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  • richardmitnick 3:23 pm on April 15, 2017 Permalink | Reply
    Tags: , , Science, Teleocrater   

    From Science: “Curious fossil could rewrite early days of the dinosaurs” 

    Science Magazine

    Apr. 12, 2017
    Carolyn Gramling

    In this artist’s rendition of life in the middle Triassic, carnivorous Teleocrater rhadinus, newly identified as a very early ancestor of dinosaurs and pterosaurs, feasts on mammallike reptile Cynognathus. Natural History Museum, London, artwork by Mark Witton

    How did the dinosaur become the dinosaur? Somewhere along the line, the ancestor of dinosaurs diverged from the ancestor of crocodiles, a momentous split in the evolution of vertebrates that ultimately set the stage for the age of dinos. But the details of that split remain mysterious, thanks to a dearth of fossils of early dinosaur relatives. Enter the newly identified 247-million- to 242-million-year-old Teleocrater rhadinus, a close relative of dinosaurs that also happened to walk on all fours and share some key features with the ancestors of crocodiles. These shared features, the authors say, suggest that it’s time to rethink what we thought we knew about dinosaurs’ earliest ancestors.

    “We’ve been waiting a long time to find fossils like this that fit in this part of the family tree,” says Randall Irmis, a paleontologist at the Natural History Museum of Utah in Salt Lake City, who was not involved in the work. “This has pretty big implications for how we understand the early evolution of dinosaurs.”

    Some 251 million years ago, at the end of the Permian period, a mass extinction wiped out most of life on Earth. In its wake arose a group of egg-laying reptile precursors called archosaurs, the common ancestors of dinosaurs, flying reptiles known as pterosaurs, and crocodiles. At some point during the next period, the Triassic, pterosaurs and dinosaurs split off from the crocodile lineage.

    Those two different lineages, avian versus crocodilian, have long been identified by their types of ankle joints. Dinosaurs and pterosaurs all have a version of a hinged, birdlike ankle, rather than the crocodilelike ankle with ball-and-socket joint.

    But exactly what early dinosaurs and their closest relatives looked like has been something of a mystery, because few fossils exist from the dawn of the dinosaurs. And many of the fossils that do exist, collected perhaps decades to a century ago, languish unidentified in museum drawers.

    Indeed, Teleocrater isn’t a completely new discovery. A specimen was first unearthed in what is now Tanzania in the 1930s and sat in London’s Natural History Museum until 1956, when Ph.D. candidate Alan Charig (later a paleontologist at the museum) dubbed it T. rhadinus (referring to the shape of the animal’s hip and its slender body). Charig, who died in 1997 but is included as an author on the new paper, speculated that it was some sort of early dinosaur relative. But the fossil was in pieces, just bits of vertebrae and pelvis and limb, and difficult to place on the family tree.

    Then in 2015, Sterling Nesbitt, a paleontologist at Virginia Polytechnic Institute and State University in Blacksburg, and a team of researchers headed back to southern Tanzania to take another look at the middle Triassic rocks where Teleocrater was first discovered. This time, the rocks—estimated to be about 247 million to 242 million years old—yielded several individuals of the same species. With that new bounty, the researchers were able to catalog many more of the creature’s features—enough to place it on the vertebrate family tree.

    Teleocrater, Nesbitt and his co-authors report online today in Nature, belongs at the very base of the avian lineage that later gave rise to dinosaurs. It has a characteristic muscle scar on the upper leg bone that is found only in the avian lineage of birds and dinosaurs and is missing in crocodiles and their relatives. But Teleocrater also had a crocodilelike ankle, with a ball-and-socket joint. That suggests that the crocodile ankle came first, and the bird ankle evolved later.

    That’s key, because the ankle joint has been used for decades as an indicator of avian versus crocodilian lineage, so Teleocrater must be close to the split between them. And in several respects, Nesbitt says, “Teleocrater looks more like the relatives of the crocodiles than the relatives of dinosaurs.” The carnivorous animal, which was roughly the size of a small lion, walked on all fours, its forelimbs and hindlimbs are similar in proportion, and the limbs themselves are pretty short relative to the length of the body.

    Seemingly small details like these can produce ripples throughout paleontology collections, because they can help researchers properly classify fossils that had seemed to be walking contradictions. “These fossils exist in museums around the world, but until you find a keystone—something that helps you understand the full anatomy [of a species]—you won’t understand where these animals go on the tree of life,” Nesbitt says.

    After identifying Teleocrater as an ancestor along the avian lineage, the authors could group it with several other difficult-to-place animals, including Dongusuchus and Spondylosoma, naming a new group of long-necked, carnivorous quadrupeds dubbed Aphanosauria (hidden or obscure lizards, in Greek). Aphanosaurs, they suggest, are the earliest group in the avian stem lineage to diverge from the crocodile lineage. And that suggests that these bird and dinosaur ancestors were far more diverse and widely distributed across the globe during the middle Triassic than once thought.

    The find may also alter what paleontologists hunt for in the field, as well as how they understand existing collections, says Max Langer, a paleontologist at the University of São Paulo in Rio Claro, Brazil. “Now that we know the diagnostic features of this group of archosaurs, everybody working on middle Triassic rocks will be looking for something similar.”

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  • richardmitnick 7:18 pm on February 24, 2017 Permalink | Reply
    Tags: , , Science   

    From Science: “Spinning black holes could fling off clouds of dark matter particles” 

    Science Magazine

    Feb. 22, 2017
    Adrian Cho


    A spinning black hole (white) should produce huge clouds of particles called axions (blue), which would then produce detectable gravitational waves, a new calculation predicts. Masha Baryakhtar

    Few things are more mind bending than black holes, gravitational waves, and the nearly massless hypothetical particles called axions, which could be the mysterious dark matter whose gravity holds galaxies together. Now, a team of theoretical physicists has tied all three together in a surprising way. If the axion exists and has the right mass, they argue, then a spinning black hole should produce a vast cloud of the particles, which should, in turn, produce gravitational waves akin to those discovered a year ago by the Laser Interferometer Gravitational-Wave Observatory (LIGO). If the idea is correct, LIGO might be able to detect axions, albeit indirectly.

    “It’s an awesome idea,” says Tracy Slatyer, a particle astrophysicist at the Massachusetts Institute of Technology (MIT) in Cambridge, who was not involved in the work. “The [LIGO] data is going to be there, and it would be amazing if we saw something.” Benjamin Safdi, a theoretical particle physicist at MIT, is also enthusiastic. “This is really the best idea we have to look for particles in this mass range,” he says.

    A black hole is the intense gravitational field left behind when a massive star burns out and collapses to a point. Within a certain distance of that point—which defines the black hole’s “event horizon”—gravity grows so strong that not even light can escape. In September 2015, LIGO detected a burst of ripples in space called gravitational waves that emanated from the merging of two black holes.

    The axion—if it exists—is an uncharged particle perhaps a billionth as massive as the electron or lighter. Dreamed up in the 1970s, it helps explain a curious mathematical symmetry in the theory of particles called quarks and gluons that make up protons and neutrons. Axions floating around might also be the dark matter that’s thought to make up 85% of all matter in the universe. Particle physicists are searching for axions in experiments that try to convert them into photons using magnetic fields.

    But it may be possible to detect axions by studying black holes with LIGO and its twin detectors in Louisiana and Washington states, argue Asimina Arvanitaki and Masha Baryakhtar, theorists at the Perimeter Institute for Theoretical Physics in Waterloo, Canada, and their colleagues.

    If its mass is in the right range, then an axion stuck in orbit around a black hole should be subject to a process called superradiance that occurs in many situations and causes photons to multiply in a certain type of laser. If an axion strays near, but doesn’t cross, a black hole’s event horizon, then the black hole’s spin will give the axion a boost in energy. And because the axion is a quantum particle with some properties like those of the photon, that boost will create more axions, which will, in turn, interact with the black hole in the same way. The runaway process should thus generate vast numbers of the particles.

    But for this to take place, a key condition has to be met. A quantum particle like the axion can also act like a wave, with lighter particles having longer wavelengths. For superradiance to kick in, the axion’s wavelength must be as long as the black hole is wide. So the axion’s mass must be extremely light: between 1/10,000,000 and 1/10,000 the range probed in current laboratory experiments. The axions wouldn’t just emerge willy-nilly, either, but would crowd into huge quantum waves like the orbitals of the electrons in an atom. As fantastical as that sounds, the basic physics of superradiance is well established, Safdi says.

    The axion cloud might reveal itself in multiple ways, Baryakhtar says. Most promising, axions colliding in the cloud should annihilate one another to produce gravitons, the particles thought to make up gravitational waves just as photons make up light. Emerging from orderly quantum clouds, the gravitons would form continuous waves with a frequency set by the axion’s mass. LIGO would be able to spot thousands of such sources per year [Physical Review D], Baryakhtar and colleagues estimate in a paper published 8 February in Physical Review D—although tracking those continuous signals may be harder than detecting bursts from colliding black holes. Spotting multiple same-frequency sources would be a “smoking gun” for axions, Slatyer says.

    The axion clouds could produce indirect signals, too. In principle, a black hole can spin at near light speed. However, generating axions would sap a black hole’s angular momentum and slow it. As a result, LIGO should observe that the spins of colliding black holes never reach that ultimate speed, but top out well below it, Baryakhtar says. Detecting that limit on spin would be challenging, as LIGO can measure a colliding black hole’s spin with only 25% precision.

    Safdi cautions that the analysis assumes that LIGO will see lots of black-hole mergers and will perform as expected. And if LIGO doesn’t see the signals, it won’t rule out the axion, he says. Still, he says, “This is probably the most promising paper I’ve seen so far on the new physics we might probe with gravitational waves.”

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  • richardmitnick 11:29 am on January 22, 2017 Permalink | Reply
    Tags: , , How white blood cells rip holes in your blood vessels—and how your blood vessels recover, Science   

    From Science: “How white blood cells rip holes in your blood vessels—and how your blood vessels recover” 

    Science Magazine

    A. Barzilai et. al. Cell Reports 18, 3 (17 January 2017) © 2017 Elsevier Inc.

    Jan. 17, 2017
    Emma Hiolski

    White blood cells are constantly tearing holes in your blood vessel walls. But these guardians of the immune system are doing it to protect you: Once they ride through the bloodstream to infected tissues—where they make antibodies and eat foreign invaders—they need a way to get inside. Now, scientists have discovered just how they do it without permanently damaging blood vessels, which they slip into and out of up to 10 times each day. First, researchers added fluorescent tags to their nuclei and to the structural fibers of blood vessel walls, which keep out foreign particles and seal in blood, plasma, and immune cells. The researchers then tracked the process with video-microscopy. They found that blood vessel cells were not the ones making the openings, as previously thought. Instead, immune cells make their own way across. By softening their bulky nuclei and pushing them to the front edge of their cells, white blood cells probe apart scaffolding in the blood vessel walls and squeeze through, researchers report online today in Cell Reports. This process (seen above) snaps smaller, threadlike fibers that form the flexible scaffolding of blood vessel walls; the cells easily repair that breakage later as part of routine cellular maintenance. The researchers hope to use their discovery to better understand how metastatic cancer cells migrate into the bloodstream and spread cancer throughout the body.

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  • richardmitnick 2:41 pm on January 9, 2017 Permalink | Reply
    Tags: , Science, The fetal brain   

    From Science: “Pioneering study images activity in fetal brains” 



    The human brain undergoes a remarkable transition in utero, but until recently scientists have had few tools to study how this process unfolds.
    iStock Photo

    Jan. 9, 2017
    Greg Miller

    Babies born prematurely are prone to problems later in life—they’re more likely to develop autism or attention deficit hyperactivity disorder, and more likely to struggle in school. A new study that’s among the first to investigate brain activity in human fetuses suggests that the underlying neurological issues may begin in the womb. The findings provide the first direct evidence of altered brain function in fetuses that go on to be born prematurely, and they might ultimately point to ways to remediate or even prevent such early injuries.

    In the new study, published 9 January in Scientific Reports, developmental neuroscientist Moriah Thomason of Wayne State University School of Medicine in Detroit, Michigan, and colleagues report a difference in how certain brain regions communicate with each other in fetuses that were later born prematurely compared with fetuses that were carried to term. Although the findings are preliminary because the study was small, Thomason and other researchers say the work illustrates the potential (and the challenges) of the emerging field of fetal neuroimaging. “Harnessing the power of these advanced tools is offering us for the very first time the opportunity to explore the onset of neurologic insults that are happening in utero,” says Catherine Limperopoulos, a pediatric neuroscientist at Children’s National Medical Center in Washington, D.C.

    Thomason and colleagues used functional magnetic resonance imaging (fMRI) to investigate brain activity in 32 fetuses. The pregnant mothers were participants in a larger, long-term study of brain development led by Thomason. “The majority have just normal pregnancies, but they’re drawn from a low-resource population that’s at greater risk of early delivery and developmental problems,” she says. In the end, 14 of the fetuses were born prematurely.

    The team’s approach relied on methods developed in the past decade or so to study “functional connectivity” in the adult human brain—essentially using fMRI to determine which brain regions have synchronized activity when the subject is not engaged in any particular task. Synchronized activity between brain regions, the thinking goes, shows that those regions are well connected and sharing information.

    Colored regions in these MRI images of a human fetus (shown from two perspectives) indicate brain regions where connectivity grows stronger between the 20th and 40th weeks of gestation. Data courtesy of Moriah E. Thomason, Wayne State University School of Medicine.

    One feature stood out in the brains of the fetuses that were ultimately born prematurely: A small patch on the left side of the brain, in an area that develops into a language processing center, had weaker connectivity with other brain regions than it did in fetuses carried to full term. “That they can detect this difference in connectivity so early is something interesting,” says Hao Huang, who studies neonatal brain development at the University of Pennsylvania. “Usually with earlier detection you have better chances for intervention.” Language problems are common in children born prematurely, and Thomason plans to track these children as they develop.

    Previous studies have reported altered connectivity in the brains of premature infants, but only after birth, leaving open the possibility that stress, oxygen deprivation, or other injury during delivery is to blame. But Thomason and her colleagues not only found that the impairment starts earlier; they also found a hint of a cause. The mothers who delivered prematurely had more inflammation in their placental tissue, which leads Thomason to suspect that maternal infection or inflammation might play a role.

    This type of study would have been impossible only a short time ago. One of the biggest problems in fetal neuroimaging is that a fetus is a moving target, bobbing around inside the amniotic sac. “A fetus has so many degrees of freedom,” says Veronika Schöpf, a mathematician at the University of Graz in Austria who is developing computational tools for fetal neuroimaging. That’s a problem because an MRI scan is like a stack of pancakes—thin slices piled neatly on top of one another. Any movement throws the slices out of register. But Schöpf says better algorithms are helping scientists stitch together slices taken from slightly different angles because the subject moved. At the same time, MRI machines have gotten faster, making it possible to collect more slices in a shorter time. That’s a big deal, Thomason says, because it means getting more data during periods when a fetus is staying still.

    The fetal brain is a moving target in another sense, too. Its anatomy is in constant flux as it matures, which means researchers need templates and atlases for different developmental time points to be able to make comparisons across subjects. Several research groups around the world are currently developing these resources.

    The ability to image the fetal brain at work opens up questions in basic science, too, Huang says. In the course of a pregnancy, the human brain transforms from a simple fluid-filled tube into a complex organ ready to perceive and interact with the outside world. How this process unfolds is largely a mystery, and Huang is eager to probe such questions as how and when the networks found in the mature brain develop and become active for the first time. At last, he says, “The techniques are catching up” to the questions.

    See the full article here .

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  • richardmitnick 2:28 pm on December 4, 2016 Permalink | Reply
    Tags: , , Cold brown dwarfs, , Science   

    From Science: “Alien life could thrive in the clouds of failed stars” 

    Science Magazine

    The comfortably warm atmosphere of a brown dwarf is an underappreciated potential home for alien life, scientists say. Mark Garlick/Science Source

    Dec. 2, 2016
    Joshua Sokol

    There’s an abundant new swath of cosmic real estate that life could call home—and the views would be spectacular. Floating out by themselves in the Milky Way galaxy are perhaps a billion cold brown dwarfs, objects many times as massive as Jupiter but not big enough to ignite as a star. According to a new study, layers of their upper atmospheres sit at temperatures and pressures resembling those on Earth, and could host microbes that surf on thermal updrafts.

    The idea expands the concept of a habitable zone to include a vast population of worlds that had previously gone unconsidered. “You don’t necessarily need to have a terrestrial planet with a surface,” says Jack Yates, a planetary scientist at the University of Edinburgh in the United Kingdom, who led the study.

    Atmospheric life isn’t just for the birds. For decades, biologists have known about microbes that drift in the winds high above Earth’s surface. And in 1976, Carl Sagan envisioned the kind of ecosystem that could evolve in the upper layers of Jupiter, fueled by sunlight. You could have sky plankton: small organisms he called “sinkers.” Other organisms could be balloonlike “floaters,” which would rise and fall in the atmosphere by manipulating their body pressure. In the years since, astronomers have also considered the prospects of microbes in the carbon dioxide atmosphere above Venus’s inhospitable surface.

    Yates and his colleagues applied the same thinking to a kind of world Sagan didn’t know about. Discovered in 2011, some cold brown dwarfs have surfaces roughly at room temperature or below; lower layers would be downright comfortable. In March 2013, astronomers discovered WISE 0855-0714, a brown dwarf only 7 light-years away that seems to have water clouds in its atmosphere. Yates and his colleagues set out to update Sagan’s calculations and to identify the sizes, densities, and life strategies of microbes that could manage to stay aloft in the habitable region of an enormous atmosphere of predominantly hydrogen gas. Sink too low and you are cooked or crushed. Rise too high and you might freeze.

    On such a world, small sinkers like the microbes in Earth’s atmosphere or even smaller would have a better chance than Sagan’s floaters, the researchers will report in an upcoming issue of The Astrophysical Journal. But a lot depends on the weather: If upwelling winds are powerful on free-floating brown dwarfs, as seems to be true in the bands of gas giants like Jupiter and Saturn, heavier creatures can carve out a niche. In the absence of sunlight, they could feed on chemical nutrients. Observations of cold brown dwarf atmospheres reveal most of the ingredients Earth life depends on: carbon, hydrogen, nitrogen, and oxygen, though perhaps not phosphorous.

    The idea is speculative but worth considering, says Duncan Forgan, an astrobiologist at the University of St. Andrews in the United Kingdom, who did not participate in the study but says he is close to the team. “It really opens up the field in terms of the number of objects that we might then think, well, these are habitable regions.”

    So far, only a few dozen cold brown dwarfs have been discovered, though statistics suggest there should be about 10 within 30 light-years of Earth. These should be ripe targets for the James Webb Space Telescope (JWST), which is sensitive in the infrared where brown dwarfs shine brightest.

    NASA/ESA/CSA Webb Telescope annotated
    NASA/ESA/CSA Webb Telescope annotated

    After it launches in 2018, the JWST should reveal the weather and the composition of their atmospheres, says Jackie Faherty, an astronomer at the Carnegie Institution for Science in Washington, D.C. “We’re going to start getting gorgeous spectra of these objects,” she says. “This is making me think about it.”

    Testing for life would require anticipating a strong spectral signature of microbe byproducts like methane or oxygen, and then differentiating it from other processes, Faherty says. Another issue would be explaining how life could arise in an environment that lacks the water-rock interfaces, like hydrothermal vents, where life is thought to have begun on Earth. Perhaps life could develop through chemical reactions on the surfaces of dust grains in the brown dwarf’s atmosphere, or perhaps it gained a foothold after arriving as a hitchhiker on an asteroid. “Having little microbes that float in and out of a brown dwarf atmosphere is great,” Forgan says. “But you’ve got to get them there first.”

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  • richardmitnick 7:54 am on August 11, 2016 Permalink | Reply
    Tags: , , Science, Yellow Fever   

    From Science: “Yellow fever emergency forces officials to combat virus with tiny dose of vaccine” 



    Aug. 10, 2016
    Kai Kupferschmidt

    Mothers wait to have their children vaccinated during routine vaccination at a health center in the town of Nyunzu in the Democratic Republic of the Congo. Olivier Asselin/Alamy Stock Photo

    It’s an unprecedented emergency measure, but one that could become the norm: In a bid to stop an outbreak of yellow fever, more than 8 million people in Kinshasa, the capital of the Democratic Republic of the Congo (DRC), will be vaccinated using just one-fifth the normal dose. The campaign, scheduled to start next week, comes as yellow fever continues to spread in the DRC and vaccine demand outstrips supply.

    Scientists feel confident that the lower doses will offer protection, at least for the short term, but they are urging studies accompanying the campaign to assess whether routine use of the lower dose is an option.

    The current outbreak started in neighboring Angola in December of last year and later spread to the DRC. According to the World Health Organization (WHO), more than 16 million people in the two countries have already been vaccinated, and Angola has reported no new cases for more than 6 weeks. But new cases are still emerging in the DRC, which has reported more than 2000 suspected cases so far and 95 deaths.

    WHO’s emergency stockpile of yellow fever vaccine, which was depleted earlier this year, has been restocked and is now back to 5 million doses. But the Congolese government, worried that the virus could spread rapidly among Kinshasa’s 10 million residents, has decided to stretch the 1.7 million doses it has received by giving people 0.1 milliliters of the vaccine each instead of the standard 0.5 milliliters.

    The yellow fever virus is primarily transmitted by Aedes aegypti, the mosquito species that also spreads Zika and dengue. Most people who are infected have no symptoms, but about 15% develop serious disease, and about half these patients die. There is no cure, but the vaccine, although cumbersome to produce, is highly effective: A single dose confers lifelong protection.

    Fearing that the disease could spread to Asia, which has never seen a yellow fever outbreak, some experts had urged governments and WHO to adopt the vaccine-saving strategy. In June, WHO’s Strategic Advisory Group of Experts (SAGE) on Immunization concluded that the lower dose would still offer protection for at least 12 months. (The recommendation was made in an emergency session, but the group has planned a formal evaluation for October.) “We felt very comfortable with the data that was presented to go ahead and make the recommendation,” says SAGE chair Jon Abramson, a pediatrician at Wake Forest School of Medicine in Winston-Salem, North Carolina. “We feel the benefit of vaccinating as many people as we can far outweighs the small risk that somebody won’t respond who could have responded to a larger dose.”

    SAGE advised that children under 2 years of age should receive the full dose, however, and it pointed out some practical problems as well, such as the need for millions of smaller syringes. A WHO spokesperson says that problem has been solved by using syringes stored in China and Denmark for polio vaccination programs.

    Abramson and other experts argue that the effects of the campaign need to be studied. One important question is safety. The yellow fever vaccine is itself a living virus that can replicate inside the body and, in very rare cases, cause a disease in which the vaccine virus proliferates in multiple organs, often leading to death. Although a lower dose would be expected to lead to fewer side effects, that may not be the case. Some researchers have argued that lower doses may be slower to kick the immune system into gear, which could cause the vaccine virus to linger in the body for longer and actually increase the risk of some side effects. A few studies have found no such effect, but because severe side effects are very rare (about one in 2 million), small trials cannot provide definitive answers.

    The other question is efficacy. A recent study on 749 men in Brazil showed that a 46-fold diluted vaccine triggered the same antibody response as a full dose. A study in the Netherlands found that a fifth of a normal dose injected intradermally was just as effective as a normal dose injected subcutaneously (the usual route).

    But more data on the efficacy of the lower dose need to be collected, especially because an African population may react differently to those studied in the trials. Ideally, scientists would set up a randomized, controlled clinical trial to assess the immune response to the lower dose, says Tom Monath, a virologist who has studied yellow fever for decades and currently works at NewLink Genetics, a biotech company in Ames, Iowa. But Monath concedes that that is unlikely given the time pressure and the logistical problems. At the very least, researchers should collect blood samples and compare the antibody responses from people who received the full and the lower dose, he argues. “It wouldn’t be a formal study but it would give you some confidence that people have responded appropriately,” Monath says. “I think that really should be done.”

    Another important question is whether 0.1 milliliters of the vaccine also offers lifelong protection. If not, the population will have to be revaccinated in the future. It’s also not clear whether lower doses will be protective in young children.

    In a paper advocating the dose-sparing strategy that Monath and eight other scientists just submitted, they go one step further. “If the worst-case scenario were to come to pass and yellow fever spread in Asia, serious consideration should be given to using a one-tenth dose,” the authors write. “Although it would probably protect any age group for only a few months, a one-tenth dose should mitigate the severity of a yellow fever infection, preventing some deaths.“

    See the full article here .

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  • richardmitnick 9:37 am on August 3, 2016 Permalink | Reply
    Tags: Antiaging trial, , , Science   

    From Science: “Young blood antiaging trial raises questions” 



    Aug. 1, 2016
    Jocelyn Kaiser

    A controversial pay-to-participate clinical trial will test whether plasma from young donors can counteract aging. Martin Schutt/picture-alliance/dpa/AP Images

    It was one of the most mind-bending scientific reports in 2014: Injecting old mice with the plasma portion of blood from young mice seemed to improve the elderly rodents’ memory and ability to learn. Inspired by such findings, a startup company has now launched the first clinical trial in the United States to test the antiaging benefits of young blood in relatively healthy people. But there’s a big caveat: It’s a pay-to-participate trial, a type that has raised ethical concerns before, most recently in the stem cell field.

    The firm’s co-founder and trial principal investigator is a 31-year-old physician named Jesse Karmazin. His company, Ambrosia in Monterey, California, plans to charge participants $8000 for lab tests and a one-time treatment with young plasma. The volunteers don’t have to be sick or even particularly aged—the trial is open to anyone 35 and older. Karmazin notes that the study passed ethical review and argues that it’s not that unusual to charge people to participate in clinical trials.

    To some ethicists and researchers, however, the trial raises red flags, both for its cost to participants and for a design that they say is unlikely to deliver much science. “There’s just no clinical evidence [that the treatment will be beneficial], and you’re basically abusing people’s trust and the public excitement around this,” says neuroscientist Tony Wyss-Coray of Stanford University in Palo Alto, California, who led the 2014 young plasma study in mice.

    Decades ago, so-called parabiosis studies, in which the circulation of old and young animals was connected so that their blood mingles, suggested that young blood can rejuvenate aging mice. A recent revival of the unusual approach has shown beneficial effects on muscle, the heart, brain, and other organs, and some researchers are scrutinizing young blood for specific factors that explain these observations. The 2014 study, however, suggested that repeated injections of plasma from young animals were an easy alternative to parabiosis. Wyss-Coray has since started a company, Alkahest, that, with Stanford, has launched a study of young plasma in 18 people with Alzheimer’s disease, evaluating its safety and monitoring whether the treatment relieves any cognitive problems or other symptoms. The company covers the participants’ costs. Wyss-Coray expects results by the end of this year. (Another trial at a research hospital in South Korea is examining whether cord blood or plasma can prevent frailty in the elderly.)

    In Ambrosia’s trial, 600 people age 35 and older would receive plasma from a donor under age 25, according to the description registered on ClinicalTrials.gov, the federal website intended to track human trials and their results. Karmazin says each person will receive roughly 1.5 liters over 2 days. Before the infusions and 1 month after, their blood will be tested for more than 100 biomarkers that may vary with age, from hemoglobin level to inflammation markers. The $8000 fee—not mentioned on ClinicalTrials.gov—will cover costs such as plasma from a blood bank, lab tests, the ethics review, insurance, and an administrative fee, Karmazin says. “It adds up fairly quickly.”

    Kamarzin became interested in aging as an undergraduate. In medical school at Stanford, where he rotated through labs focused on stem cells and aging, he took note of the young plasma mouse study and other parabiosis research. Karmazin was also intrigued by the story of a Russian physician named Alexander Bogdanov, who in the 1920s gave himself infusions of young human blood that he claimed boosted his energy level and bestowed a more youthful appearance. There are “overwhelming data” suggesting that young plasma will be beneficial to people, Karmazin says.

    Last year, Karmazin co-founded a company called xVitality Sciences that aimed to offer plasma treatments at clinics overseas. The venture didn’t pan out—Karmazin left, and the company is now apparently defunct. Karmazin then started Ambrosia with Craig Wright, a former chief scientific officer at a vaccine company, who now runs a clinic in Monterey. The company’s study, which was reviewed by a commercial ethics board used by some for-profit stem cell clinics, doesn’t need approval by the U.S. Food and Drug Administration, the pair says, because plasma transfusions are a well-established, standard treatment. Karmazin says he and Wright have now heard from about 20 prospective participants, and have enrolled three, all elderly. Wright will likely transfuse plasma into the first person in late August.

    To bioethicist Leigh Turner at the University of Minnesota, Twin Cities, the study brings to mind a growing number of scientifically dubious trials registered in ClinicalTrials.gov by private, for-profit stem cell clinics. The presence of such trials in the database confers “undeserved legitimacy,” he says.

    The scientific design of the trial is drawing concerns as well. “I don’t see how it will be in any way informative or convincing,” says aging biologist Matt Kaeberlein of the University of Washington, Seattle. The participants won’t necessarily be elderly, making it hard to see any effects, and there are no well-accepted biomarkers of aging in blood, he says. “If you’re interested in science,” Wyss-Coray adds, why doesn’t such a large trial include a placebo arm? Karmazin says he can’t expect people to pay knowing they may get a placebo. With physiological measurements taken before and after treatment, each person will serve as their own control, he explains.

    Doubts aside, Ambrosia’s trial has already attracted attention from the investment company of billionaire Peter Thiel, who is apparently interested in trying young plasma treatments himself, Inc. reported today. Karmazin says he’s filling a void, suggesting that most companies wouldn’t be interested in developing human plasma as an antiaging treatment. “It’s this extremely abundant therapeutic that’s just sitting in blood banks,” he insists.

    *Correction, 2 August, 10:23 a.m.: This story has been corrected to clarify that it is the enrolled patients in the study who are elderly.

    See the full article here .

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  • richardmitnick 10:40 am on July 29, 2016 Permalink | Reply
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    From Science- “Forbidden planets: Understanding alien worlds once thought impossible” 



    Jul. 28, 2016
    Daniel Clery

    The exoplanet HR 8799 b, a super-Jupiter (seen from a speculative moon), takes 460 years to orbit its star. NASA/ESA/G. Bacon (STSCI)

    When astronomers discovered the first exoplanet around a normal star 2 decades ago, there was joy—and bewilderment. The planet, 51 Pegasi b, was half as massive as Jupiter, but its 4-day orbit was impossibly close to the star, far smaller than the 88-day orbit of Mercury. Theorists who study planet formation could see no way for a planet that big to grow in such tight confines around a newborn star. It could have been a freak, but soon, more “hot Jupiters” turned up in planet searches, and they were joined by other oddities: planets in elongated and highly tilted orbits, even planets orbiting their stars “backward”—counter to the star’s rotation.

    The planet hunt accelerated with the launch of NASA’s Kepler spacecraft in 2009, and the 2500 worlds it has discovered added statistical heft to the study of exoplanets—and yet more confusion.

    NASA/Kepler Telescope
    NASA/Kepler Telescope

    Kepler found that the most common type of planet in the galaxy is something between the size of Earth and Neptune—a “super-Earth,” which has no parallel in our solar system and was thought to be almost impossible to make. Now, ground-based telescopes are gathering light directly from exoplanets, rather than detecting their presence indirectly as Kepler does, and they, too, are turning up anomalies. They have found giant planets several times the mass of Jupiter, orbiting their star at more than twice the distance Neptune is from the sun—another region where theorists thought it was impossible to grow large planets. Other planetary systems looked nothing like our orderly solar system, challenging the well-worn theories that had been developed to explain it.

    “It’s been really obvious things didn’t fit pretty much from day one,” says Bruce Macintosh, a physicist at Stanford University in Palo Alto, California. “There has never been a moment when theory has caught up with observations.”

    Theorists are trying to catch up—coming up with scenarios for growing previously forbidden kinds of planets, in places once thought off-limits. They are envisioning how planets could form in much more mobile and chaotic environments than they ever pictured before, where nascent planets drift from wide to narrow orbits or get ricocheted into elongated or off-kilter paths by other planets or passing stars. But the ever-expanding zoo of exotic planets that observers are tallying means every new model is provisional. “You can discover something new every day,” says astrophysicist Thomas Henning of the Max Planck Institute for Astronomy in Heidelberg, Germany. “It’s a Gold Rush situation.”

    (Graphic) J. You/Science: (Data) Exoplanets.eu

    The traditional model of how stars and their planets form dates back to the 18th century, when scientists proposed that a slowly rotating cloud of dust and gas could collapse under its own gravity. Most of the material forms a ball that ignites into a star when its core gets dense and hot enough. Gravity and angular momentum herd the leftover material around the protostar into a flat disk. Dust is key to transforming this disk into a set of planets. The dust, which accounts for a small fraction of the disk’s mass, is made up of microscopic specks of iron and other solids. As they swirl in the roiling disk, the specks occasionally collide and stick together by electromagnetic forces. Over a few million years, the dust builds up into grains, pebbles, boulders, and, eventually, kilometer-wide planetesimals.

    At that point gravity takes over, pulling in other planetesimals and vacuuming up dust and gas until planet-sized bodies take shape. By the time that happens in the inner part of the disk, most of its gas has been stripped away, either gobbled up by the star or blown away by its stellar wind. The dearth of gas means inner planets remain largely rocky, with thin atmospheres.

    This growth process, known as core accretion, proceeds faster in the outer parts of the disk, where it is cold enough for water to freeze. The ice beyond this “snowline” supplements the dust, allowing protoplanets to consolidate more quickly. They build up a solid core five to 10 times the mass of Earth—quickly enough that the disk remains gas-rich and the core can pull in a thick atmosphere, producing a gas giant like Jupiter. (One of the goals of NASA’s Juno spacecraft, which arrived at Jupiter earlier this month, is to see whether the planet really does have a massive core.)

    This scenario naturally produces a planetary system just like our own: small, rocky planets with thin atmospheres close to the star, a Jupiter-like gas giant just beyond the snowline, and the other giants getting progressively smaller at greater distances because they move more slowly through their orbits and take longer to hoover up material. All the planets remain roughly where they formed, in circular orbits in the same plane. Nice and tidy.

    But the discovery of hot Jupiters suggested something was seriously amiss with the theory. A planet with an orbit measured in days travels an extremely short distance around the star, which limits the amount of material it can scoop up as it forms. It seemed inconceivable that a gas giant could have formed in such a location. The inevitable conclusion was that it must have formed farther out and moved in.

    Theorists have come up with two possible mechanisms for shuffling the planetary deck. The first, known as migration, requires there to be plenty of material left in the disk after the giant planet has formed. The planet’s gravity distorts the disk, creating areas of higher density, which, in turn, exert a gravitational “drag” on the planet, causing it to gradually drift inward toward the star.

    There is supporting evidence for the idea. Neighboring planets often end up in a stable, gravitational relationship known as orbital resonance. This happens when the lengths of their orbits are in a ratio of small whole numbers. Pluto, for example, orbits the sun two times for every three orbits of Neptune. It’s highly unlikely that they just happened to form that way, so they must have drifted into that position, where they were locked in by the extra stability. Migration early in our solar system’s history could account for other oddities, including the small size of Mars and the sparse, disrupted asteroid belt. To explain them, theorists have invoked a maneuver called the grand tack, in which Jupiter originally formed closer to the sun, drifted inward almost to the orbit of Earth, and then drifted out again to its current position.

    Some modelers find such scenarios unnecessarily complex. “I do have faith in Occam’s razor,” says Greg Laughlin, an astronomer at the University of California (UC), Santa Cruz. Laughlin argues that planets are more likely to form in place and stay put. He says it’s possible for large planets to form close to their star if protoplanetary disks contain much more material there than previously believed. Some movement of planets may still occur—enough to explain resonances, for example—but “it’s a final subtle adjustment, not a major conveyor belt,” Laughlin says.

    But others say that there simply could not be enough material to form close-in planets like 51 Pegasi b and others that are even closer. “They cannot have formed in situ,” physicist Joshua Winn of the Massachusetts Institute of Technology in Cambridge declares flatly. And the sizable fraction of exoplanets that appear to be in elongated, tilted, or even backward orbits also seems to imply some kind of planet shuffling.

    For these oddballs, theorists invoke a gravitational melee rather than a sedate migration. A mass-rich disk could produce many planets close together, where gravitational tussles would fling them into the star, into weird orbits, or out of the system. Another potential disruptor is a companion star in an elongated orbit. Most of the time it would be too far away to have an influence, but occasionally it could swing in and stir things up. Or, if the parent star is a member of a tight-knit stellar cluster, a neighboring star might drift too close and wreak havoc. “There are a lot of ways to break a system,” Winn says.

    Kepler’s surprising finding that 60% of sunlike stars are orbited by a super-Earth, however, requires a whole new class of theories. Most super-Earths, thought to be largely solid rock and metal with modest amounts of gas, follow tighter orbits than Earth, and often a star has several. The Kepler-80 system, for example, has four super-Earths, all with orbits of 9 days or less. The traditional theory holds that inside the snowline core accretion is too slow to produce something so large. And super-Earths are rarely found in resonant orbits, suggesting that they haven’t migrated, but formed where they sit.

    Researchers are coming up with ways around the problem. One idea is to speed up accretion, through a process known as pebble accretion. The gas in a rich disk exerts a lot of drag on pebble-sized objects. This generally slows them down, causing them to drift in toward the star. If they pass a planetesimal along the way, their slow speed means they can be captured more easily, boosting accretion. But faster accretion and a gas-rich disk raise their own problem: The super-Earths ought to pull in a thick atmosphere once they exceed a certain size. “How do you keep them from becoming gas giants?” asks astrophysicist Roman Rafikov of the Institute for Advanced Study in Princeton, New Jersey.

    V. Altounian/Science

    Eugene Chiang, an astronomer at UC Berkeley, says there is no need to speed up accretion, so long as the disk is solid-rich and gas-poor. He says that an inner disk 10 times denser than the one that formed the solar system could easily produce one or more super-Earths. Chiang has his super-Earths avoid collecting too much residual gas by forming in the dying days of the disk when most of the gas has dissipated.

    Some early observations from the Atacama Large Millimeter/submillimeter Array (ALMA), an international facility nearing completion in northern Chile, support this proposal.

    ESO/NRAO/NAOJ ALMA Array in Chile in the Atacama at  Chajnantor plateau, at 5,000 metres
    ESO/NRAO/NAOJ ALMA Array in Chile in the Atacama at Chajnantor plateau, at 5,000 metres

    ALMA can map radio emissions from the warm dust and gravel in disks. The few it has studied so far seem to be relatively massive. But the observations aren’t yet a smoking gun, because ALMA is not yet fully operational and it can only see the outer parts of disks, not the regions where super-Earths reside. “Getting close in, that’s the trick,” Chiang says—something that ALMA may perform when all 66 of its antennas are working.

    Chiang also has an explanation for another discovery of Kepler’s: superpuffs, a rare and equally problematic set of planets that have a smaller mass than super-Earths but appear huge, with a puffed-up atmosphere making up 20% of their mass. Such planets are thought to form in a gas-rich disk. But in the inner disk, warm gas would fight against the planet’s weak gravity, so the cold and dense gas of the outer disk is the more likely womb. Chiang invokes migration to explain their close orbits—a notion supported by the fact that superpuffs are often found locked in resonant orbits.

    Most of the attention in exoplanet research has so far focused on the inner parts of planetary systems, roughly within a distance equivalent to the orbit of Jupiter, for the simple reason that that’s all existing detection methods can see. The two main methods—measuring the wobble of stars caused by the gravitational tug of an orbiting planet and measuring the periodic dimming of a star as a planet passes in front—both favor big planets in close orbits. Imaging the planets themselves is extremely difficult, because their faint light is all but swamped by the glare from their star, which can be a billion times brighter.

    But by stretching the limits of the world’s biggest telescopes, astronomers have seen a handful of planets directly. And over the past couple years, two new instruments designed specifically to image exoplanets have joined the hunt. Europe’s Spectro-Polarimetric High-contrast Exoplanet REsearch (SPHERE) and the U.S.-backed Gemini Planet Imager (GPI) are attached to big telescopes in Chile and employ sophisticated masks, called coronagraphs, to block out the light of the star.

    ESO SPHERE extreme adaptive optics system and coronagraphic facility on the extreme adaptive optics system and coronagraphic facility on the VLT
    ESO SPHERE extreme adaptive optics system and coronagraphic facility on the extreme adaptive optics system and coronagraphic facility on the VLT, Cerro Paranal, Chile

    NOAO Gemini Planet Imager on Gemini South
    NOAO Gemini Planet Imager on Gemini South, Cerro Tololo Inter-American Observatory (CTIO) campus near La Serena, Chile

    Not surprisingly, planets far from their stars are the easiest targets.

    One of the earliest and most astounding systems found by direct imaging is the one around the star HR 8799, where four planets range in orbits from beyond that of Saturn out to more than twice the distance of Neptune. What’s most surprising is that all four are huge, more than five times the mass of Jupiter. According to theory, planets in such distant orbits move so slowly that they should grow at a glacial rate and top out at masses well short of Jupiter’s before the disk disperses. Yet the planets’ nice circular orbits suggest they weren’t flung there from closer to their stars.

    Such distant giants lend support to the most radical challenge to standard theory, in which some planets form not by core accretion, but by a process called gravitational instability. This process requires a gas-rich protoplanetary disk, which breaks up into clumps under its own gravity. These blobs of gas would collapse over time directly into giant planets without having to form a solid core first. Models suggest that the mechanism will only work in particular circumstances: The gas has to be cold, it mustn’t be spinning too fast, and the contracting gas must be able to shed heat efficiently. Can it explain the planets of HR 8799? Only the outer two are distant and cold enough, Rafikov says. “It’s still quite a puzzling system,” he says.

    In the past, radio telescope observations of protoplanetary disks have provided some support for gravitational instability. Sensitive to cold gas, the telescopes saw disks spattered with messy, asymmetrical blobs. But recent images from ALMA paint a different picture. ALMA is sensitive to shorter wavelengths that come from dust grains in the midplane of the disk, and its images of the star HL Tauri in 2014 and TW Hydrae this year showed smooth, symmetrical disks with dark circular “gaps” extending far beyond Neptune-like orbits (see picture below). “It was a tremendous surprise. The disk was not a mess, but has a nice, regular, beautiful structure,” Rafikov says. These images, suggestive of planets sweeping their orbits clean as they grow by core accretion, were a blow to advocates of gravitational instability.

    An image of HL Tauri’s protoplanetary disk. Are planets forming in the gaps? ALMA (ESO/NAOJ/NRAO)

    It’s too early to tell what other surprises GPI and SPHERE may find in the outer reaches of planetary systems. But the region between those outlying neighborhoods and the close-in domains of hot Jupiters and super-Earths remains stubbornly out of reach: too close to the star for direct imaging, too far for indirect techniques relying on stellar wobbles or dimming. As a result, it is hard for theorists to get a full picture of what exoplanetary systems are like. “We’re basing things on fragmentary and incomplete observations,” Laughlin says. “Right now, everyone’s probably wrong.”

    Astronomers won’t have to wait long for better data. Next year, NASA will launch its Transiting Exoplanet Survey Satellite (TESS), and the following year the European Space Agency (ESA) is expected to launch the Characterizing Exoplanets Satellite (CHEOPS).



    Unlike Kepler, which surveyed a large number of stars in sparse detail to compile an exoplanetary census, TESS and CHEOPS will focus on bright, sunlike stars close to Earth, enabling researchers to explore the midorbit terra incognita. And because the targeted stars are nearby, ground-based telescopes should be able to assess the mass of their planets, allowing researchers to calculate the planets’ density, indicating which are rocky or gassy.

    The James Webb Space Telescope, due for launch in 2018, will go further, analyzing starlight that passes through an exoplanet’s atmosphere to determine its makeup.

    NASA/ESA/CSA Webb Telescope annotated
    NASA/ESA/CSA Webb Telescope annotated

    “Composition is an important clue to formation,” Macintosh says. For example, finding heavier elements in the atmospheres of super-Earths could suggest that a disk rich in such elements is needed to form planetary cores fast enough. And next decade, spacecraft such as NASA’s Wide Field Infrared Survey Telescope [WFIRST] and ESA’s Planetary Transits and Oscillations [PLATO]will join the hunt, alongside a new generation of enormous ground-based telescopes with mirrors 30 meters across or more.



    If the past is anything to go by, modelers will have to keep on their toes. “Nature is smarter than our theories,” Rafikov says.

    See the full article here .

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  • richardmitnick 6:54 am on July 28, 2016 Permalink | Reply
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    From Science: “Neurons get fresh ‘batteries’ after stroke” 



    Jul. 27, 2016
    Emily Underwood

    When neurons are damaged, cells called astrocytes (above) may assist by donating cellular power plants called mitochondria, a new study suggests. GerryShaw/Wikimedia Commons

    If your car’s battery dies, you might call on roadside assistance—or a benevolent bystander—for a jump. When damaged neurons lose their “batteries,” energy-generating mitochondria, they call on a different class of brain cells, astrocytes, for a boost, a new study suggests. These cells respond by donating extra mitochondria to the floundering neurons. The finding, still preliminary, might lead to novel ways to help people recover from stroke or other brain injuries, scientists say.

    “This is a very interesting and important study because it describes a new mechanism whereby astrocytes may protect neurons,” says Reuven Stein, a neurobiologist at The Rabin Institute of Neurobiology in Tel Aviv, Israel, who was not involved in the study.

    To keep up with the energy-intensive work of transmitting information throughout the brain, neurons need a lot of mitochondria, the power plants that produce the molecular fuel—ATP—that keeps cells alive and working. Mitochondria must be replaced often in neurons, in a process of self-replication called fission—the organelles were originally microbes captured inside a cell as part of a symbiosis. But if mitochondria are damaged or if they can’t keep up with a cell’s needs, energy supplies can run out, killing the cell.

    In 2014, researchers published the first evidence that cells can transfer mitochondria in the brain—but it seemed more a matter of throwing out the trash. When neurons expel damaged mitochondria, astrocytes swallow them and break them down. Eng Lo and Kazuhide Hayakawa, both neuroscientsists at Massachusetts General Hospital in Charlestown, wondered whether the transfer could go the other way as well—perhaps astrocytes donated working mitochondria to neurons in distress. Research by other groups supported that idea: A 2012 study, for example, found that stem cells from bone marrow can donate mitochondria to lung cells after severe injury.

    To find out whether this kind of donation was taking place in the brain, Lo and Hayakawa teamed up with researchers in Bejing to test whether astrocytes could be coaxed into expelling healthy, working mitochondria. Previous studies hinted that astrocytes may pick up on neurons’ “help me” signals using an enzyme called CD38, Lo says. The enzyme, produced throughout the body in response to injury or damage, is also made by astrocytes. When Lo and colleagues genetically engineered mice to produce excess CD38, astrocytes from the rodents—extracted and deposited into fluid-filled dishes—expelled large numbers of still-functional mitochondrial particles. Researchers then dumped the mitochondria-rich fluid into another dish containing dying mouse neurons, and found that the cells did, in fact, absorb the mitochondria within 24 hours. The recharged neurons also grew new branches, lived longer, and had higher levels of ATP than cells not receiving the replacement batteries, suggesting that the astrocytes’ mitochondria were beneficial.

    Next, the team needed to determine whether the same phenomenon happens in living animals. So they subjected live, anesthetized mice to a strokelike injury and then injected damaged brain regions with astrocyte-derived mitochondria. After 24 hours, scientists killed the mice, cut into their brains, and examined the tissue microscopically. They saw that the mice neurons had not only absorbed the mitochondria, but also had significantly higher levels of molecules known to promote survival in distressed cells than did mice that had not received the mitochondrial cocktail.

    Finally, the team tested whether CD38 was necessary for the transfer. They injected mice with short segments of RNA designed to interfere with the enzyme’s function. Mice who received the treatment after their simulated “strokes” had far fewer astrocytic mitochondria in their neurons. The rodents also fared twice as badly on neurological tests compared with ones in which CD38 was unblocked , the team reports today in Nature. Lo emphasizes that the work is merely a “proof-of-concept study,” but adds that the outcomes of the neurological tests “tells you [the enzyme] is clinically relevant.”

    Given that CD38 plays many important roles throughout the body, including the immune system, the data are “way too preliminary” to start pursuing drugs that would increase or alter its activity, cautions Frances Lund, a microbiologist at the University of Birmingham in Alabama. It’s not clear, for example, whether the transfer of mitochondria was caused by, or merely correlated with, CD38 levels, she says.

    Still, Jun Chen, a neurobiologist at the University of Pittsburgh in Pennsylvania, is hopeful that the finding could lead to new treatments for diseases attributed to mitochondrial dysfunction. Parkinson’s disease, for example, is a neurodegenerative disorder strongly associated with mitochondrial dysfunction, in which dopamine-producing neurons in certain brain regions die en masse. If the new research pans out, he says, clinicians may one day be able to deliver healthy mitochondria into sick, but still viable, neurons.

    See the full article here .

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  • richardmitnick 8:45 am on July 22, 2016 Permalink | Reply
    Tags: , , Proteins, , Science, , This protein designer aims to revolutionize medicines and materials   

    From Science: “This protein designer aims to revolutionize medicines and materials” 



    David Baker shows off models of some of the unnatural proteins his team has designed and made.

    Jul. 21, 2016
    Robert F. Service

    David Baker appreciates nature’s masterpieces. “This is my favorite spot,” says the Seattle native, admiring the views from a terrace at the University of Washington (UW) here. To the south rises Mount Rainier, a 4400-meter glacier-draped volcano; to the west, the white-capped Olympic Mountain range.

    But head inside to his lab and it’s quickly apparent that the computational biochemist is far from satisfied with what nature offers, at least when it comes to molecules. On a low-slung coffee table lie eight toy-sized, 3D-printed replicas of proteins. Some resemble rings and balls, others tubes and cages—and none existed before Baker and his colleagues designed and built them. Over the last several years, with a big assist from the genomics and computer revolutions, Baker’s team has all but solved one of the biggest challenges in modern science: figuring out how long strings of amino acids fold up into the 3D proteins that form the working machinery of life. Now, he and colleagues have taken this ability and turned it around to design and then synthesize unnatural proteins intended to act as everything from medicines to materials.


    Already, this virtuoso proteinmaking has yielded an experimental HIV vaccine, novel proteins that aim to combat all strains of the influenza viruses simultaneously, carrier molecules that can ferry reprogrammed DNA into cells, and new enzymes that help microbes suck carbon dioxide out of the atmosphere and convert it into useful chemicals. Baker’s team and collaborators report making cages that assemble themselves from as many as 120 designer proteins, which could open the door to a new generation of molecular machines.

    f the ability to read and write DNA spawned the revolution of molecular biology, the ability to design novel proteins could transform just about everything else. “Nobody knows the implications,” because it has the potential to impact dozens of different disciplines, says John Moult, a protein-folding expert at the University of Maryland, College Park. “It’s going to be totally revolutionary.”

    Baker is by no means alone in this pursuit. Efforts to predict how proteins fold, and use that information to fashion novel versions, date back decades. But today he leads the charge. “David has really inspired the field,” says Guy Montelione, a protein structure expert at Rutgers University, New Brunswick, in New Jersey. “That’s what a great scientist does.”

    Baker, 53, didn’t start out with any such vision. Though both his parents were professors at UW—in physics and atmospheric sciences—Baker says he wasn’t drawn to science growing up. As an undergraduate at Harvard University, Baker tried studying philosophy and social studies. That was “a total waste of time,” he says now. “It was a lot of talk that didn’t necessarily add content.” Biology, where new insights can be tested and verified or discarded, drew him instead, and he pursued a Ph.D. in biochemistry. During a postdoc at the University of California, San Francisco, when he was studying how proteins move inside cells, Baker found himself captivated instead by the puzzle of how they fold. “I liked it because it’s getting at something fundamental.”

    In the early 1960s, biochemists at the U.S. National Institutes of Health (NIH) recognized that each protein folds itself into an intrinsic shape. Heat a protein in a solution and its 3D structure will generally unravel. But the NIH group noticed that the proteins they tested refold themselves as soon as they cool, implying that their structure stems from the interactions between different amino acids, rather than from some independent molecular folding machine inside cells. If researchers could determine the strength of all those interactions, they might be able to calculate how any amino acid sequence would assume its final shape. The protein-folding problem was born.

    From DNA to proteins

    The machinery for building proteins is essential for all life on earth. Click on the arrows at the bottom or swipe horizontally to learn more.

    One way around the problem is to determine protein structures experimentally, through methods such as x-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. But that’s slow and expensive. Even today, the Protein Data Bank, an international repository, holds the structures of only roughly 110,000 proteins out of the hundreds of millions or more thought to exist.

    Knowing the 3D structures of those other proteins would offer biochemists vital insights into each molecule’s function, such as whether it serves to ferry ions across a cell membrane or catalyze a chemical reaction. It would also give chemists valuable clues to designing new medicines. So, instead of waiting for the experimentalists, computer modelers such as Baker have tackled the folding problem with computer models.

    They’ve come up with two broad kinds of folding models. So-called homology models compare the amino acid sequence of a target protein with that of a template—a protein with a similar sequence and a known 3D structure. The models adjust their prediction for the target’s shape based on the differences between its amino acid sequence and that of the template. But there’s a major drawback: There simply aren’t enough proteins with known structures to provide templates—despite costly efforts to perform industrial-scale x-ray crystallography and NMR spectroscopy.

    Templates were even scarcer more than 2 decades ago, when Baker accepted his first faculty position at UW. That prompted him to pursue a second path, known as ab initio modeling, which calculates the push and pull between neighboring amino acids to predict a structure. Baker also set up a biochemistry lab to study amino acid interactions, in order to improve his models.

    Early on, Baker and Kim Simons, one of his first students, created an ab initio folding program called Rosetta, which broke new ground by scanning a target protein for short amino acid stretches that typically fold in known patterns and using that information to help pin down the molecule’s overall 3D configuration. Rosetta required such extensive computations that Baker’s team quickly found themselves outgrowing their computer resources at UW.

    Seeking more computing power, they created a crowdsourcing extension called Rosetta@home, which allows people to contribute idle computer time to crunching the calculations needed to survey all the likely protein folds. Later, they added a video game extension called Foldit, allowing remote users to apply their instinctive protein-folding insights to guide Rosetta’s search. The approach has spawned an international community of more than 1 million users and nearly two dozen related software packages that do everything from designing novel proteins to predicting the way proteins interact with DNA.

    “The most brilliant thing David has done is build a community,” says Neil King, a former Baker postdoc, now an investigator at UW’s Institute for Protein Design (IPD). Some 400 active scientists continually update and improve the Rosetta software. The program is free for academics and nonprofit users, but there’s a $35,000 fee for companies. Proceeds are plowed back into research and an annual party called RosettaCon in Leavenworth, Washington, where attendees mix mountain hikes and scientific talks.

    Despite this success, Rosetta was limited. The software was often accurate at predicting structures for small proteins, fewer than 100 amino acids in length. Yet, like other ab initio programs, it struggled with larger proteins. Several years ago, Baker began to doubt that he or anyone else would ever manage to solve most protein structures. “I wasn’t sure whether I would get there.”

    Now, he says, “I don’t feel that way anymore.”

    What changed his outlook was a technique first proposed in the 1990s by computational biologist Chris Sander, then with the European Molecular Biology Laboratory in Heidelberg, Germany, and now with Harvard. Those were the early days of whole genome sequencing, when biologists were beginning to decipher the entire DNA sequences of microbes and other organisms. Sander and others wondered whether gene sequences could help identify pairs of amino acids that, although distant from each other on the unfolded proteins, have to wind up next to each other after the protein folds into its 3D structure.

    Clues from genome sequences

    Comparing the DNA of similar proteins from different organisms shows that certain pairs of amino acids evolve in tandem—when one changes, so does the other. This suggests they are neighbors in the folded protein, a clue for predicting structure.

    Sander reasoned that the juxtaposition of those amino acids must be crucial to a protein’s function. If a mutation occurs, changing one of the amino acids so that it no longer interacts with its partner, the protein might no longer work, and the organism could suffer or die. But if both neighboring amino acids are mutated at the same time, they might continue to interact, and the protein might work as well or even better.

    The upshot, Sander proposed, was that certain pairs of amino acids necessary to a protein’s structure would likely evolve together. And researchers would be able to read out that history by comparing the DNA sequences of genes from closely related proteins in different organisms. Whenever such DNA revealed pairs of amino acids that appeared to evolve in lockstep, it would suggest that they were close neighbors in the folded protein. Put enough of those constraints on amino acid positions into an ab initio computer model, and the program might be able to work out a protein’s full 3D structure.

    Unfortunately, Sander says, his idea “was a little ahead of its time.” In the 1990s, there weren’t enough high-quality DNA sequence data from enough similar proteins to track coevolving amino acids.

    By the early part of this decade, however, DNA sequences were flooding in thanks to new gene-sequencing technology. Sander had also teamed up with Debora Marks at Harvard Medical School in Boston to devise a statistical algorithm capable of teasing out real coevolving pairs from the false positives that plagued early efforts. In a 2011 article in PLOS ONE, Sander, Marks, and colleagues reported that the coevolution technique could constrain the position of dozens of pairs of amino acids in 15 proteins—each from a different structural family—and work out their structures. Since then, Sander and Marks have shown that they can decipher the structure of a wide variety of proteins for which there are no homology templates. “It has changed the protein-folding game,” Sander says.

    It certainly did so for Baker. When he and colleagues realized that scanning genomes offered new constraints for Rosetta’s ab initio calculations, they seized the opportunity. They were already incorporating constraints from NMR and other techniques. So they rushed to write a new software program, called Gremlin, to automatically compare gene sequences and come up with all the likely coevolving amino acid pairs. “It was a natural for us to put them into Rosetta,” Baker says.

    The results have been powerful. Rosetta was already widely considered the best ab initio model. Two years ago, Baker and colleagues used their combined approach for the first time in an international protein-folding competition, the 11th Critical Assessment of protein Structure Prediction (CASP). The contest asks modelers to compute the structures of a suite of proteins for which experimental structures are just being worked out by x-ray crystallography or NMR. After modelers submit their predictions, CASP’s organizers then reveal the actual experimental structures. One submission from Baker’s team, on a large protein known as T0806, came back nearly identical to the experimental structure. Moult, who heads CASP, says the judge who reviewed the predicted structure immediately fired off an email to him saying “either someone solved the protein-folding problem, or cheated.”

    “We didn’t [cheat],” Sergey Ovchinnikov, a grad student in Baker’s lab, says with a chuckle.

    The implications are profound. Five years ago, ab initio models had determined structures for just 56 proteins of the estimated 8000 protein families for which there is no template. Since then, Baker’s team alone has added 900 and counting, and Marks believes the approach will already work for 4700 families. With genome sequence data now pouring into scientific databases, it will likely only be a couple years before protein-folding models have enough coevolution data to solve structures for nearly any protein, Baker and Sander predict. Moult agrees. “I have been waiting 10 years for a breakthrough,” he says. “This seems to me a breakthrough.”

    For Baker, it’s only the beginning. With Rosetta’s steadily improving algorithms and ever-greater computing power, his team has in essence mastered the rules for folding—and they’ve begun to use that understanding to try to one-up nature’s creations. “Almost everything in biomedicine could be impacted by an ability to build better proteins,” says Harvard synthetic biologist George Church.

    Baker notes that for decades researchers pursued a strategy he refers to as “Neandertal protein design,” tweaking the genes for existing proteins to get them to do new things. “We were limited by what existed in nature. … We can now short-cut evolution and design proteins to solve modern-day problems.”

    Take medicines, such as drugs to combat the influenza virus. Flu viruses come in many strains that mutate rapidly, which makes it difficult to find molecules that can knock them all out. But every strain contains a protein called hemagglutinin that helps it invade host cells, and a portion of the molecule, known as the stem, remains similar across many strains. Earlier this year, Baker teamed up with researchers at the Scripps Research Institute in San Diego, California, and elsewhere to develop a novel protein that would bind to the hemagglutinin stem and thereby prevent the virus from invading cells.

    The effort required 80 rounds of designing the protein, engineering microbes to make it, testing it in the lab, and reworking the structure. But in the 4 February issue of PLOS ONE, the researchers reported that when they administered their final creation to mice and then injected them with a normally lethal dose of flu virus, the rodents were protected. “It’s more effective than 10 times the dose of Tamiflu,” an antiviral drug currently on the market, says Aaron Chevalier, a former Baker Ph.D. student who now works at a Seattle biotech company called Virvio here that is working to commercialize the protein as a universal antiflu drug.

    Another potential addition to the medicine cabinet: a designer protein that chops up gluten, the infamous substance in wheat and other grains that people with Celiac disease or gluten sensitivity have trouble digesting. Ingrid Swanson Pultz began crafting the gluten-breaker even before joining Baker’s lab as a postdoc and is now testing it in animals and working with IPD to commercialize the research. And those self-assembling cages that debut this week could one day be filled with drugs or therapeutic snippets of DNA or RNA that can be delivered to disease sites throughout the body.

    The potential of these unnatural proteins isn’t limited to medicines. Baker, King, and their colleagues have also attached up to 120 copies of a molecule called green fluorescent protein to the new cages, creating nano-lanterns that could aid research by lighting up as they move through tissues.

    Church says he believes that designer proteins might soon rewrite the biology inside cells. In a paper last year in eLife, he, Baker, and colleagues designed proteins to bind to either a hormone or a heart disease drug inside cells, and then regulate the activity of a DNA-cutting enzyme, Cas9, that is part of the popular CRISPR genome-editing system. “The ability to design sensors [inside cells] is going to be big,” Church says. The strategy could allow researchers or physicians to target the powerful gene-editing system to a specific set of cells—those that are responding to a hormone or drug. Biosensors could also make it possible to switch on the expression of specific genes as needed to break down toxins or alert the immune cells to invaders or cancer.

    Protein for every purpose

    The ability to predict how an amino acid sequence will fold—and hence how the protein will function—opens the way to designing novel proteins that can catalyze specific chemical reactions or act as medicines or materials. Genes for these proteins can be synthesized and inserted into microbes, which build the proteins.

    2D arrays can be used as nanomaterials in various applications.


    Information can be coded into protein sequences, like DNA.


    Antagonists bind to a target protein, blocking its activation.


    Channels through membranes act as gateways.


    Cages can contain medicinal cargo or carry it on their surfaces.


    Sensors travel throughout the body to detect various signals.


    Baker’s lab is abuzz with other projects. Last year, his group and collaborators reported engineering into bacteria a completely new metabolic pathway, complete with a designer protein that enabled the microbes to convert atmospheric carbon dioxide into fuels and chemicals. Two years ago, they unveiled in Science proteins that spontaneously arrange themselves in a flat layer, like interlocking tiles on a bathroom floor. Such surfaces may lead to novel types of solar cells and electronic devices.

    In perhaps the most thought-provoking project, Baker’s team has designed proteins to carry information, imitating the way DNA’s four nucleic acid letters bind and entwine in the genetic molecule’s famed double helix. For now, these protein helixes can’t convey genetic information that cells can read. But they symbolize something profound: Protein designers have shed nature’s constraints and are now only limited by their imagination. “We can now build a whole new world of functional proteins,” Baker says.

    See the full article here .


    Rosetta@home runs on software from Berkeley Open Infrastructure for Network Computing (BOINC).
    Visit the BOINC website, download and install the BOINC software, attach to the Rosetta@home project. It is that simple. The project will use the available cpu cycles of your computer, tablet or cell phone to “crunch” data for the Baker Lab.

    While you are at the BOINC website, check out some of the other really important projects running at universities and institutions all over the world. They could all use your help and would run simultaneously with no conflicts on your devices.


    BOINC WallPaper

    The American Association for the Advancement of Science is an international non-profit organization dedicated to advancing science for the benefit of all people.

    Please help promote STEM in your local schools.
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