Wednesday, December 7th, 2016

Time	Event
1:00p	Unique visual stimulation may be new treatment for Alzheimer’s Using LED lights flickering at a specific frequency, MIT researchers have shown that they can substantially reduce the beta amyloid plaques seen in Alzheimer’s disease, in the visual cortex of mice. This treatment appears to work by inducing brain waves known as gamma oscillations, which the researchers discovered help the brain suppress beta amyloid production and invigorate cells responsible for destroying the plaques. Further research will be needed to determine if a similar approach could help Alzheimer’s patients, says Li-Huei Tsai, the Picower Professor of Neuroscience, director of MIT’s Picower Institute for Learning and Memory, and senior author of the study, which appears in the Dec. 7 online edition of Nature. “It’s a big ‘if,’ because so many things have been shown to work in mice, only to fail in humans,” Tsai says. “But if humans behave similarly to mice in response to this treatment, I would say the potential is just enormous, because it’s so noninvasive, and it’s so accessible.” Tsai and Ed Boyden, an associate professor of biological engineering and brain and cognitive sciences at the MIT Media Lab and the McGovern Institute for Brain Research, who is also an author of the Nature paper, have started a company called Cognito Therapeutics to pursue tests in humans. The paper’s lead authors are graduate student Hannah Iaccarino and Media Lab research affiliate Annabelle Singer. “This important announcement may herald a breakthrough in the understanding and treatment of Alzheimer's disease, a terrible affliction affecting millions of people and their families around the world,” says Michael Sipser, dean of MIT’s School of Science. “Our MIT scientists have opened the door to an entirely new direction of research on this brain disorder and the mechanisms that may cause or prevent it. I find it extremely exciting.” Brain wave stimulation Alzheimer’s disease, which affects more than 5 million people in the United States, is characterized by beta amyloid plaques that are suspected to be harmful to brain cells and to interfere with normal brain function. Previous studies have hinted that Alzheimer’s patients also have impaired gamma oscillations. These brain waves, which range from 25 to 80 hertz (cycles per second), are believed to contribute to normal brain functions such as attention, perception, and memory. In a study of mice that were genetically programmed to develop Alzheimer’s but did not yet show any plaque accumulation or behavioral symptoms, Tsai and her colleagues found impaired gamma oscillations during patterns of activity that are essential for learning and memory while running a maze. Next, the researchers stimulated gamma oscillations at 40 hertz in a brain region called the hippocampus, which is critical in memory formation and retrieval. These initial studies relied on a technique known as optogenetics, co-pioneered by Boyden, which allows scientists to control the activity of genetically modified neurons by shining light on them. Using this approach, the researchers stimulated certain brain cells known as interneurons, which then synchronize the gamma activity of excitatory neurons. After an hour of stimulation at 40 hertz, the researchers found a 40 to 50 percent reduction in the levels of beta amyloid proteins in the hippocampus. Stimulation at other frequencies, ranging from 20 to 80 hertz, did not produce this decline. Tsai and colleagues then began to wonder if less-invasive techniques might achieve the same effect. Tsai and Emery Brown, the Edward Hood Taplin Professor of Medical Engineering and Computational Neuroscience, a member of the Picower Institute, and an author of the paper, came up with the idea of using an external stimulus — in this case, light — to drive gamma oscillations in the brain. The researchers built a simple device consisting of a strip of LEDs that can be programmed to flicker at different frequencies. Using this device, the researchers found that an hour of exposure to light flickering at 40 hertz enhanced gamma oscillations and reduced beta amyloid levels by half in the visual cortex of mice in the very early stages of Alzheimer’s. However, the proteins returned to their original levels within 24 hours. The researchers then investigated whether a longer course of treatment could reduce amyloid plaques in mice with more advanced accumulation of amyloid plaques. After treating the mice for an hour a day for seven days, both plaques and free-floating amyloid were markedly reduced. The researchers are now trying to determine how long these effects last. Furthermore, the researchers found that gamma rhythms also reduced another hallmark of Alzheimer’s disease: the abnormally modified Tau protein, which can form tangles in the brain. “What this study does, in a very carefully designed and well-executed way, is show that gamma oscillations, which we have known for a long time are linked to cognitive function, play a critical role in the capacity of the brain to clean up deposits,” says Alvaro Pascual-Leone, a professor of neurology at Harvard Medical School who was not involved in the research. “That’s remarkable and surprising, and it opens up the exciting prospect of possible translation to application in humans.” Tsai’s lab is now studying whether light can drive gamma oscillations in brain regions beyond the visual cortex, and preliminary data suggest that this is possible. They are also investigating whether the reduction in amyloid plaques has any effects on the behavioral symptoms of their Alzheimer’s mouse models, and whether this technique could affect other neurological disorders that involve impaired gamma oscillations. Two modes of action The researchers also performed studies to try to figure out how gamma oscillations exert their effects. They found that after gamma stimulation, the process for beta amyloid generation is less active. Gamma oscillations also improved the brain’s ability to clear out beta amyloid proteins, which is normally the job of immune cells known as microglia. “They take up toxic materials and cell debris, clean up the environment, and keep neurons healthy,” Tsai says. In Alzheimer’s patients, microglia cells become very inflammatory and secrete toxic chemicals that make other brain cells more sick. However, when gamma oscillations were boosted in mice, their microglia underwent morphological changes and became more active in clearing away the beta amyloid proteins. “The bottom line is, enhancing gamma oscillations in the brain can do at least two things to reduced amyloid load. One is to reduce beta amyloid production from neurons. And second is to enhance the clearance of amyloids by microglia,” Tsai says. The researchers also sequenced messenger RNA from the brains of the treated mice and found that hundreds of genes were over- or underexpressed, and they are now investigating the possible impact of those variations on Alzheimer’s disease. The research was funded by the JPB Foundation, the Cameron Hayden Lord Foundation, a Barbara J. Weedon Fellowship, the New York Stem Cell Foundation Robertson Award, the National Institutes of Health, the Belfer Neurodegeneration Consortium, and the Halis Family Foundation. (Comment on this)
1:59p	Printable electronics The next time you place your coffee order, imagine slapping onto your to-go cup a sticker that acts as an electronic decal, letting you know the precise temperature of your triple-venti no-foam latte. Someday, the high-tech stamping that produces such a sticker might also bring us food packaging that displays a digital countdown to warn of spoiling produce, or even a window pane that shows the day’s forecast, based on measurements of the weather conditions outside. Engineers at MIT have invented a fast, precise printing process that may make such electronic surfaces an inexpensive reality. In a paper published today in Science Advances, the researchers report that they have fabricated a stamp made from forests of carbon nanotubes that is able to print electronic inks onto rigid and flexible surfaces. A. John Hart, the Mitsui Career Development Associate Professor in Contemporary Technology and Mechanical Engineering at MIT, says the team’s stamping process should be able to print transistors small enough to control individual pixels in high-resolution displays and touchscreens. The new printing technique may also offer a relatively cheap, fast way to manufacture electronic surfaces for as-yet-unknown applications. “There is a huge need for printing of electronic devices that are extremely inexpensive but provide simple computations and interactive functions,” Hart says. “Our new printing process is an enabling technology for high-performance, fully printed electronics, including transistors, optically functional surfaces, and ubiquitous sensors.” Sanha Kim, a postdoc in MIT’s department of Mechanical Engineering, is the lead author, and Hart is the senior author. Their co-authors are Hossein Sojoudi, a postdoc in mechanical engineering and chemical engineering; Hangbo Zhao and Dhanushkodi Mariappan, graduate students in mechanical engineering; Gareth McKinley, the School of Engineering Professor of Teaching Innovation; and Karen Gleason, professor of chemical engineering and MIT’s associate provost. A stamp from tiny pen quills There have been other attempts in recent years to print electronic surfaces using inkjet printing and rubber stamping techniques, but with fuzzy results. Because such techniques are difficult to control at very small scales, they tend to produce “coffee ring” patterns where ink spills over the borders, or uneven prints that can lead to incomplete circuits. “There are critical limitations to existing printing processes in the control they have over the feature size and thickness of the layer that’s printed,” Hart says. “For something like a transistor or thin film with particular electrical or optical properties, those characteristics are very important.” Hart and his team sought to print electronics much more precisely, by designing “nanoporous” stamps. (Imagine a stamp that’s more spongy than rubber and shrunk to the size of a pinky fingernail, with patterned features that are much smaller than the width of a human hair.) They reasoned that the stamp should be porous, to allow a solution of nanoparticles, or “ink,” to flow uniformly through the stamp and onto whatever surface is to be printed. Designed in this way, the stamp should achieve much higher resolution than conventional rubber stamp printing, referred to as flexography. Kim and Hart hit upon the perfect material to create their highly detailed stamp: carbon nanotubes — strong, microscopic sheets of carbon atoms, arranged in cylinders. Hart’s group has specialized in growing forests of vertically aligned nanotubes in carefully controlled patterns that can be engineered into highly detailed stamps. “It’s somewhat serendipitous that the solution to high-resolution printing of electronics leverages our background in making carbon nanotubes for many years,” Hart says. “The forests of carbon nanotubes can transfer ink onto a surface like massive numbers of tiny pen quills.” Printing circuits, roll by roll To make their stamps, the researchers used the group’s previously developed techniques to grow the carbon nanotubes on a surface of silicon in various patterns, including honeycomb-like hexagons and flower-shaped designs. They coated the nanotubes with a thin polymer layer (developed by Gleason’s group) to ensure the ink would penetrate throughout the nanotube forest and the nanotubes would not shrink after the ink was stamped. Then they infused the stamp with a small volume of electronic ink containing nanoparticles such as silver, zinc oxide, or semiconductor quantum dots. The key to printing tiny, precise, high-resolution patterns is in the amount of pressure applied to stamp the ink. The team developed a model to predict the amount of force necessary to stamp an even layer of ink onto a substrate, given the roughness of both the stamp and the substrate, and the concentration of nanoparticles in the ink. To scale up the process, Mariappan built a printing machine, including a motorized roller, and attached to it various flexible substrates. The researchers fixed each stamp onto a platform attached to a spring, which they used to control the force used to press the stamp against the substrate. “This would be a continuous industrial process, where you would have a stamp, and a roller on which you’d have a substrate you want to print on, like a spool of plastic film or specialized paper for electronics,” Hart says. “We found, limited by the motor we used in the printing system, we could print at 200 millimeters per second, continuously, which is already competitive with the rates of industrial printing technologies. This, combined with a tenfold improvement in the printing resolution that we demonstrated, is encouraging.” After stamping ink patterns of various designs, the team tested the printed patterns’ electrical conductivity. After annealing, or heating, the designs after stamping — a common step in activating electronic features — the printed patterns were indeed highly conductive, and could serve, for example, as high-performance transparent electrodes. Going forward, Hart and his team plan to pursue the possibility of fully printed electronics. “Another exciting next step is the integration of our printing technologies with 2-D materials, such as graphene, which together could enable new, ultrathin electronic and energy conversion devices,” Hart says. This research was supported, in part, by the National Science Foundation and the MIT Energy Initiative. (Comment on this)
2:50p	Agitating the aluminum pot Industrial aluminum slabs are typically produced by blending small amounts of copper or manganese in a reservoir of molten aluminum that is rapidly cooled, a process known as direct-chill casting. Variations in the way these elements solidify can yield uneven results that weaken the final product, with castings sometimes ending on the scrap heap. Controlling the distribution of strengthening elements to aluminum throughout a casting is thus key to reducing waste and improving product reliability. Over the past three years, MIT assistant professor of metallurgy Antoine Allanore and his student Samuel R. Wagstaff PhD ’16 developed a new process that uses a turbulent jet to reduce this uneven distribution in aluminum alloy structures by 20 percent. The researchers were able to pinpoint a single number — the “macrosegregation index” — that quantifies the difference between the ideal chemical makeup and the actual chemical makeup at specific points in the solidification process. “We have now tested the technology all along the supply chain, and we did confirm that the 20 percent improvement in macrosegregation index was good enough to allow further increase in productivity,” Allanore says. Wagstaff’s and Allanore’s experimental results and theoretical explanations on direct-chill aluminum processing are published in a pair of articles in the journal Metallurgical and Materials Transactions B, with a third pending publication. The work was done in collaboration with global aluminum processor Novelis, with all the experiments taking place at Novelis Solatens Technology Center in Spokane, Washington; some aspects of the research have been patented. Fighting unbalanced structures Macrosegregation is the uneven distribution of alloying elements within a solidified aluminum part, creating, for example, copper-poor regions. This is most likely to occur in the center of a casting, where it remains hidden until the casting is reprocessed for another use such as rolling a thick slab into a flat sheet. These unbalanced structures can form on a scale from several fractions of an inch to several yards and they can lead to cracking, shearing or other mechanical failure of the material. This issue is particularly significant as industry moves toward faster production schedules and larger sheet metal runs — for example, parts for pickup trucks and airplane wings. Greater emphasis on aluminum recycling also poses issues where the composition of secondary elements may be unpredictable. “Analyzing the structure, and in particular the presence of solid grains, formed as the aluminum alloy turns from liquid to solid is difficult because you cannot see through aluminum, and the material is rapidly cooled from 700 degrees Celsius (1,292 degrees Fahrenheit), and differently sized grains are moving as the aluminum solidifies at the rate of about 2 to 3 inches per minute, Allanore says. The problem is typically a lack of the alloying element near the center of the solidifying slab or ingot. “It’s a very perverse situation in the sense that from the outside the solid slab could look very nice, ready to go to the next treatment, and it’s only later on that you discover that there was this defect in a section, or in an area, which basically means a huge loss of productivity for the entire supply chain,” Allanore explains. Making uniform alloys “In our experiments, we did some specific tests at full scale to quench, so to basically sample the molten metal as it’s cast, and we’ve seen grains anywhere between 10 microns up to 50 microns, and those grains are, according to our development, the ones responsible for macrosegregation,” Allanore says. Their solution is inserting a jet stream to recirculate the hot liquid so those grains get redistributed uniformly as opposed to accumulating in one region of the ingot. “It’s like a hose of water in a swimming pool,” he explains. “From a purely fluid mechanics perspective, the mixture is homogeneous. It’s just a full, complete mixture of the alloying elements and aluminum.” “The introduction of the jet induced a completely different recirculation of the grains and therefore you get different microstructure, all along the section. It’s not just on the edges or not just in the center, it’s really across the entire section,” Allanore says. The researchers were able to calculate the optimal jet power needed for the most common aluminum alloys, and then tested their predictions. “Professor Allanore’s work is an excellent example of application of solidification theory to solution of a real world industrial problem,” says Merton C. Flemings, the Toyota Professor Emeritus of Materials Processing at MIT. Steeped in metal work Sam Wagstaff, lead author of the three papers with Allanore, finished his doctorate at MIT in September after just three years and now works for Novelis in Sierre, Switzerland. “The reason why this project is successful is, of course, because of Sam Wagstaff,” Allanore says. “He’s been an amazing graduate student.” Wagstaff, 27, is a great-grandson of George Wagstaff, and grandson of William Wagstaff, whose Spokane, Wash., area machine shop grew into Wagstaff Inc., which specializes in the chillers used to produce solid aluminum alloys from molten liquid (but which was not involved in this research). Sam Wagstaff’s father, Robert, works for Novelis, and Sam himself first worked for Novelis at age 14. After he earned his bachelor’s degree in mechanical and aerospace engineering at Cornell University, Novelis offered Wagstaff the opportunity to pursue a PhD to help the company solve the problem of macrosegregation by developing a method to stir aluminum. “Being in an environment [in which Novelis is] okay with me taking the project and at the same time MIT letting me take it wherever I felt it needed to go, it ended up being an amazing experience,” Wagstaff says. “I don’t know of too many other companies or places that would have let me grow as much as I did, and for that I’m really grateful,” Wagstaff says. “The problem you have with aircraft-grade or aerospace-grade plate is you have very significant macrosegregation regions in the center of that plate, so you have drastic drops in mechanical properties in the very center,” Wagstaff says. “Our research started with the idea we want to be able to stop macrosegregation,” Wagstaff says. Instead of studying many different ways to stir aluminum, Wagstaff says he and Allanore proposed developing a mixing criterion just like those used in chemical engineering. Because the worst problems were occurring in the center of ingots, with up to 20 percent variation in composition there, that became the focus of the research, he says. “We knew we could figure out how to mix things up and we could stir things around, but being able to compare A to B to C would have been really difficult, and so that’s where the macrosegregation index came from. That’s just a numerical scheme that we invented to compare type A mixing to type B mixing to type C mixing, so then we can somehow relate all of the different mixing parameters together to say this kind of mixing is better,” he says. The index punishes ingots depending on their deviation from the desired composition as a function of their distance from the center and a lower index number represents higher quality. The solution was to design a jet that would work with existing direct-chill casting machines. “All we did was change the jet power as a function of diameter using a magnetic pump to control speed, power and velocity of that jet throughout the casting,” Wagstaff says. “The great thing about jets is they are pretty well defined, we understand how they expand, how their forces are distributed as a function of time, as a function of space, so they are a relatively easy phenomenon to study. We ended up coupling magnets with the jet and built a non-contact magnetic pump to generate our jet.” Optimizing jet power The team developed formulas to calculate how fast and how strong the jet power has to be to prevent clustering of defects in the center for a given set of alloying elements and mold dimensions. While the papers report improvement of 20 percent, Wagstaff says with optimization of the jet pump, improvement up to 60 percent is possible. Small variations in individual grains [microsegregation] can sometimes be healed by reheating the aluminum casting, but when large-scale uneven distribution occurs with a weak centerline, it is impractical because it would take far too long for the copper or other alloying element to migrate through the material. Materials science graduate student Carolyn M. Joseph in Allanore’s group is studying how these grains that cause macrosegregation form in an aluminum alloy that is 4.5 percent copper by weight. Using the new jet stirring technique, she takes samples during casting near the two-phase region (slurry), in which grains of solid metal circulate in the liquid aluminum. She does this by rapidly cooling the metal at various locations along the ingot as it is being formed, and she studies the samples under a microscope for differences in grain size, shape, composition and distribution. “The size of your solid structure, how fine or coarse it is, depends on the rate at which you’re cooling it,” Joseph explains. Microscopic images she made of samples showing large grain structures are evidence those grains were solid in the slurry before it was rapidly cooled, she says. “In the liquid, they are mixed, the cooper and aluminum form a solution, but when you go from liquid to solid, there is segregation of the alloying elements,” Joseph says. Grains that form early are depleted in copper and tend to cluster in the center of a slab. “The advantage of this is that it’s an intermediate type of snapshot. Instead of looking at the final cross-section and studying its grain size and composition, we can see it at an intermediate stage, while it’s a semi-solid mixture, what’s going on,” explains Joseph, who is working toward a master’s degree in materials science. “On the macroscale, you want an even distribution of copper, and that’s what Sam’s mixing has been able to achieve,” she says. Role in recycling Allanore believes the jet-stirred aluminum process can also play a role in recycling. “Not all recycled products of aluminum are the same, because some of them come from a former plane and some of them come from a former beverage can, and these are two different alloys,” he says. “So when it comes to society being able to recycle and make new aluminum products of high-quality, we can clearly see that there is an issue of how are we going to deal with those alloying elements. The work that we have done, I believe, is one example of how we can modify existing technologies so that they become more ready to have more recycled material without compromising at the end with the quality of the product that you are making.” “By doing the proper amount of theoretical work and experimental work and working in collaboration, hand-in-hand with industry, we can find these type of solutions that allow higher productivity, more recycled materials which means less energy and less environmental impact, something very exciting,” Allanore says. (Comment on this)
4:25p	Experts gather at MIT to urge more innovation in health care delivery Nearly 200 leading health care scholars, practitioners, and providers gathered on Nov. 17 and 18 to discuss innovations in health care delivery and explore how research and evidence-informed policymaking can improve the health of vulnerable populations in the United States. “Just as randomized controlled trials transformed modern medicine, there is an exciting movement in health policy focused on the use of rigorous evaluation to improve the way we deliver health care,” said Quentin Palfrey, executive director of J-PAL North America, a regional office of MIT’s Abdul Latif Jameel Poverty Action Lab, which hosted the conference. “It was inspiring to connect with so many passionate, committed people interested in building this movement.” J-PAL North America seeks to reduce poverty by ensuring that policy is informed by scientific research and works to improve social programs by running randomized controlled trials, disseminating policy lessons, and building the evaluation capacity of governments and non-profits. In the conference keynote address, Atul Gawande, a surgeon, writer, and leading public health scholar, called for simple, scalable, and evidence-informed solutions to improve health care delivery, stating that “the role of evidence will only increase” in the future. Highlighting a “lack of execution”, Gawande cited research finding that among Americans and Europeans who died before the age of 75, at least 30 percent would not have died had they received appropriate medical care for their conditions. Gawande described the work of Ariadne Labs, the health systems innovation center he directs, in developing, evaluating, and scaling checklists that are transforming surgical and childbirth practices globally. J-PAL North America Scientific Director Amy Finkelstein, a professor of economics at MIT, discussed her landmark study of the impact of Medicaid expansion, which has shaped the policy conversation in the United States about Medicaid coverage. The so-called Oregon Health Insurance Experiment capitalized on a lottery run by the State of Oregon to allocate scarce Medicaid expansion slots to measure the impact of newly acquired Medicaid coverage. Over a one- to two-year time horizon, the study found (among other results) that Medicaid coverage caused across-the-board increases in health care utilization — primary care, emergency room visits, hospitalization, and drugs — as well as decreased financial strain. Finkelstein applauded the growing use of research leveraging a similar randomized design to examine other high-priority issues in health care delivery, including the effectiveness of coordinated care for high-need patients, bundled payments, and workplace wellness programs. Ashish Jha of Harvard University spoke about the power of evidence in reforming U.S. health care. Jha called for modernization of health care delivery, increased investment towards innovation, and further research into the impact of new health care practices. Of the $3.2 trillion that is spent on health care annually, Jha noted that only a tiny fraction is available to support innovation and experimentation in delivery. Highlighting a potentially cost-effective approach, Wes Yin of the University of California at Los Angeles presented new research that found a simple letter reminding individuals to sign up for health insurance caused an 18 percent increase in enrollment (1.8 percentage points), and attracted younger and healthier individuals into the insurance market. Calling it “the lightest touch,” Yin underscored the importance of behavioral factors in insurance decisions. Katherine Baicker of Harvard University, Tamar Bauer of the Nurse-Family Partnership, and Joseph Doyle of the MIT Sloan School of Management discussed ongoing large-scale evaluations of flagship programs to provide care coordination for high-need patients and nurse-home visits for first-time, low-income mothers.   Providing a philanthropic perspective on research, Katherine Hempstead of the Robert Wood Johnson Foundation discussed how funders use research and suggested topics where more rigorous evidence is needed, including the impact of gaining and losing health insurance coverage, supporting consumers with insurance take-up and plan choice, insurance benefit design, interventions targeting high-need patients, treatment for substance-use disorders, and paid sick time/family leave, among others. Representatives from the four winners of J-PAL’s recent Health Care Delivery Innovation Competition described their efforts to rigorously test innovative approaches to connect recently released inmates with substance-use disorder treatment to curb recidivism, provide financial incentives to engage disconnected patients, and integrate health care and social services to address social determinants of health. The conference also included a workshop session between academics, policymakers, and practitioners to support the development of new research around innovative health care delivery models, including novel breast cancer screening tools and pediatrician-assisted post-partum counseling during newborn well visits, among others. J-PAL North America was established with generous support from the Alfred P. Sloan Foundation and the Laura and John Arnold Foundation. The conference was hosted by J-PAL’s U.S. Health Care Delivery Initiative, which receives support from the Laura and John Arnold Foundation and the Robert Wood Johnson Foundation. (Comment on this)

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