News Article | September 12, 2016
The U.S. Department of Energy's (DOE) Exascale Computing Project (ECP) today announced its first round of funding with the selection of 15 application development proposals for full funding and seven proposals for seed funding, representing teams from 45 research and academic organizations. Exascale refers to high-performance computing systems capable of at least a billion billion calculations per second, or a factor of 50 to 100 times faster than the nation's most powerful supercomputers in use today. The 15 awards being announced total $39.8 million, targeting advanced modeling and simulation solutions to specific challenges supporting key DOE missions in science, clean energy and national security, as well as collaborations such as the Precision Medicine Initiative with the National Institutes of Health's National Cancer Institute. Of the proposals announced that are receiving full funding, two are being led by principal investigators at the DOE's Argonne National Laboratory: 1. Computing the Sky at Extreme Scales equips cosmologists with the ability to design foundational simulations to create "virtual universes" on demand at the extreme fidelities demanded by future multi-wavelength sky surveys. The new discoveries that will emerge from the combination of sky surveys and advanced simulation provided by the ECP will shed more light on three key ingredients of our universe: dark energy, dark matter and inflation. All three of these concepts reach beyond the known boundaries of the Standard Model of particle physics. 2. Exascale Deep Learning and Simulation Enabled Precision Medicine for Cancer focuses on building a scalable deep neural network code called the CANcer Distributed Learning Environment (CANDLE) that addresses three top challenges of the National Cancer Institute: understanding the molecular basis of key protein interactions, developing predictive models for drug response and automating the analysis and extraction of information from millions of cancer patient records to determine optimal cancer treatment strategies. Rick Stevens, Principal Investigator, Argonne National Laboratory, with Los Alamos National Laboratory, Lawrence Livermore National Laboratory, Oak Ridge National Laboratory and the National Institutes of Health's National Cancer Institute (NIH/NCI). Additionally, a third project led by Argonne will be receiving seed funding: Multiscale Coupled Urban Systems will create an integrated modeling framework comprising data curation, analytics, modeling and simulation components that will equip city designers, planners and managers to scientifically develop and evaluate solutions to issues that affect cities now and in the future. The framework will focus first on integrating urban atmosphere and infrastructure heat exchange and air flow; building energy demand at district or city-scale, generation and use; urban dynamics and socioeconomic models; population mobility and transportation; and hooks to expand to include energy systems (biofuels, electricity and natural gas) and water resources. The application efforts will help guide DOE's development of a U.S. exascale ecosystem as part of President Obama's National Strategic Computing Initiative. DOE, the U.S. Department of Defense and the National Science Foundation have been designated as lead agencies, and ECP is the primary DOE contribution to the initiative. The ECP's multi-year mission is to maximize the benefits of high-performance computing for U.S. economic competitiveness, national security and scientific discovery. In addition to applications, the DOE project addresses hardware, software, platforms and workforce development needs critical to the effective development and deployment of future exascale systems. Leadership of the Exascale Computing Project comes from six DOE national laboratories: the Office of Science's Oak Ridge, Argonne and Lawrence Berkeley national labs and NNSA's Lawrence Livermore, Los Alamos and Sandia national labs.
News Article | April 19, 2016
Transplants of insulin-producing pancreas cells are a long hoped-for treatment for diabetes - and a new study shows they can protect the most seriously ill patients from a life-threatening complication of the disease, an important step toward U.S. approval. These transplants are used in some countries but in the U.S. they're available only through research studies. Armed with Monday's findings, researchers hope to license them for use in a small number of people with Type 1 diabetes who are most at risk for drops in blood sugar so severe they can lead to seizures, even death. "Cell-based diabetes therapy is real and works and offers tremendous potential for the right patient," said study lead author Dr. Bernhard Hering of the University of Minnesota, whose team plans to seek a Food and Drug Administration license for the therapy. In Type 1 diabetes, the immune system destroys the pancreatic cells responsible for making insulin, a hormone crucial to converting blood sugar into energy. About 1 million Americans have Type 1 diabetes and depend on regular insulin shots to survive but still can experience complications due to swings in their blood sugar. Diabetics who get kidney transplants sometimes also receive pancreas transplants at the same time, essentially curing their diabetes. But it's an uncommon and grueling operation, so scientists for years have worked on a minimally invasive alternative: Infusing patients with just islet cells, the insulin factories inside the pancreas. The questions: How best to obtain those islet cells from deceased donors, and who benefits most from transplants? When glucose levels drop too low, most people with Type 1 diabetes experience early warning signs - slurred speech, tremors, sweating, heart palpitations - so they know to eat or drink something for a quick sugar boost. But even with optimal care, about 30 percent eventually quit experiencing those symptoms, a condition called hypoglycemia unawareness. They can be in grave danger if their blood sugar plummets when no one else is around to help. Continuous glucose monitors can counteract that problem, but even those don't help everyone. The National Institutes of Health targeted that fraction of highest-risk patients, funding a study that gave 48 people at eight medical centers at least one islet cell transplant. A year later, 88 percent were free of severe hypoglycemia events, had their awareness of blood sugar dips restored, and harbored glucose levels in near-normal ranges. Two years later, 71 percent of participants still were faring that well, concluded the study published by the journal Diabetes Care. The goal wasn't insulin independence, which requires more functioning islet cells than merely restoring blood sugar awareness. But some patients - 52 percent after one year - no longer needed insulin shots and others used lower doses. "It's just an amazing gift," said Lisa Bishop of Eagle River, Wisconsin, who received new islet cells in 2010 and no longer needs insulin shots. Bishop recalls the terror of learning she'd become hypoglycemic unaware, and the difficulty of even holding a job. She hasn't had hypoglycemia since the transplant and says if her blood sugar occasionally dips a bit after exercise, "now my body senses it." Another key: The transplants have long been used experimentally but different hospitals use different methods to cull the islet cells from a donated pancreas and purify them - and it wasn't clear which worked best, explained Dr. Nancy Bridges, chief of the transplant branch at NIH's National Institute for Allergy and Infectious Diseases. The FDA made clear that there had to be a standard method for islet cell transplants if they were ever to be approved - which is necessary for insurance coverage - so the researchers developed that recipe, Bridges said. Side effects include bleeding and infection, and recipients need lifelong immune-suppressing drugs to avoid rejecting their new cells. Even if given the OK for more routine use, donated pancreas cells are in limited supply. Still, "it's a very beautiful study," said Dr. Julia Greenstein of the diabetes advocacy organization JDRF, who wasn't involved in the latest research. "For most people in the U.S., this was not an available choice, and this is the first step in making that an available choice."
Scientists have shown that a process known as oxidative stress is at work during encounters between certain nanoparticles and immune cells, selectively modifying proteins on macrophages, a type of immune cell. The findings, by researchers at the Department of Energy's Pacific Northwest National Laboratory, were published in the journal ACS Nano. While oxidative stress is a common way for cell damage to occur, the findings were a surprise in some ways. "Oxidative stress is occurring selectively even at low levels of exposure to nanoparticles," said Brian Thrall, a nanotoxicology expert at PNNL and a corresponding author of the study. "We've demonstrated an approach that is sensitive enough to detect effects of nanoparticles on macrophages long before those cells die. This gives us the opportunity to understand the most sensitive cellular targets of oxidative stress and the pathways involved more completely than before. "This is important information for understanding how nanoparticles can alter cell function and for beginning to identify functions that allow cells to adapt versus those that are potentially involved in adverse effects," Thrall added. Nanoparticles are typically smaller than 100 nanometers wide, less than one one-thousandth the width of a human hair. If a standard basketball were blown up to the size of the Earth, a nanoparticle enlarged proportionately would be roughly the size of a beach ball in comparison. The particles are used broadly in biomedical applications, clothing, the electronics industry, cosmetics, food packaging and sunscreens; they're also a component in many forms of air pollution. As scientists have refined their ability to make a diversity of nanoparticles used in manufactured goods, there is a greater need to study their potential effects. Oftentimes, these studies look at whether or not exposure to the particles results in cell death. The PNNL study is more nuanced, looking in more depth at specific proteins in cells that are the targets of oxidative damage caused by nanoparticles. "This study shows that some nanoparticles which we consider non-toxic can have many effects on macrophages," said analytical chemist Wei-Jun Qian, also a corresponding author of the study. The findings depend on a method recently developed by PNNL scientists to measure protein oxidation at very specific sites in cells like macrophages. Qian developed a very sensitive measure of protein modifications in cells to allow scientists to look at specific sites in the cell where scientists know certain functions are carried out. The method, known as a quantitative redox proteomics approach, utilizes an advanced mass spectrometer to look at thousands of sites involved in redox reactions simultaneously. Thrall's and Qian's teams worked together to analyze modifications in all the proteins in mouse cells. The group looked at the effects of three types of nanoparticles which vary in their potential to cause oxidative stress and cell death: The team took a close look at more than 2,000 cellular hotspots where a process known as S-glutathionylation, a specific type of protein modification known to be involved in immune functions when a cell is under oxidative stress, occurs. In macrophages exposed to nanoparticles, the team found molecular "footprints" of activity — an increase in S-glutathionylation. However, the specific pattern of oxidative modifications on proteins varied depending on the type of nanoparticle. By looking at these modifications, researchers were able to identify specific molecular pathways that were most sensitive to low levels of oxidative stress, and distinguish those from other pathways that were associated with high levels of oxidative stress linked to cell death. The idea that a nanoparticle would damage the body's macrophages is no surprise: Macrophages are the body's first responders when it comes to recognizing and neutralizing an invader. Some nanoparticles can weaken macrophages' ability to recognize, hold onto and engulf the particles. Two years ago, Thrall's team showed that when macrophages are exposed to nanoparticles, the cells don't work as well and are less able to recognize and remove Streptococcus pneumonia, the leading cause of community-acquired pneumonia. The pattern of protein changes identified in this study provides new clues to the types of nanoparticles that cause these effects and the proteins involved. Qian developed the method as part of his work studying redox reactions which play an important role regulating photosynthesis in plants. Understanding how plants capture, process and funnel the Sun's energy naturally helps scientists develop efficient new energy systems to do the same. Qian has used the system to discover more than 2,100 molecular locations where redox reactions are likely to occur in cyanobacteria, which are important for producing biofuels. The work by Qian's group is funded in part by an Early Career Research Award from the Department of Energy, as well as an NIH Director's New Innovator Award. The spectrometric analyses took place at EMSL, the Environmental Molecular Sciences Laboratory, a DOE Office of Science User Facility at PNNL. Support for this study came from the National Institute of Environmental Health Sciences.
News Article | August 16, 2016
Researchers from Polytechnique Montréal, Université de Montréal, and McGill University have just achieved a spectacular breakthrough in cancer research. They have developed new nanorobotic agents capable of navigating through the bloodstream to administer a drug with precision by specifically targeting the active cancerous cells of tumors. This way of injecting medication ensures the optimal targeting of a tumor and avoids jeopardizing the integrity of organs and surrounding healthy tissues. As a result, the drug dosage that is highly toxic for the human organism could be significantly reduced. This scientific breakthrough has just been published in the prestigious journal Nature Nanotechnology in an article titled “Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumor hypoxic regions.” The article notes the results of the research done on mice, which were successfully administered nanorobotic agents into colorectal tumors. “These legions of nanorobotic agents were actually composed of more than 100 million flagellated bacteria — and therefore self-propelled — and loaded with drugs that moved by taking the most direct path between the drug’s injection point and the area of the body to cure,” explains Professor Sylvain Martel, holder of the Canada Research Chair in Medical Nanorobotics and Director of the Polytechnique Montréal Nanorobotics Laboratory, who heads the research team’s work. “The drug’s propelling force was enough to travel efficiently and enter deep inside the tumors.” When they enter a tumor, the nanorobotic agents can detect in a wholly autonomous fashion the oxygen-depleted tumor areas, known as hypoxic zones, and deliver the drug to them. This hypoxic zone is created by the substantial consumption of oxygen by rapidly proliferative tumor cells. Hypoxic zones are known to be resistant to most therapies, including radiotherapy. But gaining access to tumors by taking paths as minute as a red blood cell and crossing complex physiological micro-environments does not come without challenges. So Professor Martel and his team used nanotechnology to do it. To move around, bacteria used by Martel’s team rely on two natural systems. A kind of compass created by the synthesis of a chain of magnetic nanoparticles allows them to move in the direction of a magnetic field, while a sensor measuring oxygen concentration enables them to reach and remain in the tumor’s active regions. By harnessing these two transportation systems and by exposing the bacteria to a computer-controlled magnetic field, researchers showed that these bacteria could perfectly replicate artificial nanorobots of the future designed for this kind of task. “This innovative use of nanotransporters will have an impact not only on creating more advanced engineering concepts and original intervention methods, but it also throws the door wide open to the synthesis of new vehicles for therapeutic, imaging and diagnostic agents,” Martel adds. “Chemotherapy, which is so toxic for the entire human body, could make use of these natural nanorobots to move drugs directly to the targeted area, eliminating the harmful side effects while also boosting its therapeutic effectiveness.” The work by Professor Martel obtained the very valuable support of the Consortium québécois sur la découverte du médicament (Québec consortium for drug discovery — CQDM), the Canada Research Chairs, the Natural Sciences and Engineering Research Council of Canada (NSERC), the Research Chair in Nanorobotics of Polytechnique Montréal, Mitacs, the Canada Foundation for Innovation (CFI), and the National Institutes of Health (NIH). Montréal’s Jewish General Hospital, the McGill University Health Centre (MUHC), the Institute for Research in Immunology and Cancer (IRIC), and the Rosalind and Morris Goodman Cancer Research Centre also took part in this promising research work.
News Article | February 4, 2016
A team of National Health Institute researchers has for the first time uncovered the genetic roots of one of the strangest allergies: vibrations. The vibration allergy, which is just as it sounds, may be quite rare, but understanding it more completely may yield important insights into the fundamental malfunctioning of immune cells in the presence of allergens. The group's findings are published in the New England Journal of Medicine. In addition to being uncommon, the vibration allergy is not very dangerous. In most cases, the allergic response is limited to hives—the pale, prickly rash most often associated with allergic and autoimmune reactions. Other less common symptoms include headaches, blurry vision, fatigue, and flushing. The triggering vibrations are everyday things: jogging, jackhammering, riding a motorcycle, towel drying. Symptoms appear within a few minutes of exposure and are gone usually within an hour. The vibration allergy sounds weirder than it is. What's more properly known as vibratory urticaria (urticaria = hives) is in the broader category of physical urticarias. In contrast to usually more dire allergic reactions involving a chemical trigger, like penicillin or shellfish, physical triggers include everyday things like heat, cold, pressure, sweating, and exercise. As a kid, I'd sometimes wind up with intensely itchy full-body hives after gym class. It sucked, but not nearly as bad as having my throat close up because of a strawberry. The NIH group, led by allergist Hirsh Komarow, had only three families to work with—36 subjects in all. The families each had multiple generations that experienced the vibration allergy, but not all members of the families had the allergy. This was important as it allowed the researches to root out genetic mutations present in the vibration-allergic group but not in the the non-allergic group. The culprit turned out to be a shared mutation in the ADGRE2 gene. As Komarow and his group explain, it's this mutation that allows for the triggering of the immune response via a "purely mechanical means." The ADGRE2 gene encodes for a protein of the same name, which is found on the surfaces of cells known as mast cells—white blood cells responsible for the release of histamine, the compound behind localized immune activity and which plays a key role in the immune system's inflammatory response. The ADGRE2 protein consists of two chemically bound subunits. The alpha subunit is located on the outside surface of mast cell while the beta subunit is located within the cellular membrane itself. As explained in current study, the interaction between these two subunits has a not-very-well-understood role in normal immune system functioning, but the ADGRE2 genetic mutation predisposes the two protein subunits to coming apart when they're not supposed to, such as in the presence of normal vibration. The vibration causes a shear force, which causes the subunits to separate or cleave. What happens next is "aberrant degranulation" within the mast cells. Basically, these cells feature various immunoactive compounds which are stored in tiny vesicles called granules within the cells. When the cells get the right signal, the granules start sticking to the surrounding cellular membrane, with the result being the release of their contents into the outside world. Such contents may include histamine. While the vibration allergy may be rare, the process by which the ADGRE2 alpha and beta subunits mediate immune system reactions has implications for everyone. Mast cells play a central role in immune system activity, generally: autoimmune diseases, allergic reactions, and normal physiological responses to pathogens. Understanding the process of degranulation thus means better understanding how the body fights off outside invaders in the very first place.