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  • richardmitnick 7:09 am on April 25, 2017 Permalink | Reply
    Tags: 4-in-1 catalyst, , Brown, , Researchers develop eco-friendly   

    From Brown: “Researchers develop eco-friendly, 4-in-1 catalyst” 

    Brown University
    Brown University

    April 24, 2017
    Kevin Stacey
    kevin_stacey@brown.edu
    401-863-3766

    1
    More reactions, less waste. Catalysts like this new one developed at Brown University might help make industrial chemistry more sustainable. Sun lab / Seto lab / Brown University

    Brown University researchers have developed a new composite catalyst that can perform four separate chemical reactions in sequential order and in one container to produce compounds useful in making a wide range of pharmaceutical products.

    “It normally takes multiple catalysts to carry out all of the steps of this reaction,” said Chao Yu, a post-doctoral researcher at Brown who co-led the work with graduate student Xuefeng Guo. “But we found a single nanocatalyst that can perform this multistep reaction by itself.”

    The research, described in the Journal of the American Chemical Society, was a collaboration between the labs of Brown professors Christopher Seto and Shouheng Sun, who are coauthors of the paper.

    The work was done, the researchers said, with an eye toward finding ways of making the chemical industry more environmentally sustainable. Multi-reaction catalysts like this one are a step toward that goal.

    “If you’re running four different reactions separately, then you’ve got four different steps that require solvents and starting materials, and they each leave behind waste contaminated with byproducts from the reaction,” Seto said. “But if you can do it all in one pot, you can use less solvent and reduce waste.”

    The team made their new catalyst by growing silver-palladium nanoparticles on the surface of nanorods made of oxygen-deficient tungsten-oxide (tungsten-oxide with a few of its oxygen atoms missing). The researchers showed that it could catalyze the series of reactions needed to convert common starting materials formic acid, nitrobenzene and an aldehyde into a benzoxazole, which can be used to make antibacterials, antifungals and NSAID painkillers. The researchers showed that the catalyst could also be used to create another compound, quinazoline, which is used in a variety of anti-cancer drugs.

    Experiments showed that the catalyst could perform the four reactions with a nearly quantitative yield — meaning it produces the maximum possible amount of product for a given amount of starting materials. The reactions were performed at a lower temperature, in a shorter amount of time, and using solvents that are more environmentally friendly than those normally used for these reactions.

    “The temperature we used to synthesize this product is around 80 degrees Celsius,” Guo said. “Normally the reaction happens around 130 degrees and you need to run the reaction for one or two days. But we can get a similar yield at 80 degrees in eight hours.”

    The new catalyst also is able to make the benzoxazole compounds using starting materials that are more environmentally benign than those generally used. The reaction chain requires a hydrogen source for its initial step. That source could be pure hydrogen gas, which is difficult to store and transport, or it could be extracted from a chemical compound. A compound called ammonia borane is often used for this purpose, but the new catalyst enables formic acid to be used instead, which is “cheaper, greener and less toxic,” Yu said.

    And while many catalysts tested in these reactions cannot be used more than once without severely damaging their efficiency, the researchers were able to use the new catalyst up to five times with little drop-off in reaction yield.

    Sun says that studies like this one represents an emerging line of research in greener chemistry.

    “Normally in catalysis we’re doing one reaction at a time, with a different catalyst for each reaction” said Shouheng Sun, a professor of chemistry at Brown. “But there’s growing interest in coming up with catalysts that can perform multiple reactions in one pot, and that’s what we’ve done here.”

    The work was supported in part by the U.S. Army Research Laboratory and the U.S. Army Research Office (W911NF-15-1-0147).

    See the full article here .

    Please help promote STEM in your local schools.

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    Welcome to Brown

    Brown U Robinson Hall
    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

    Undergraduates pursue bachelor’s degrees in more than 70 concentrations, ranging from Egyptology to cognitive neuroscience. Anything’s possible at Brown—the university’s commitment to undergraduate freedom means students must take responsibility as architects of their courses of study.

     
  • richardmitnick 3:41 pm on February 4, 2017 Permalink | Reply
    Tags: , “Giant acceleration of diffusion” or GAD, , Brown, Brownian motion, , ,   

    From Brown: “Research pushes concept of entropy out of kilter” 

    Brown University
    Brown University

    [THIS POST IS DEDICATED TO EBM, READY TO ROCK THE CAMPUS]

    February 2, 2017
    Kevin Stacey
    kevin_stacey@brown.edu
    401-863-3766

    Entropy, the measure of disorder in a physical system, is something that physicists understand well when systems are at equilibrium, meaning there’s no external force throwing things out of kilter. But new research by Brown University physicists takes the idea of entropy out of its equilibrium comfort zone.

    The research, published in Physical Review Letters, describes an experiment in which the emergence of a non-equilibrium phenomenon actually requires an entropic assist.

    1
    DNA drag race. Fluorescent stained DNA molecules make their way across of fluid channel pocked with tiny pits. The pits act as “entropic barriers.”
    Stein Lab / Brown University

    “It’s not clear what entropy even means when you’re moving away from equilibrium, so to have this interplay between a non-equilibrium phenomenon and an entropic state is surprising,” said Derek Stein, a Brown University physicist and co-author of the work. “It’s the tension between these two fundamental things that is so interesting.”

    The phenomenon the research investigated is known as “giant acceleration of diffusion,” or GAD. Diffusion is the term used to describe the extent to which small, jiggling particles spread out. The jiggling refers to Brownian motion, which describes the random movement of small particles as a result of collisions with surrounding particles. In 2001, a group of researchers developed a theory of how Brownian particles would diffuse in a system that was pushed out of equilibrium.

    Imagine jiggling particles arranged on a surface with undulating bumps like a washboard. Their jiggle isn’t quite big enough to enable the particles to jump over the bumps in the board, so they don’t diffuse much at all. However, if the board were tilted to some degree (in other words, moved out of equilibrium) the bumps would become easier to jump over in the downward-facing direction. As tilt begins to increase, some particles will jiggle free of the washboard barriers and run down the board, while others will stay put. In physics terms, the particles have become more diffusive — more spread-out — as the system is moved out of equilibrium. The GAD theory quantifies this diffusivity effect and predicts that as tilt starts to increase, diffusivity accelerates. When the tilt passes the point where all the particles are able to jiggle free and move down the washboard, then diffusivity decreases again.

    The theory is important, Stein says, because it’s one of only a few attempts to make solid predictions about how systems behave away from equilibrium. It’s been tested in a few other settings and has been found to make accurate predictions.

    But Stein and his team wanted to test the theory in an unfamiliar setting — one that introduces entropy into the mix.

    For the experiment, Stein and his colleagues placed DNA strands into nanofluidic channels — essentially, tiny fluid-filled hallways through which the molecules could travel. The channels were lined however with nanopits — tiny rectangular depressions that create deep spots within the relatively narrower channels. At equilibrium, DNA molecules tend to arrange themselves in disordered, spaghetti-like balls. As a result, when a molecule finds its way into a nanopit where it has more room to form a disordered ball, it tends to stay stuck there. The pits can be seen as being somewhat like the dips between bumps on the theoretical GAD washboard, but with a critical difference: The only thing actually holding the molecule in the pit is entropy.

    “This molecule is randomly jiggling around in the pit — randomly selecting different configurations to be in — and the number of possible configurations is a measure of the molecule’s entropy,” Stein explained. “It could, at some point, land on a configuration that’s thin enough to fit into the channel outside the pit, which would allow it to move from one pit to another. But that’s unlikely because there are so many more shapes that don’t go through than shapes that do. So the pit becomes an ‘entropic barrier.’”

    Stein and his colleagues wanted to see if the non-equilibrium GAD dynamic would still emerge in a system where the barriers were entropic. They used a pump to apply pressure to the nanofluidic channels, pushing them out of equilibrium. They then measured the speeds of each molecule to see if GAD emerged. What they saw was largely in keeping with the GAD theory. As the pressure increased toward a critical point, the diffusivity of the molecules increased — meaning some molecules zipped across the channel while others stayed stuck in their pits.

    “It wasn’t at all clear how this experiment would come out,” Stein said. “This is a non-equilibrium phenomenon that requires barriers, but our barriers are entropic and we don’t understand entropy away from equilibrium.”


    Anastasios Matzavinos, a professor of applied math at Brown, developed computer simulations of the experiment to help understand the forces at play.

    The fact that the barriers remained raises interesting questions about the nature of entropy, Stein says.

    “Non-equilibrium and entropy are two concepts that are kind of at odds, but we show a situation in which one depends on the other,” he said. “So what’s the guiding principle that tells what the tradeoff is between the two? The answer is: We don’t have one, but maybe experiments like this can start to give us a window into that.”

    In addition to the more profound implications, there may also be practical applications for the findings, Stein says. The researchers showed that they could estimate the tiny piconewton forces pushing the DNA forward just by analyzing the molecules’ motion. For reference, one newton of force is roughly the weight of an average apple. A piconewton is one trillionth of that.

    The experiment also showed that, with the right amount of pressure, the diffusivity of the DNA molecules was increased by factor of 15. So a similar technique could be useful in quickly making mixtures. If such a technique were developed to take advantage of GAD, it would be a first, Stein says.

    “No one has ever harnessed a non-equilibrium phenomenon for anything like that,” he said. “So that would certainly be an interesting possibility.”

    The work was led by Stein’s graduate student Daniel Kim. Co-authors were Clark Bowman, Jackson T. Del Bonis-O’Donnell and Anastasios Matzavinos, all from Brown. The work was supported by the National Science Foundation.

    See the full article here .

    Please help promote STEM in your local schools.

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    Stem Education Coalition
    Welcome to Brown

    Brown U Robinson Hall
    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

    Undergraduates pursue bachelor’s degrees in more than 70 concentrations, ranging from Egyptology to cognitive neuroscience. Anything’s possible at Brown—the university’s commitment to undergraduate freedom means students must take responsibility as architects of their courses of study.

     
  • richardmitnick 11:17 pm on December 23, 2016 Permalink | Reply
    Tags: Brown, Galápagos, Jon Witman   

    From Brown: “Galápagos waters illustrate ecological drama of climate change” 

    Brown University
    Brown University

    December 21, 2016
    David Orenstein

    1
    Algae cage
    Brown biology graduate student Robbie Lamb cages off an area of algae as part of an experiment to investigate patterns of grazing by herbivorous fish and urchins. Images: Jon Witman

    Brown marine biologist Jon Witman and students have spent much of 2016 in the Galápagos Islands, continuing years of chronicling the complex and dramatic ecological changes wrought by the increasingly volatile El Niño – La Niña cycle.

    When Brown University Professor Jon Witman returned this year to a small patch of coral off the Galápagos Islands that he had first marked off for study in 2000, he saw virtually nothing — and that told him a lot. An underwater ecosystem that had been teeming with diverse life 16 years ago was now a barren patch, an apparent victim of increasingly strong El Niño weather systems amid global climate change.

    “The 2015-16 El Niño was exceptionally strong,” Witman said. “Climatologists predict that the frequency of strong El Niños will increase with climate change.”

    2
    Degraded diversity
    The same patch of coral in 2000 (left) and 2016 (right) shows a severe decline in its biodiversity. Image: Jon Witman

    This year, with funding from the National Science Foundation, Witman has made several expeditions with graduate and undergraduate students to witness the effects of the latest El Niño. He journeyed to the Galápagos in January, March and again last summer, and he’s there again now through February on sabbatical. He celebrated Thanksgiving with graduate student Robert Lamb and colleagues at the Charles Darwin Research Station with a holiday meal of ahi tuna, cornbread, pumpkin soup and baked sweet potato.

    It’s been a busy year.

    “During this past year of fieldwork in Galápagos, there were so many surprises that we could hardly keep up with all the effects of the strong El Niño,” Witman said.

    Amid the warmest water at the beginning of the year, for example, Lamb discovered the emergence of a skin-wasting disease in the reef fishes that he studies.

    “We were surprised to find this novel wildlife disease running rampant in at least 20 different species,” Lamb said. “Such outbreaks of disease are one of the least understood but potentially devastating manifestations of climate change.”

    The disease abated later in the year as the cooler La Niña took over from El Niño. But other changes associated with the warm water were apparent, too: rampant grazing of algae by sea urchins, for example, and the ominous emergence of mats of cyanobacteria.

    “The cyanobacteria is a species that we haven’t seen at these sites in all the time we’ve been working there,” said Fiona Beltram, a Brown junior from Glocester, R.I., who has been a member of the Witman lab for two years. “I’m interested in determining if the cyanobacteria cover leads to bleaching in coralline algae, which are important foundation species on the Galápagos reefs.”

    Among the responsibilities assigned to Beltram, who joined the team in the Galápagos this summer, was to set up experiments to study the cyanobacteria. She also helped to measure what’s been going on at about two dozen specific areas, or “transects,” that Witman has been monitoring for years.

    “I’ve been really passionate about marine science since I was a kid, so it was incredibly exciting to travel down there and actively contribute to fieldwork,” Beltram said. “It’s also just a beautiful place, especially underwater.”

    A cycle out of balance

    3
    Bleached and barren…
    Warm El Niño waters harm the corals.

    4
    …But barnacles grow in
    The colder La Niña encouranges the growth of barnacles, a major food source, on the corals.

    The question, though, is whether that beautiful place will last. Over the years, Witman said, the El Niño – La Niña cycle has yielded a pattern that alternately seems to destroy, but at other times redeem the subtidal ecosystem’s stunning biodiversity.

    “Corals bleach and sometimes die during the extreme temperature variability from the high temperatures during El Niño and the low temperatures of the ensuing La Niña,” he said. “But as La Niña brings more productive water, barnacles reproduce and settle on the stressed corals and all over the bottom.”

    That deteriorates the corals further, but the barnacles serve as food for many other species, promoting a rebound in the undersea life. But the more Witman and his team dives in — literally and figuratively — the more they see that the long-term trend is worrisome.

    “With continued El Niños, the Galápagos subtidal ecosystem may be shifting to a system with more barnacles and their predators and fewer corals,” he said. “I’m concerned, however, that this may be a lower diversity system, which may make it less resilient to future climate shocks.”

    Who eats whom

    At least for now, the food webs in the area remain full of characters, all of whom have a role to be studied. Lamb and Witman spent November formulating experiments to test hypotheses about what species are grazing on algae and how much. They deployed cages that selectively exclude herbivorous fishes or sea urchins, the two major groups of herbivores in this ecosystem.

    “We want to understand the individual and combined ecological roles of these two important groups,” Lamb said. “Because of their different life histories and feeding strategies, they may be vastly different in how they respond to changes in the environment such as increased wave turbulence from storms generated during El Niño.”

    Because algae serve as the basis of much of an ecosystem’s productivity, the answers to these questions come with profound implications. Too much algae consumption can undermine the food supply for other species and reduce biodiversity.

    5
    Survival rivals
    A triggerfish (top) swims along with its rival the hogfish, which will take urchins out of its mouth.

    The food webs play out in complicated ways, Witman has found, as species fight to survive. As it did for Darwin, the Galápagos still deliver plenty of new lessons about how nature works — the critical role of triggerfish, for example.

    “Our research has discovered that triggerfish are keystone predators,” Witman said. “They prey heavily on sea urchins and consequently increase the productivity of the marine ecosystem by releasing algae from consumption by sea urchins. Sea urchins are like underwater lawnmowers mowing down bottom-dwelling algae; anything that changes their consumption of algae has a dramatic effect on productivity. We found that Spanish hogfish slow the rate of triggerfish predation on sea urchins by trying to take the urchin out of the triggerfish’s mouth.”

    Around the world

    As Witman and his students — over the years he’s trained nine undergraduates, six doctoral students and three postdoctoral scholars in the Galápagos alone — continue to piece together how subtidal life is changing with climate in the islands, he’s also working globally. He took a side trip in early December, for example, to check on another of his regular spots: coral reefs near Easter Island, far off the coast of Chile.

    When he’s home in New England, Witman can often be found in the Gulf of Maine at Cashes Ledge, the largest and deepest offshore kelp forest in the North Atlantic. There, too, climate change may threaten biodiversity.

    “We are studying the resilience of the kelp forest to warming, as it is such an ecologically important species, and also trying to achieve permanent protection for the spectacular marine communities on Cashes Ledge as a U.S. Marine National Monument,” Witman said.

    Lamb is working concurrently to show how the unique kelp forests on Cashes Ledge are home to some of the healthiest populations of cod and pollock in the southern Gulf of Maine.

    Whether in the warm waters of the South Pacific or the much chillier North Atlantic, the goal is to understand how ocean ecosystems work so that people can help them thrive rather than threatening their survival.

    “Sound management of the oceans requires understanding the roles that key species and biodiversity play in ecosystem functioning,” Witman said. “And, of course, how this is being altered by human disturbance.”

    See the full article here .

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    Welcome to Brown

    Brown U Robinson Hall
    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

    Undergraduates pursue bachelor’s degrees in more than 70 concentrations, ranging from Egyptology to cognitive neuroscience. Anything’s possible at Brown—the university’s commitment to undergraduate freedom means students must take responsibility as architects of their courses of study.

     
  • richardmitnick 10:49 am on December 11, 2016 Permalink | Reply
    Tags: , , Brown, CB chondrites, Grand Tack, , Jupiter would have stirred up the asteroid belt enough to produce the high-impact velocities necessary to form these CB chondrites, NASA's Solar System Exploration Virtual Institute, Southwest Research Institute, Vaporizing iron requires really high-velocity impacts   

    From Brown: “Research offers clues about the timing of Jupiter’s formation” 

    Brown University
    Brown University

    December 9, 2016
    Kevin Stacey
    kevin_stacey@brown.edu
    401-863-3766

    The new study shows that Jupiter had probably reached its present day size by about 5 million years after the first solids in the solar system formed.

    1
    Jupiter is the king of the planets of our solar system. http://cosmobiologist.blogspot.com/2016/02/jupiter-king-of-worlds.html

    A peculiar class of meteorites has offered scientists new clues about when the planet Jupiter took shape and wandered through the solar system.

    Scientists have theorized for years now that Jupiter probably was not always in its current orbit, which is about five astronomical units from the sun (Earth’s distance from the sun is one astronomical unit). One line of evidence suggesting a Jovian migration deals with the size of Mars. Mars is much smaller than planetary accretion models predict. One explanation for that is that Jupiter once orbited much closer to the sun than it does now. During that time, it would have swept up much of the material needed to create supersized Mars.

    But while most scientists agree that giant planets migrate, the timing of Jupiter’s formation and migration has been a mystery. That’s where the meteorites come in.

    Meteorites known as CB chondrites were formed as objects in the early solar system—most likely in the present-day asteroid belt—slammed into each other with incredible speed. This new study, published in the journal Science Advances, used computer simulations to show that Jupiter’s immense gravity would have provided the right conditions for these hypervelocity impacts to occur. That in turn suggests that Jupiter was near its current size and sitting somewhere near the asteroid belt when the CB chondrules were formed, which was about 5 million years after formation of the first solar system solids.

    “We show that Jupiter would have stirred up the asteroid belt enough to produce the high-impact velocities necessary to form these CB chondrites,” said Brandon Johnson, a planetary scientist at Brown University who led the research. “These meteorites represent the first time the solar system felt the awesome power of Jupiter.”

    Strange structures

    Chondrites are a class of meteorites made up of chondrules, tiny spheres of previously molten material, and are among the most common meteorites found on Earth. The CB chondrites are a relatively rare subtype that have long fascinated meteoriticists. Part of what makes the CB chondrites so interesting is that their chondrules all date back to a very narrow window of time in the early solar system.

    “The chondrules in other meteorites give us a range of different ages,” Johnson said. “But those in the CB chondrites all date back to this brief period 5 million years after the first solar system solids.”

    2
    Chondrules found in CB chondrites were formed in ultra-high-speed collisions.
    Alexander Krot, University of Hawai’i Manoa

    But to Johnson, who studies impact dynamics, there is something else interesting about CB chondrites: They contain metallic grains that appear to have been condensed directly from vaporized iron. “Vaporizing iron requires really high-velocity impacts,” Johnson said. “You need to have an impact speed of around 20 kilometers per second to even begin to vaporize iron, but traditional computer models of the early solar system only produce impact speeds of around 12 kilometers per second at the time when the CB chondrites were formed.”

    So Johnson worked with Kevin Walsh of the Southwest Research Institute in Boulder to generate new computer models of the chondrule-forming period—models that include the presence of Jupiter near the present day position of the asteroid belt.

    Gravity boost

    Big planets generate lots of gravity, which can slingshot nearby objects at high speeds. NASA often takes advantage of this dynamic, swinging spacecraft around planets to generate velocity. Walsh and Johnson included in their simulations a scenario of Jupiter’s formation and migration considered likely by many planetary scientists.

    The scenario, known as the Grand Tack (a term taken from sailing), suggests that Jupiter formed somewhere in the outer solar system. But as it accreted its thick atmosphere, it changed the distribution of mass in the gassy solar nebula surrounding it. That change in mass density caused the planet to migrate, moving inward toward the sun to about where the asteroid belt is today. Later, the formation of Saturn created a gravitational tug that pulled both planets back out to where they are today.

    “When we include the Grand Tack in our model at the time the CB chondrites formed, we get a huge spike in impact velocities in the asteroid belt,” Walsh said. “The speeds generated in our models are easily fast enough to explain the vaporized iron in CB chondrites.”

    The most extreme collision in the model was an object with a 90-kilometer diameter slamming into a 300-kilometer body at a speed of around 33 kilometers per second. Such a collision would have vaporized 30 to 60 percent of the larger body’s iron core, providing ample material for CB chondrites.

    The models also show that the increase in impact velocities would have been short-lived, lasting only about 500,000 years or so (a blink of an eye on the cosmic timescale). That short timescale allowed the researchers to conclude that Jupiter formed and migrated at roughly the same time the CB chondrites formed.

    The researchers say that while the study is strong evidence for the Grand Tack migration scenario, it doesn’t necessarily preclude other migration scenarios. “It’s possible that Jupiter formed closer to the sun and then migrated outward, rather than the in then out migration of the Grand Tack,” Johnson said.

    Whatever the scenario, the study provides strong constraints on the timing of Jupiter’s presence in the inner solar system.

    “In retrospect, it seems obvious that you would need something like Jupiter to stir the asteroid belt up this much,” Johnson said. “We just needed to create these models and calculate the impact speeds to connect the dots.”

    Other co-authors on the paper were David Minton (Purdue University), Alexander Krot (University of Hawai’i, Mānoa) and Harold Levison (Southwest Research Institute). Funding was provided by NASA’s Solar System Exploration Virtual Institute (NNA14AB03A). Computer simulations were run on the National Science Foundation’s XSEDE computer cluster.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition
    Welcome to Brown

    Brown U Robinson Hall
    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

    Undergraduates pursue bachelor’s degrees in more than 70 concentrations, ranging from Egyptology to cognitive neuroscience. Anything’s possible at Brown—the university’s commitment to undergraduate freedom means students must take responsibility as architects of their courses of study.

     
  • richardmitnick 6:16 am on December 6, 2016 Permalink | Reply
    Tags: 20S proteasome, , , Brown, New compound targets TB bacterium’s defense against the immune system, Syringolins   

    From Brown: “New compound targets TB bacterium’s defense against the immune system” 

    Brown University
    Brown University

    December 5, 2016
    Kevin Stacey
    401-863-3766

    1
    Rational design
    Researchers have designed a new compound that inhibits a key enzyme in Mycobacterium tuberculosis, which makes the bacterium more susceptible to the human immune system. Sello lab / Brown University

    Developed by chemists at Brown University in conjunction with colleagues at MIT and Cornell, the compound could enable a new drug strategy for treating tuberculosis.

    Part of the reason tuberculosis-causing bacteria are so good at colonizing the human body is that they have defenses against the body’s immune system. A research team led by Brown University chemists has developed a new compound that can take down one of those defenses in Mycobacterium tuberculosis. The researchers are hopeful that the compound could be part of a new drug strategy for treating tuberculosis.

    “Given the increasing resistance of Mycobacterium tuberculosis to drugs, we contemplated the treatment of tuberculosis in a fundamentally different way,” said Jason Sello, associate professor of chemistry at Brown who directed the research. “Instead of seeking conventional drug leads that kill M. tuberculosis directly, we hoped to develop compounds that could render the bacterium susceptible to the immune system. We were successful in designing compounds that make laboratory-grown bacteria sensitive to a chemical produced during the immune response.”

    Kyle Totaro, who recently earned his Ph.D. from Brown, led Sello’s team. They also worked collaboratively with research groups at the Massachusetts Institute of Technology and Weill Cornell Medicine. A paper describing the work is published in the journal ACS Infectious Diseases.

    2
    Jason Sello (left) with Kyle Totaro. No image credit.

    The team’s strategy was to inhibit an enzyme found in M. tuberculosis called the 20S proteasome. It acts like a molecular trash collector, disposing of damaged proteins within the bacterial cell. It specializes in cleaning up proteins damaged by nitric oxide, a chemical produced by the innate immune system to help fight pathogens. The ability of the 20S proteasome to dispose of nitric oxide-damaged proteins helps the bacteria survive within the host.

    To inhibit the proteasome, Sello and his team envisioned reactive compounds that mimic key chemical attributes of its substrates — the proteins that the enzyme normally breaks down. They anticipated that the proteasome would bind these compounds as it does any other protein and that their reactivity would disable the enzyme. With the proteasome disabled, proteins damaged by nitric oxide will accumulate inside the bacteria and cause their death.

    But there was a key problem the researchers needed to contend with. Humans have a very similar system for the degradation of damaged proteins, and inhibition of this system is known to be lethal to cells. So any compound Sello and his team developed would have to selectively disrupt that bacterial proteasome, without significantly affecting the human version.

    To do that, the researchers drew inspiration from nature. A bacterium called Pseudomonas syringae, a pathogen that infects plants, is known to produce compounds called syringolins, which are known to inhibit the plant proteasome by mimicking its substrates. The compounds are also known to inhibit the human proteasome and have promise as anticancer agents. Sello and his team used predictions about how the syringolins bind the human proteasome and knowledge about the substrates of the M. tuberculosis proteasome to design selective inhibitors.

    Research had indicated that syringolins bound and inhibited the human proteasome by mimicking a preferred substrate have a specific chemical residue (valine) at two key positions. Research had also indicated that the bacterial proteasome prefers to degrade proteins having two different chemical residues (tryptophan and glycine) at the same two key positions. So, the researchers predicted that a syringolin analog in which the valine residue was swapped for structures resembling the tryptophan and glycine, the compound would selectively inhibit the bacterial proteasome.

    Sello and his students at Brown synthesized the designed compound as well as others that matched or conflicted with their design model. In turn, their collaborators at MIT systematically assessed the capacities of the compounds to inhibit both the human and bacterial proteasomes in a test tube.

    The team found that the natural syringolin product was 160-fold more specific for the human proteasome. One of the engineered syringolin analogs, in contrast, was 74-fold more specific for the bacterial proteasome.

    “Using this rational design approach and chemical synthesis, we were able to generate selective inhibitors of the M. tuberculosis 20S proteaseome,” Sello said. “In the best case, our engineering of the syringolins increased the inhibition of the bacterial enzyme by 220-fold, yet reduced the reaction with the human enzyme by 99.6 percent. Our success validated both the apparent substrate specificity of the M. tuberculosis proteasome and the structural model for proteasome inhibition by the syringolins.”

    The next step was to see whether the engineered compounds could indeed make bacteria more susceptible to nitric oxide, the chemical produced during the immune response. Sello’s collaborators at the Weill Cornell Medicine added the engineered syringolins to cultures of M. tuberculosis in the presence and absence of a source of nitric oxide. As expected, they found that the bacteria treated with the compounds were highly susceptible to nitric oxide. In keeping with their weak inhibition of the human proteasome, the engineered syringolin did not inhibit the growth of human cell models.

    “We were pleased to have engineered out the toxicity of the syringolins to human cells,” Sello said. That suggested that an engineered syringolin could be safe in humans.” Sello and his colleagues are hopeful that this initial round of testing could lay the groundwork for developing new drugs to treat tuberculosis. “We’ve only modified the syringolins in two ways,” Sello said. “There are many other possibilities for structural modification that could improve potency and other pharmacological properties of the molecules. We can now see a long but feasible pathway towards the development of a novel therapeutic agent for tuberculosis.”

    Sello says it’s plausible that a drug strategy like this one could be used alongside traditional antibiotics.

    “One of the things that’s clear in the treatment of tuberculosis is that combining drugs can be effective,” he said. “So combining a blocker of the bacterium’s defense against the immune system with a traditional antibiotic could be kind of a one-two punch.”

    Other authors on the paper were Dominik Barthelme (MIT), Peter T. Simpson (a Brown Class of 2014 graduate), Xiujiu Jiang, Gang Lin, Carl Nathan (Weill Cornell Medicine) and Robert Sauer (MIT). The work was supported by the Brown University and its Undergraduate Teaching and Research Award program, the Lura Cook Hull Trust, the National Institutes of Health (AI-16892, 1R21 AI101393, U19 AI111143) and Deutsche Forschungsgemeinschaft (BA 4890/1-1, BA 4890/3-1).

    See the full article here .

    Please help promote STEM in your local schools.

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    Welcome to Brown

    Brown U Robinson Hall
    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

    Undergraduates pursue bachelor’s degrees in more than 70 concentrations, ranging from Egyptology to cognitive neuroscience. Anything’s possible at Brown—the university’s commitment to undergraduate freedom means students must take responsibility as architects of their courses of study.

     
  • richardmitnick 10:46 am on October 1, 2016 Permalink | Reply
    Tags: , , Brown   

    From Brown: “BRAIN grant of $1.6 million powers study of neural signals” 

    Brown University
    Brown University

    September 29, 2016
    David Orenstein
    david_orenstein@brown.edu

    Three-year project will develop a software tool to help scientists and doctors understand how recorded brainwaves emerge from underlying neural activity.

    1
    Thinking cap. An array of electroencephalography sensors allows detailed sensing of neural signals. New software will help researchers understand that data better. Michael Cohea/Brown University

    In her research at Brown University, Stephanie Jones, research associate professor of neuroscience, has led the development of a unique computational model that explains how individual neurons and circuits of them produce the signals detected by external brainwave measurements, such as EEG or MEG sensors. Now, with a three-year, $1.6 million grant from the federal government’s BRAIN Initiative, she hopes to share her innovation with other scientists.

    “The aim of the grant is to turn the model into a user-friendly software tool that researchers and clinicians can use to test hypotheses about the neural origin of their MEG/EEG or electrocorticography data,” said Jones, a member of the Brown Institute for Brain Science. “We are calling this tool the ‘Human Neocortical Neurosolver.'”

    Jones leads the research, which officially starts Sept. 30 in collaboration with Dr. Matti Hamalainen at Massachusetts General Hospital and Dr. Michael Hines at Yale University.

    The team will also “integrate the neural model into existing source localization software so that researchers can study the location, time course and neural mechanisms of their human brain imaging data all in one software package,” Jones added.

    She said the software will not only aid neuroscience, but also future patient care.

    “While there are numerous studies connecting human MEG/EEG data to healthy and abnormal functions, the circuit level interpretation of the underlying neural dynamics is lacking,” she said. “This tool will foster the translational relevance of these technologies by allowing researchers to generate testable hypotheses that can guide further studies and ultimately novel therapeutics.”

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

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    Welcome to Brown

    Brown U Robinson Hall
    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

    Undergraduates pursue bachelor’s degrees in more than 70 concentrations, ranging from Egyptology to cognitive neuroscience. Anything’s possible at Brown—the university’s commitment to undergraduate freedom means students must take responsibility as architects of their courses of study.

     
  • richardmitnick 7:15 am on September 28, 2016 Permalink | Reply
    Tags: , , Brown, Liquid water beneath Pluto’s surface, Sputnik Planum   

    Brown: “Pluto’s ‘heart’ sheds light on a possible buried ocean” 

    Brown University
    Brown University

    September 23, 2016
    Kevin Stacey

    1
    Pluto’s famous “heart,” half of which was created by an ancient impact, offers clues about a possible subsurface ocean. NASA/APL/SwRI.

    Ever since NASA’s New Horizons spacecraft flew by Pluto last year, evidence has been mounting that the dwarf planet may have a liquid ocean beneath its icy shell.

    NASA/New Horizons spacecraft
    NASA/New Horizons spacecraft

    Now, by modeling the impact dynamics that created a massive crater on Pluto’s surface, a team of researchers has made a new estimate of how thick that liquid layer might be.

    The study, led by Brown University geologist Brandon Johnson and published in Geophysical Research Letters, finds a high likelihood that there’s more than 100 kilometers of liquid water beneath Pluto’s surface. The research also offers a clue about the composition of that ocean, suggesting that it likely has a salt content similar to that of the Dead Sea.

    “Thermal models of Pluto’s interior and tectonic evidence found on the surface suggest that an ocean may exist, but it’s not easy to infer its size or anything else about it,” said Johnson, who is an assistant professor in Brown’s Department of Earth, Environmental and Planetary Sciences. “We’ve been able to put some constraints on its thickness and get some clues about composition.”

    The research focused on Sputnik Planum, a basin 900 kilometers across that makes up the western lobe the famous heart-shaped feature revealed during the New Horizons flyby. The basin appears to have been created by an impact, likely by an object 200 kilometers across or larger.

    The story of how the basin relates to Pluto’s putative ocean starts with its position on the planet relative to Pluto’s largest moon, Charon. Pluto and Charon are tidally locked with each other, meaning they always show each other the same face as they rotate. Sputnik Planum sits directly on the tidal axis linking the two worlds. That position suggests that the basin has what’s called a positive mass anomaly — it has more mass than average for Pluto’s icy crust. As Charon’s gravity pulls on Pluto, it would pull proportionally more on areas of higher mass, which would tilt the planet until Sputnik Planum became aligned with the tidal axis.

    But a positive mass anomaly would make Sputnik Planum a bit of an odd duck as craters go.

    “An impact crater is basically a hole in the ground,” Johnson said. “You’re taking a bunch of material and blasting it out, so you expect it to have negative mass anomaly, but that’s not what we see with Sputnik Planum. That got people thinking about how you could get this positive mass anomaly.”

    Part of the answer is that, after it formed, the basin has been partially filled in by nitrogen ice. That ice layer adds some mass to the basin, but it isn’t thick enough on its own to make Sputnik Planum have positive mass, Johnson says.

    The rest of that mass may be generated by a liquid lurking beneath the surface.

    Like a bowling ball dropped on a trampoline, a large impact creates a dent on a planet’s surface, followed by a rebound. That rebound pulls material upward from deep in the planet’s interior. If that upwelled material is denser than what was blasted away by the impact, the crater ends up with the same mass as it had before the impact happened. This is a phenomenon geologists refer to as isostatic compensation.

    Water is denser than ice. So if there were a layer of liquid water beneath Pluto’s ice shell, it may have welled up following the Sputnik Planum impact, evening out the crater’s mass. If the basin started out with neutral mass, then the nitrogen layer deposited later would be enough to create a positive mass anomaly.

    “This scenario requires a liquid ocean,” Johnson said. “We wanted to run computer models of the impact to see if this is something that would actually happen. What we found is that the production of a positive mass anomaly is actually quite sensitive to how thick the ocean layer is. It’s also sensitive to how salty the ocean is, because the salt content affects the density of the water.”

    The models simulated the impact of an object large enough to create a basin of Sputnik Planum’s size hitting Pluto at a speed expected for that part in the solar system. The simulation assumed various thicknesses of the water layer beneath the crust, from no water at all to a layer 200 kilometers thick.

    The scenario that best reconstructed Sputnik Planum’s observed size depth, while also producing a crater with compensated mass, was one in which Pluto has an ocean layer more than 100 kilometers thick, with a salinity of around 30 percent.

    “What this tells us is that if Sputnik Planum is indeed a positive mass anomaly —and it appears as though it is — this ocean layer of at least 100 kilometers has to be there,” Johnson said. “It’s pretty amazing to me that you have this body so far out in the solar system that still may have liquid water.”

    As researchers continue to look at the data sent by New Horizons, Johnson is hopeful that a clearer picture of Pluto’s possible ocean will emerge.

    Johnson’s co-authors on the paper were Timothy Bowling of the University of Chicago and Alexander Trowbridge and Andrew Freed from Purdue University.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

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    Welcome to Brown

    Brown U Robinson Hall
    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

    Undergraduates pursue bachelor’s degrees in more than 70 concentrations, ranging from Egyptology to cognitive neuroscience. Anything’s possible at Brown—the university’s commitment to undergraduate freedom means students must take responsibility as architects of their courses of study.

     
  • richardmitnick 10:14 am on September 7, 2016 Permalink | Reply
    Tags: , , Brown, ,   

    From Brown: “Brown to lead $9.7M grant to advance theory of aging” 

    Brown University
    Brown University

    September 6, 2016
    David Orenstein
    david_orenstein@brown.edu
    401-863-1862

    A new multi-university research effort will seek to determine whether rogue elements of DNA promote or even cause aging and whether interventions against them could help people live longer and more healthfully.

    Over the last few years, scientists — including a team at Brown University — have produced mounting evidence that mobility within genome of potentially harmful DNA snippets, called retrotransposable elements, may cause health problems associated with aging.

    With a new $9.67 million, five-year grant from the National Institutes of Health, researchers at Brown University, New York University and the University of Rochester will collaborate to further strengthen the evidence and to advance toward the goal of applying the findings medically.

    “There are a lot of provocative data and a lot of very cool ideas, but the issue now is how to nail this down,” said John Sedivy, the Hermon C. Bumpus Professor of Biology at Brown University and principal investigator of the grant. “Let’s take the bull by the horns and see what’s really going on. Is this a legitimate mechanism of aging and can we control it for therapeutic purposes?”

    Previous studies have shown that as cells age, or become senescent, they lose their ability to prevent retrotransposable elements from spreading into new places in the genome. In three new projects supported by two core facilities, the grant will spur the study of how retrotransposable elements function in cells and how their activity might cause specific diseases, and test possible ways of suppressing that activity. The researchers will not only work with human cells but also with mice and fruit flies, or Drosophila, where they can ask more direct questions, obtain faster answers and therefore better inform eventual interventions for people.

    Sedivy will lead one of the effort’s three projects, “Regulation of Retrotransposable Element Activity in Cellular Senescence and Aging,” and the administrative core. Dr. Stephen Helfand, a fellow Brown professor of biology, will lead the second project, “Regulation of Retrotransposable Element Activity in Drosophila.”

    Professor Jef Boeke of NYU will lead the Retrotransposon Engineering and Genomics Core. Rochester Associate Professor Andrei Seluanov will lead the Mouse Intervention and Aging Core, while Rochester Professor Vera Gorbunova will lead the third project, “Repression of Retrotransposable Elements by the Longevity Gene SIRT6.”

    The results could shed important light on the health consequences of retrotransposable element activity, Sedivy said. Experiments demonstrating the best interventions could then become translated into future human clinical trials.

    In fact, Sedivy notes, some drugs already exist and are widely used against one well known retrotransposable element, HIV. Brown researchers have already shown that some of these drugs also suppress some endogenous retrotransposable elements, although they were never intended for that purpose.

    “Hence, if endogenous retrotransposable elements do promote aging in some contexts, we already have pretty good drugs that could be tested right away,” Sedivy said. “What you want to come out with is a therapeutic that is directed against retrotransposable elements and then use that therapeutic to target a number of diseases. But at this point, we don’t really know which human diseases are linked with these retrotransposition events.”

    The new grant, Sedivy said, will help the field get there.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

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    Welcome to Brown

    Brown U Robinson Hall
    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

    Undergraduates pursue bachelor’s degrees in more than 70 concentrations, ranging from Egyptology to cognitive neuroscience. Anything’s possible at Brown—the university’s commitment to undergraduate freedom means students must take responsibility as architects of their courses of study.

     
  • richardmitnick 11:55 am on September 4, 2016 Permalink | Reply
    Tags: , Brown, , Mitosis   

    From Brown: “Mitosis study finds potential cancer target” 

    Brown University
    Brown University

    August 30, 2016
    David Orenstein

    1
    An unusual relationship. A rendering depicts the specific and unique interaction between proteins PP1-gamma and either RepoMan or Ki-67, which presents a potential target for cancer. Senthil Kumar/Brown University.

    By drilling down to the atomic level of how specific proteins interact during cell division, or mitosis, a team of scientists has found a unique new target for attacking cancer.

    Structural biologists show in a new study [eLife] that an apparently key step in the process of cell division depends on a unique interaction among specific proteins, including one that is strongly linked to cancer. Their hope now is that the detailed new characterization of the interaction will make it a target for exploring a new cancer therapy.

    Cell division, or mitosis, is a staple of high school biology classwork, but scientists are still making new discoveries about its intricate workings. Now, researchers have discovered that as copied chromosomes begin to exit mitosis and pull away from their sisters to form a new cell, a stage called anaphase, a protein called Ki-67 brings a protein called PP1 to the chromosomes.

    Mitosis is essential to life, but it is also a process that occurs to a runaway degree in cancer. And that made Ki-67 of particular interest to the authors of the new study, which appears in the journal eLife, because Ki-67 is highly expressed throughout the various stages of mitosis, said lead author Senthil Kumar, assistant professor (research) of molecular pharmacology, physiology and biotechnology at Brown University.

    “Ki-67 is a protein that is widely used as a prognostic marker in cancer biology,” Kumar said. “People use this as a marker to study how far cancer has progressed.”

    Along with fellow Brown faculty members Wolfgang Peti and Rebecca Page and colleagues from other institutions, Kumar therefore wanted to understand exactly how Ki-67 interacts with PP1 in anaphase to bring it to the chromosomes. It turns out that Ki-67 binds to PP1 very tightly and — they also show this to exacting degrees in the new study — that another protein called RepoMan acts just like Ki-67.

    Understanding how the proteins and PP1 interact during anaphase, the researchers hoped, could reveal a way to perhaps reduce or slow down mitosis in tumors.

    It was particularly important to achieve a precise characterization of Ki-67 and RepoMan’s interaction with PP1, Page said, because PP1 interacts with hundreds of proteins in the body, which regulate many key processes that they wouldn’t want to hinder. Instead, they wanted to see if there was something specific in mitosis with these two regulator proteins that they could pinpoint.

    “PP1 has this interaction with 200 different regulators, but a number of those regulators use a couple of [binding] sites over and over again,” said Page, professor of molecular, cellular biology and biochemistry. “You obviously can’t develop an inhibitor for those two sites, because then you’d disrupt PP1 function in a whole array of biological processes. But the really neat thing that Senthil discovered is that this whole interaction is completely unique to these two regulators.”

    Kumar and Page led the effort by using nuclear magnetic resonance and x-ray crystallography that resolved the proteins and their interactions down to the scale of individual atoms — 1.3 tenths of billionths of a meter. What he and the team found was that RepoMan and Ki-67 were binding with PP1 in an unusual way, forming a “hairpin” shape on the surface of PP1 at specific locations. A bioinformatics database search later confirmed that the binding was unique.

    Moreover, they identified a novel binding region which is unique only to RepoMan and Ki-67. This novel region could be a potential target for cancer therapy, Kumar said.

    Crucial to the research was that in the anaphase of mitosis the binding is even more specific than just either protein linking up with just any form of PP1. Instead they showed that in anaphase, RepoMan and Ki-67 link to a particular form of PP1 called gamma. The proteins’ selectivity for PP1-gamma, they found, depended on just one amino acid on the PP1 protein at position 20.

    The team, including co-authors at Brunel University in London and the University of Leuven in Belgium, confirmed this in living cells in imaging studies. They also confirmed that preference for Ki-67 and RepoMan to the gamma form of PP1 happens in the live cells during mitosis. In addition, they showed that substituting the single amino acid at position 20 stopped the function.

    The exact role that PP1-gamma or the two regulator proteins may play in cancer is not yet known, Page said, but now they know exactly how they interact and that the interaction is unique. That pushes the door wide open to develop a way to hinder it so they can see what the consequences are for cancer when they do.

    “Now we have an approach for trying to dissect what’s really happening because we can target this interface in particular,” Page said.

    In addition to Kumar, Page and Peti at Brown, the study’s other authors are Ezgi Gokhan and Paola Vagnarelli at Brunel and Sofie De Munter and Matthieu Bollen at Leuven.

    The National Institutes of Health (U.S.), the Fund for Scientific Research (Belgium) and the Biotechnology and Biological Science Research Council (U.K.) funded the research.

    See the full article here .

    Please help promote STEM in your local schools.

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    Welcome to Brown

    Brown U Robinson Hall
    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

    Undergraduates pursue bachelor’s degrees in more than 70 concentrations, ranging from Egyptology to cognitive neuroscience. Anything’s possible at Brown—the university’s commitment to undergraduate freedom means students must take responsibility as architects of their courses of study.

     
  • richardmitnick 7:47 pm on August 18, 2016 Permalink | Reply
    Tags: , , Brown,   

    From Brown: “Study shows how mutations disrupt ALS-linked protein” 

    Brown University
    Brown University

    August 18, 2016
    David Orenstein
    david_orenstein@brown.edu
    401-863-1862

    1
    Concentrate not aggregate. New research explains how the protein TDP43 normally concentrates into droplets and how ALS-related mutations disrupt that, leading to them to form more problematic aggregates that afflict cells. Gül Zerze, Lehigh University

    In amyotrophic lateral sclerosis, aggregates of the protein TDP-43 are almost always found in afflicted neurons and glial cells. Meanwhile, about 50 ALS-linked mutations are known to affect a particular region of TDP-43. Yet scientists have never understood how those two associations connect. A new study in the journal Structure shows how ALS mutations disrupt the protein at the atomic level, preventing it from executing its proper function and instead leading to those aggregates.

    “We knew that part of TDP-43 builds up in aggregates and that there are 50 mutations in that domain, but we didn’t know the job of that domain, how it goes wrong and why it aggregates,” said study corresponding author Nicolas Fawzi, assistant professor in the Department of Molecular Pharmacology, Physiology and Biotechnology at Brown University.

    In general, TDP-43 acts like a chaperone for RNA in a cell, binding to it, guiding its processing, transporting it to where it needs to go and regulating it, so that other proteins can be expressed properly. Using nuclear magnetic resonance, computer simulations and microscopy, Fawzi, Brown graduate student Alexander Conicella and colleagues at Lehigh University were able to show that under normal circumstances, TDP-43 molecules concentrate into little droplets, a process called “liquid-liquid phase separation.” It’s within these droplets that they could process and ferry RNA.

    The team’s focus was on a particular region of TDP-43, called the “C-terminal domain,” which appeared to be crucial in the concentration of molecules that leads to phase separation.

    “We were looking for a functional role for this part of the protein,” Fawzi said “Its job can’t just be to do nothing and then aggregate in disease.”

    The observations showed that the interactions and resulting concentration of TDP-43 molecules depend on a small corkscrew-shaped part of the protein’s C-terminal domain termed a helix. The same sequence of DNA specifying that corkscrew shape has been exactly preserved by evolution in many vertebrate animals suggesting it has an important biological function.

    What Fawzi and his teams observed is that as one TDP-43 molecule meets another, the corkscrews stabilize and lengthen, promoting a bond between them.

    Finally, the team shows in the paper that the various ALS mutations disrupt this process, either by upsetting the formation of the corkscrews or their ability to lengthen and stabilize.

    “Mutations in this [corkscrew] region blow that interaction up,” Fawzi said.

    The result is that the concentration and phase separation does not occur. Instead the proteins can combine in a more potentially harmful way — in the aggregates seen in diseased neurons.

    By ferreting out this mechanistic connection between the mutations, the loss of protein’s proper phase separation behavior and how it frees molecules up to aggregate, the team shows how the mutations could lead to disease, Fawzi said.

    “That might be one mechanism by which ALS mutation cause ALS — by disrupting TDP-43’s normal function,” he said.

    The paper further emphasizes the urgency of an overarching question in ALS. Only about 10 percent of ALS cases are traceable to a genetic cause. It remains unclear what’s happening to disrupt TDP-43 in many cases when a known mutation is not the cause.

    But now scientists have new a new set of data and an explanation of how TDP-43 appears to work and what can make it fail.

    That’s also important, Fawzi noted, because TDP-43 is implicated in other degenerative neural diseases as well.

    “Given the recent evidence that TDP-43 also accumulates in Alzheimer’s disease, understanding the role of TDP-43 is all the more urgent,” he said.

    In addition to Fawzi and Conicella, the paper’s other authors are Gul Zerze and Jeetain Mittal of Lehigh.

    The U.S. National Institutes of Health and Department of Energy supported the research which occurred, in part, at the the Leduc Bioimaging Facility and Structural Biology Core Facility at Brown.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition
    Welcome to Brown

    Brown U Robinson Hall
    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

    Undergraduates pursue bachelor’s degrees in more than 70 concentrations, ranging from Egyptology to cognitive neuroscience. Anything’s possible at Brown—the university’s commitment to undergraduate freedom means students must take responsibility as architects of their courses of study.

     
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