AIDS.

    See the full article here.

    Did you know that you can help in the fight against AIDS? By donating time on your computer to the Fight Aids at Home project of World Community Grid, you can become a part of the solution. The work is called “crunching” because you are crunching computational data the results of which will then be fed back into the necessary lab work. We save researchers literally millions of hours of lab time in this process.
    Vsit World Community Grid (WCG) or Berkeley Open infrastructure for Network Computing (BOINC). Download the BOINC software and install it on your computer. Then visit WCG and attach to the FAAH project. The project will send you computational work units. Your computer will process them and send the results back to the project, the project will then send you more work units. It is that simple. You do nothing, unless you want to get into the nuts and bolts of the BOINC software. If you take up this work, and if you see it as valuable, please tell your family, friends and colleagues, anyone with a computer, even an Android tablet. We found out that my wife’s oncologist’s father in Brazil is a cruncher on two projects from WCG.

    This is the projects web site. Take a look.

    While you are visiting BOINC and WCG, look around at all of the very valuable projects being conducted at some of the worlds most distinguished universities and scientific institutions. You can attach to as many as you like, on one or a number of computers. You can only be a help here, particpating in Citizen Science.

    This is a look at the present and past projects at WCG:

    Please visit the project pages-

    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
    ibm

    IBM – Smarter Planet
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    Stem Education Coalition

    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 4:52 pm on November 6, 2014 Permalink | Reply
    Tags: , , , FightAIDs@home,   

    From FAAH at WCG: “Teamwork yields experimental support for FightAIDS@Home calculations” 

    New WCG Logo

    By: The FightAIDS@Home research team
    6 Nov 2014

    Summary
    Imaging studies have now confirmed some of the computational predictions made during FightAIDS@Home, providing important confirmation of our methodology and the value of your computational results. This work is ongoing, but promises to increase our understanding of how HIV protease can be disrupted.

    site
    The “exo-site” discovered in HIV protease (shown here in green), showing the original bound 4d9 fragment (shown here as red and orange sticks) and the volume (shown as the orange mesh) that is being targeted by FightAIDS@Home. (image credit: Stefano Forli, TSRI)

    Our lab at the Scripps Research Institute, La Jolla, is part of the HIV Interaction and Viral Evolution (HIVE) Center – a group of investigators with expertise in HIV crystallography, virology, molecular biology, biochemistry, synthetic chemistry and computational biology. This means that we have world-class resources available to verify and build upon our computational work, including the nuclear magnetic resonance (NMR) facility at the Scripps Research Institute, Florida. NMR is a technique for determining the molecular structure of a chemical sample, and therefore is very useful for validating some of the predictions made during the computational phase of FightAIDS@Home.

    We’re excited to announce that our collaborators at Scripps Florida have now optimized their NMR experiments and have been able to characterize the binding of promising ligands with the prospective allosteric sites on the HIV protease. These sites represent new footholds in the search for therapies that defeat viral drug resistance. The NMR experiment allows us to detect the location of the interactions between the candidate inhibitors and the protein, but unlike X-ray crystallography experiments, these interactions are measured in solution, which better represents the biological environment.

    In fact, the first results from the NMR experiments validated the exo site we so thoroughly investigated in FightAIDS@Home. As a result, we now have experimental evidence that a small molecule binds to the exo site in solution with structural effects that seem to perturb the dynamic behavior of protease, even with a known inhibitor in the active site.

    There are many more NMR experiments still to run, but another advantage of NMR over crystallography is that it does not require the lengthy step of growing diffraction-quality crystals. This allows higher experimental throughput, so we look forward to experimental confirmation of many more compounds in much shorter time. So far we have shipped 15 compounds to test and another batch is going to be sent this week. The new compounds will help to validate another potential interaction site on one of HIV protease’s two movable “flaps”.

    Once the validation is completed, we will proceed to test a number of compounds that we identified in different FightAIDS@Home experiments for all of the target protease allosteric sites.

    As always, thank you for your support! This research would not be possible without your valuable computing time.

    The Scripps research team needs your help to continue making progress on developing new treatments for AIDS! Take part in our decade of discovery competition by encouraging your friends to sign up to World Community Grid today to start donating their computer or mobile device’s computing power to FightAIDS@Home. There’s just over a week left and some great prizes are up for grabs – get started today!

    Here’s to another decade of discovery.

    See the full article here.

    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.

    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.

    CAN ONE PERSON MAKE A DIFFERENCE? YOU BETCHA!!

    “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-

    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
    ibm

    IBM – Smarter Planet
    sp

    ScienceSprings relies on technology from

    MAINGEAR computers

    Lenovo
    Lenovo

    Dell
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  • richardmitnick 10:16 pm on July 21, 2014 Permalink | Reply
    Tags: , , , FightAIDs@home, , ,   

    From WCG: “Pioneering a Molecular Approach to Fighting AIDS” 

    World Community Grid

    Dr. Arthur Olson
    Professor, The Scripps Research Institute
    21 Jul 2014

    Summary
    World Community Grid is being featured at the 20th International AIDS Conference which begins today in Melbourne, Australia. Dr. Arthur Olson, FightAIDS@Home principal investigator, shares his perspective on how World Community Grid is helping his team develop therapies and a potential cure for AIDS.

    The Scripps Research Institute’s FightAIDS@Home initiative is a large-scale computational research project whose goal is to use our knowledge of the molecular biology of the AIDS virus HIV to help defeat the AIDS epidemic. We rely on World Community Grid to provide massive computational power donated by people around the world to speed our research. The “virtual supercomputer” of World Community Grid enables us to model the known atomic structures of HIV molecules to help us design new drugs that could disrupt the function of these molecules. World Community Grid is an essential tool in our quest to understand and subvert the HIV virus’s ability to infect, spread and develop resistance to drug therapies.

    FightAidsOlsonLab@home

    Since the early 1980s – when AIDS was first recognized as a new epidemic and a serious threat to human health – our ability to combat the HIV virus has evolved. Using what we call “structure-based drug discovery,” researchers have been able to use information about HIV’s molecular component to design drugs to defeat it. Critical to this process has been our ability to develop and deploy advanced computational models to help us predict how certain chemical compounds could affect the HIV virus. The development of our AutoDock modelling application – combined with the computational power of World Community Grid – represents a significant breakthrough in our ability to fight HIV.

    By the mid 1990s, the first structure-based HIV protease inhibitors were approved for the treatment of AIDS. These inhibitors enabled the development of highly active antiretroviral therapy (HAART), which in turn resulted in a rapid decline of AIDS deaths where such treatment was available. In the intervening years, thanks in part to the U.S. National Institute of General Medical Sciences AIDS-related Structural Biology Program, we have learned a lot about the molecular structure of HIV. But the more we understand the structure of the virus, the more complex our computational models need to be to unlock the secrets of HIV.

    World Community Grid has enabled our research to progress well beyond what we could have dreamed of when we started our HIV research in the early 1990s. Through our FightAIDS@Home project, we can screen millions of chemical compounds to evaluate their effectiveness against HIV target proteins – including those known to be drug-resistant. By deploying these and other methods, we have significantly increased our understanding of HIV and its ability to evolve to resist treatment. Using these computational capabilities, we have just begun working with an HIV Cure researcher to help us move beyond treatment in search of a cure.

    See the full article here.

    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.

    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.

    CAN ONE PERSON MAKE A DIFFERENCE? YOU BETCHA!!

    “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-

    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

    Computing for Sustainable Water

    Mapping Cancer Markers
    Mapping Cancer Markers Banner

    World Community Grid is a social initiative of IBM Corporation
    IBM Corporation
    ibm

    IBM – Smarter Planet
    sp


    ScienceSprings is powered by MAINGEAR computers

     
  • richardmitnick 3:22 pm on July 16, 2014 Permalink | Reply
    Tags: , , , FightAIDs@home, ,   

    From FAAH@home: “Improved efficiency and processing capabilities for FightAIDS@Home” 

    FAAH
    FightAIDS@home

    16 Jul 2014
    The FightAIDS@Home research team

    Summary
    New methods and processes help the research team process World Community Grid data more efficiently and provide more accurate docking techniques.

    As the volume of data generated by World Community Grid volunteers for our FightAIDS@Home (FAAH) project has increased, so has our need to optimize how we handle and store that data. In this project update, we discuss new improvements in how we process the extremely high result data rate you generate, which is allowing us to focus more resources toward the analysis of FAAH data. Further, improved docking techniques are being created and applied from the results of deeper analysis coupled with ongoing experimental data from our collaborators.

    model
    Example of repositioned side-chain, histidine, by Vina cycling through the original space-filling representation, original stick representation (orange), and new position compared to old position (dotted black lines).

    Processing your results faster

    Managing the very large data throughput generated by World Community Grid volunteers for FAAH is a great challenge. Beside the scientific results we have achieved over the years, we also have developed novel software and protocols to process, analyze and store the results you generate quickly and efficiently.

    Recently, we exploited the parallel computational resources available at Scripps. In the last few months, we have shifted our processing of the incoming World Community Grid data to our local High Performance Computing cluster, Garibaldi. Since the implementation of the AutoDock Vina software for FAAH last year, you have generated several terabytes of compressed docking results each month, which was putting a strain on our storage system. Until recently, most of our work and resources have been focused on processing this data to make it suitable for deeper analysis. We had to devote most of our local computational power to this processing. With our new methods, we have increased the processing rate by several orders of magnitude with the use of multiple processors and the optimization of processing scripts. Processing a batch that used to take between 30 minutes to few hours now takes just a few minutes. Streamlined scripts and parallel processing has yielded 180,000 processed batches in two weeks.

    We have created new analysis programs using structural and statistical methods to mine more information from the results you generate. Statistical analysis tools will first be used to reduce over 5 million docked compounds to a few thousand top-ranking candidates. Structural information will then be used to cull the list further by filtering for key intermolecular interactions and against unfavorable interactions. A new database structure that will incorporate these programs is being developed to handle this large and fast-growing flood of results. Once optimized, the whole processing and analysis workflow will be fully automated.

    Importantly, what we have learned and are learning from these refined methods to handle big data will be made available in the AutoDockTools suite, which is utilized by many research labs worldwide.

    Improved protein-ligand binding modeling capabilities

    Proteins are typically large molecules and often can bend or flex in various ways at various points and at normal temperatures they rapidly bend to many or all of the possible configurations (bent shapes). When searching for ligands that might attach to a protein target, the ligand might not match the shape of the protein in one of its configurations, but might match in another configuration of the protein. By considering more configurations of the protein, it is more likely that a ligand can be found which matches one of the protein’s configurations. Since February 2014, we have been running flexible receptor side-chain Vina jobs on FAAH, which we expect to enhance our docking results. While our typical docking methods hold the protein structure rigid, the flexibility feature in AutoDock Vina allows selected residue side chain conformations to be sampled along with the flexible ligand molecule. This enables the protein pocket to adopt alternate shapes to better model protein-ligand binding and the so-called “induced fit”, minimizing the bias of using a rigid target structure. Currently, we are testing this approach on several sites (LEFGF, FBP, and Y3) in HIV integrase.

    The downside of performing flexible receptor calculations is that the search complexity increases, and computing run-times are therefore 5 to 10 times longer. The World Community Grid staff has been adjusting their methods to account for the different Flexible Vina work unit. Once these dockings have finished and the analyses performed, we will be able to optimize our application of Flexible Vina on World Community Grid and extend it to other targets.

    Another way to minimize rigid-protein bias in traditional docking is to dock to an ensemble of protein structures. Two ways to generate these ensembles, both used in FAAH dockings, are molecular dynamics (MD) simulations and simply using multiple available structures for a given protein receptor. The last hundred experiments have included ensembles ranging from tens to sometimes hundreds of receptor structures. Ensembles add another layer of analysis with the goal of achieving a more accurate ranking of compounds from several sources of data.

    Further experimentation

    Despite the encouraging results on the first hits previously reported, we are encountering experimental issues that are making the process of identifying hits very challenging. As often happens in science (and particularly in HIV-related experiments!), it is hard to achieve robust and consistent statistics from biological assays.

    See the full article here.

    FightAIDS@Home is a project run by the Olson Laboratory that uses distributed computing to contribute your computer’s idle resources to accelerate research into new drug therapies for HIV, the virus that causes AIDS. FightAIDS@Home made history in September 2000 when it became the first biomedical Internet-based grid computing project. FightAIDS@Home was started with Scott Kurowski, founder of Entropia. People all around the World continue to donate their home computer’s idle cycles to running our AutoDock software on HIV-1 protease inhibitor docking problems. With the generous assistance of IBM, we joined World Community Grid in late 2005, and launched FightAIDS@Home on World Community Grid on 21 November, 2005.

    How do I join the FightAIDS@Home Project?

    All you need to do is download and install the free client software. Once you have done this, your computer is then automatically put to work and you can continue using your computer as usual.

    Faah Screensaver


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  • richardmitnick 12:26 pm on July 14, 2014 Permalink | Reply
    Tags: , , FightAIDs@home, , ,   

    FROM WCG: “Better tools for AIDS drug research” 

    FAAH
    FightAIDS@home

    FightAIDS@Home is a project run by the Olson Laboratory that uses distributed computing to contribute your computer’s idle resources to accelerate research into new drug therapies for HIV, the virus that causes AIDS. FightAIDS@Home made history in September 2000 when it became the first biomedical Internet-based grid computing project. FightAIDS@Home was started with Scott Kurowski, founder of Entropia. People all around the World continue to donate their home computer’s idle cycles to running our AutoDock software on HIV-1 protease inhibitor docking problems. With the generous assistance of IBM, we joined World Community Grid in late 2005, and launched FightAIDS@Home on World Community Grid on 21 November, 2005.

    How do I join the FightAIDS@Home Project?

    All you need to do is download and install the free client software. Once you have done this, your computer is then automatically put to work and you can continue using your computer as usual.


    ScienceSprings is powered by MAINGEAR computers

    24 Jun 2014

    Summary
    The Scripps research team published a paper proving the effectiveness of a method to more accurately predict bindings between protein targets and drug candidates, which could benefit FightAIDS@Home and other World Community Grid drug discovery projects.

    Paper Title:

    “Virtual screening with AutoDock Vina and the common pharmacophore engine of a low diversity library of fragments and hits against the three allosteric sites of HIV integrase: participation in the SAMPL4 protein–ligand binding challenge”

    Lay Person Abstract:

    The Olson Lab at The Scripps Institute collaborated to participate in the “SAMPL4 Challenge” which evaluated methods to predict protein target to drug candidate bindings. Olson’s lab in cooperation with Levy’s lab at Rutgers University were able to prove the utility of a method to reduce false positives and therefore potentially reduce the amount of laboratory work required to validate computational results. This should ultimately be a benefit to research projects such as FightAIDS@Home and other drug search projects on World Community Grid.

    A link to the paper is here.
    See the full article here.

    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.

    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.

    CAN ONE PERSON MAKE A DIFFERENCE? YOU BETCHA!!

    “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-

    Say No to Schistosoma
    sch

    GO Fight Against Malaria
    mal

    Drug Search for Leishmaniasis
    lish

    Computing for Clean Water
    c4cw

    The Clean Energy Project
    cep2

    Discovering Dengue Drugs – Together
    dengue

    Help Cure Muscular Dystrophy
    md

    Help Fight Childhood Cancer
    hccf

    Help Conquer Cancer
    hcc

    Human Proteome Folding
    hpf

    FightAIDS@Home
    faah

    Computing for Sustainable Water

    Computing for Sustainable Water

    World Community Grid is a social initiative of IBM Corporation
    IBM Corporation
    ibm

    IBM – Smarter Planet
    sp


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  • richardmitnick 7:58 pm on July 13, 2014 Permalink | Reply
    Tags: , , FightAIDs@home, ,   

    From FightAIDS@home: 

    FAAH
    FightAIDS@home

    hive

    Happy new year! Since February 2014, some FightAIDS@Home experiments have been using AutoDock Flexible Vina.

    vinahive
    Note: one AutoDock “batch” involves docking up to 1,000 compounds, while one AD Vina batch involves docking up to 10,000 compounds. Batches of Vina Experiments starting from Experiment 149 (from batch 865236) now include up to 100K compounds.

    FightAIDS@Home is a project run by the Olson Laboratory that uses distributed computing to contribute your computer’s idle resources to accelerate research into new drug therapies for HIV, the virus that causes AIDS. FightAIDS@Home made history in September 2000 when it became the first biomedical Internet-based grid computing project. FightAIDS@Home was started with Scott Kurowski, founder of Entropia. People all around the World continue to donate their home computer’s idle cycles to running our AutoDock software on HIV-1 protease inhibitor docking problems. With the generous assistance of IBM, we joined World Community Grid in late 2005, and launched FightAIDS@Home on World Community Grid on 21 November, 2005.

    How do I join the FightAIDS@Home Project?

    All you need to do is download and install the free client software. Once you have done this, your computer is then automatically put to work and you can continue using your computer as usual.


    ScienceSprings is powered by MAINGEAR computers

     
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