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  • richardmitnick 10:33 am on April 27, 2017 Permalink | Reply
    Tags: , Bacteria, , , Microbes Have Been Found Growing "Out of Nowhere" After a Volcanic Eruption,   

    From Science Alert: “Microbes Have Been Found Growing “Out of Nowhere” After a Volcanic Eruption” 


    Science Alert

    26 APR 2017

    George Burba/Shutterstock

    Life finds a way.

    When an underwater volcano erupts, completely altering the underwater landscape for kilometres, you’d assume it wouldn’t be the best place to look for new life.

    But researchers have discovered just that, identifying a new species of furry white bacteria covering a submerged volcano 130 metres (426 feet) below sea level in the Canary Islands.

    Even weirder – it appears to have started colonising the volcano as soon as the temperature dropped.

    “I bet there were microbes appearing there just as soon as those rocks got below 100 °C (212 °F),” says David Kirchman, from the University of Delaware, told Sam Wong at New Scientist.

    Under the microscope: a single strand of Venus’s hair. Roberto Danovaro

    Back in 2011, the Canary Islands were hit by a number of tremors, while under water the Tagoro Volcano completely blanketed the seafloor with new rock over 138 days.

    Italian and Spanish researchers went to survey the area in 2014, expecting to see the underwater region still barren.

    Instead, they discovered that the volcano was covered in white, hair-like microbes – a species the researchers hadn’t seen before.

    “It was an impressive and surreal landscape, like discovering life on Mars,” Cinzia Corinaldesi, one of the researchers from the Polytechnic University of Marche told The Atlantic.

    Satellite image of the discolored water (light blue) during the Tagoro volcano eruption in 2012. NASA Earth Observatory

    CRG Marine Geosciences

    The white hair, which they’ve called Venus’s hair, was up to 3 centimetres (1 inch) long, and around 36-90 micrometres in diameter. (For reference, a human hair is between 17 and 180 micrometres in diameter.)

    And this wasn’t a small amount of fur – the researchers say it covered an area of roughly eight tennis courts (2,000 square metres, or about 21,500 square feet) across the volcano.

    But none of that answers how the hell it got there in the first place.

    “These organisms apparently come out of nowhere,” Kirchman told New Scientist.

    And not everything is as it appears, with countless passing microbes just waiting for an opportunity to settle and grow a family.

    “It’s helpful to remember that each drop of seawater contains millions of bacteria and that only one of them, in theory, is needed to colonise a new habitat, says Kirchman.

    “The Venus’s hair bacterium could have been in this ‘rare biosphere’ and by chance came across the virgin habitat created by the volcanic eruption.”

    Although the bacteria wouldn’t grow in the lab, the team sequenced its DNA, discovering that Venus’s hair was a completely new genus and species of the order Thiotrichales. The new scientific name for the hair is Thiolava veneris.

    Venus’s hair would have fed on the large amounts of hydrogen sulphide coming out of the rocks.

    While they’re only about 82 percent of the way through the DNA sequencing, the analysis does provide some hints on how Venus’s hair survives – it has a gene that produces a protein ‘pump’ capable of removing heavy metals that leach from the new volcanic rock.

    By the time the researchers had surveyed the area, the Venus’s hair was already acting as a welcoming committee – worms and crustaceans had started making the hair their home, reigniting life in that barren location.

    “A volcanic eruption is as devastating under the sea as it is on land, spewing out molten lava and toxic gas, destroying life in its shadow and disrupting habitats for kilometres in every direction,” writes Kirchman in a Nature editorial accompanying the piece.

    “But out of this destruction comes new land and the opportunity for life to begin again.”

    The research has been published in Nature Ecology & Evolution.

    See the full article here .

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  • richardmitnick 8:35 pm on September 12, 2016 Permalink | Reply
    Tags: , Bacteria, ,   

    From Rutgers: “Rutgers Researchers Debunk ‘Five-Second Rule’: Eating Food off the Floor Isn’t Safe” 

    Rutgers University
    Rutgers University

    September 8, 2016
    Steve Manas

    Turns out bacteria may transfer to candy that has fallen on the floor no matter how fast you pick it up.

    Rutgers researchers have disproven the widely accepted notion that it’s okay to scoop up food and eat it within a “safe” five-second window. Donald Schaffner, professor and extension specialist in food science, found that moisture, type of surface and contact time all contribute to cross-contamination. In some instances, the transfer begins in less than one second.

    Their findings appear online in the American Society for Microbiology’s journal, Applied and Environmental Microbiology.

    “The popular notion of the ‘five-second rule’ is that food dropped on the floor, but picked up quickly, is safe to eat because bacteria need time to transfer,” Schaffner said, adding that while the pop culture “rule” has been featured by at least two TV programs, research in peer-reviewed journals is limited.

    “We decided to look into this because the practice is so widespread. The topic might appear ‘light’ but we wanted our results backed by solid science,” said Schaffner, who conducted research with Robyn Miranda, a graduate student in his laboratory at the School of Environmental and Biological Sciences, Rutgers University-New Brunswick.

    The researchers tested four surfaces – stainless steel, ceramic tile, wood and carpet – and four different foods (watermelon, bread, bread and butter, and gummy candy). They also looked at four different contact times – less than one second, five, 30 and 300 seconds. They used two media – tryptic soy broth or peptone buffer – to grow Enterobacter aerogenes, a nonpathogenic “cousin” of Salmonella naturally occurring in the human digestive system.

    Transfer scenarios were evaluated for each surface type, food type, contact time and bacterial prep; surfaces were inoculated with bacteria and allowed to completely dry before food samples were dropped and left to remain for specified periods. All totaled 128 scenarios were replicated 20 times each, yielding 2,560 measurements. Post-transfer surface and food samples were analyzed for contamination.

    Not surprisingly, watermelon had the most contamination, gummy candy the least. “Transfer of bacteria from surfaces to food appears to be affected most by moisture,” Schaffner said. “Bacteria don’t have legs, they move with the moisture, and the wetter the food, the higher the risk of transfer. Also, longer food contact times usually result in the transfer of more bacteria from each surface to food.”

    Perhaps unexpectedly, carpet has very low transfer rates compared with those of tile and stainless steel, whereas transfer from wood is more variable. “The topography of the surface and food seem to play an important role in bacterial transfer,” Schaffner said.

    So while the researchers demonstrate that the five-second rule is “real” in the sense that longer contact time results in more bacterial transfer, it also shows other factors, including the nature of the food and the surface it falls on, are of equal or greater importance.

    “The five-second rule is a significant oversimplification of what actually happens when bacteria transfer from a surface to food,” Schaffner said. “Bacteria can contaminate instantaneously.”

    See the full article here .

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    Rutgers, The State University of New Jersey, is a leading national research university and the state’s preeminent, comprehensive public institution of higher education. Rutgers is dedicated to teaching that meets the highest standards of excellence; to conducting research that breaks new ground; and to providing services, solutions, and clinical care that help individuals and the local, national, and global communities where they live.

    Founded in 1766, Rutgers teaches across the full educational spectrum: preschool to precollege; undergraduate to graduate; postdoctoral fellowships to residencies; and continuing education for professional and personal advancement.

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  • richardmitnick 8:46 pm on August 14, 2016 Permalink | Reply
    Tags: , Bacteria, , Dr Berkay Ozcelik, , Stopping superbugs with a protective coat   

    From CSIRO: “Stopping superbugs with a protective coat” 

    CSIRO bloc

    Commonwealth Scientific and Industrial Research Organisation

    15th August 2016
    Chris Still

    Bacteria close up. No image credit.

    Around the world 700,000 people die of drug resistant infections a year, and that figure could rise to 10 million a year by 2050. The resulting financial cost is predicted to reach $100 trillion USD. It’s a global problem with no easy solution – but Dr Berkay Ozcelik is working on it.

    A Postdoctoral Fellow in our Manufacturing business unit, Berkay’s research has taken him from potentially restoring sight to millions of people, to working on a way to save millions of lives.

    While a student at University of Melbourne, Berkay developed a special film that may help repair damaged corneas and reduce the need for donors. As a result he was named the 2016 Victorian winner of the “Fresh Science” program to promote research and discovery. Now with CSIRO, Berkay continues to work on ways to improve medical science, focussing on preventing infections resulting from medical device use.

    One solution to reduce the emergence of “superbugs” is to minimise antibiotic use by preventing bacterial infections associated with medical devices from occurring in the first place.

    Enter Dr Ozcelik. By incorporating multiple defence mechanisms, he’s developed a polymer based coating for implantable medical devices that prevent bacteria from sticking to the surface and forming into a biofilm antibiotics can’t penetrate.

    “Modern medical science uses implantable devices including catheters, endotracheal tubes, and device drivelines,” says Berkay.

    “They help in the treatment and recovery of patients and save countless lives but as they enter the body, their surfaces can also serve as a platform for bacteria to grow and infect the patient.”

    “Our novel polymer coating provides multiple layers of defence to stop this. Tests have shown it reduces bacterial colonisation on surfaces by more than 99 per cent.”

    This polymer coating has been specially designed using biocompatible polymers, and synthetic peptides that stops bacterial cells but doesn’t harm human cells or blood. Unlike other coating methods currently available, Berkay’s doesn’t involve several complex steps, an oxygen free environment or toxic solvents to bond.

    “It’s a one step process using commercially available precursors”, Berkay said. “It’s as simple as spraying or otherwise applying the coating on medical equipment, then letting it dry. That’s it. You shouldn’t have to reapply the coating at all.”

    Here is a short video of Berkay explaining his work:

    To find out more about our work in this field, you can check out our website.

    See the full article here .

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    CSIRO campus

    CSIRO, the Commonwealth Scientific and Industrial Research Organisation, is Australia’s national science agency and one of the largest and most diverse research agencies in the world.

  • richardmitnick 12:24 pm on February 3, 2016 Permalink | Reply
    Tags: , Bacteria, , Speargun-toting superbugs end up shooting each other   

    From New Scientist: “Speargun-toting superbugs end up shooting each other” 


    New Scientist

    3 February 2016
    Michael Le Page

    Bacteria spearfighting
    Not content with killing their enemies, these bacteria like to fight each other. David M. Phillips/Science Photo Libarary

    Gun owners are more likely to get shot than people who don’t own weapons – and something similar seems to be true for bacteria. Some superbugs kill rivals with powerful poison-tipped spearguns. But in crowded conditions they often end up brawling with the nearest family member.

    No superbugs actually die in kin combat, because they are immune to their own spears. So the fights, which seem to continue indefinitely, appear to be futile and a waste of energy. Why they happen at all puzzled many of the bacteriologists at a Royal Society meeting in London last week.

    “It’s mystifying given how costly it is,” says Richard Moxon of the University of Oxford, who studies bacterial infections. These weapons were only discovered a decade ago, but have turned out to be widespread in one large group of bacteria. The innocuous name – Type VI secretory systems, or T6SS – belies the fact that these astonishing weapons resemble the spearguns used by divers.

    The spear consists of a hollow tube, with various kinds of poisons loaded on to the tip or into the tube (see diagram at full article). A hollow sheath surrounds the tube, whose tip is positioned just inside the cell wall of a bacterium. When triggered, the sheath contracts and twists rapidly, both propelling the spear out of the cell and rotating it at at an incredible 100,000 revolutions per minute.

    Powerful machines

    “These machines have this enormous power,” says Marek Basler of the University of Basel, Switzerland, whose team is working out their structure, and who presented the latest findings at the meeting.

    Basler’s team has tagged a speargun protein with fluorescent molecules so they can watch the guns self-assemble (see animated .gif in full article). It turns out that Pseudomonas aeruginosa, a hospital superbug, normally uses its guns in self-defence. It aims and fires back only when attacked by others armed with T6SS spearguns. Pseudomonas will rapidly dispatch the indiscriminate shooter Vibrio cholerae, for instance, when the two are in close proximity.

    In crowded conditions, though, Pseudomonas start spearing each other. More and more cells engage in this “duelling” over time, Basler says. And the fights carry on for as long as researchers are able to watch the bacteria: hours at least.

    Besides wasting energy, duelling bacteria also lose the material they use to make spears. However, Basler is checking if the bacteria can recycle the spears shot at them by other bacteria.

    While Basler uses a mutant strain in his studies, the family feuds do reflect natural behaviour, thinks Martin Welch of the University of Cambridge, who studies Pseudomonas. The most likely place to find Pseudomonas is in the biofilms coating plugholes, he points out. So every time you clean your sink, you may be breaking up millions of vicious family fights.

    Much about the Type VI spearguns remains mysterious. While Pseudomonas respond to being fired on, it is not clear what triggers the firing or how they manage to aim their spears in the direction of their attackers.

    Surprisingly, these formidable weapons do not always guarantee victory against rivals vulnerable to the poison spears. Bacteria armed with T6SS can sometimes be outcompeted by faster growing species, Basler’s work suggests.

    Some bacteria don’t just fire on neighbouring cells: they release weapons resembling T6SS into the intercellular medium, where they bind to and destroy specific rival species. These smart mines, known as pyocins, are being developed for treating gut infections.

    See the full article here .

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  • richardmitnick 9:34 am on January 21, 2016 Permalink | Reply
    Tags: , Bacteria, ,   

    From PNNL: “Microbes take their vitamins – for the good of science” 

    PNNL Lab

    January 21, 2016
    Tom Rickey

    Temp 1
    Illustration of the PNNL team’s technology where a vitamin mimic (small blue structure) binds to a protein (larger coiled structure) to gain entry into the bacterium Chloroflexus aurantiacus. Illustration by Nathan Johnson, PNNL

    Temp 2
    The bacterium Chloroflexus aurantiacus helps give the greenish color to this pool of water in Yellowstone National Park.
    Image courtesy of Wikimedia Commons

    Temp 3
    Chloroflexus aurantiacus under the microscope. Image courtesy of Sylvia Herter and the Joint Genome Institute

    Microbes need their vitamins just like people do. Vitamins help keep both organisms healthy and energetic by enabling proteins to do their work. For bacteria, a dearth of vitamins can spell death.

    Now scientists at the Department of Energy’s Pacific Northwest National Laboratory have made a “vitamin mimic” — a molecule that looks and acts just like the natural vitamin to bacteria, but can be tracked and measured by scientists in live cells. The research offers a new window into the inner workings of living microbes that are crucial to the world’s energy future, wielding great influence in the planet’s carbon and nutrient cycle and serving as actors in the creation of new fuels.

    Vitamins are a powerful currency for researchers seeking to compel microbes to give up their secrets.

    “We have a lot to learn about how microbes accumulate and use nutrients that are necessary for their survival and growth. This provides a window for doing so,” said chemist Aaron Wright, the corresponding author of the study published in ACS Chemical Biology.

    “Perhaps we will be able to make a microbial community do what we want, by controlling its access to a specific nutrient,” Wright added.

    To control the bacteria via vitamins, Wright and his team have to know what other proteins in the cell the vitamins are consorting with, and where and when.

    Think of a planner analyzing emergency services for a large city. Knowing that an ambulance enters the city occasionally and transports some people somewhere, for instance, is not nearly as useful as knowing the precise address of the caller, the identity of the injured, and the location of the nearest hospital.

    It’s the same for scientists trying to understand microbial cells. While a cell is infinitesimally small, the activity within resembles the hustle and bustle of a large city, with many functions within carried out by thousands of entities. Knowing precisely which vitamins aid which proteins, under what circumstances, to keep things running is a must if scientists are to maximize microorganisms for energy production and other processes.

    “Microbial communities are organized based on their ability to get the resources they need to survive and grow,” said Wright. “We need to understand how the availability of nutrients, like vitamins, helps determine the structure of a microbial community as a step toward controlling that community in ways we would like to be able to do.”

    An anchor for pond scum

    Wright’s team studied the bacterium Chloroflexus aurantiacus J-10-fl, which is a common member of microbial mats — gloopy natural structures (think pond scum) where layers containing different groups of microbes band together. In these collections, C. aurantiacus often plays the role of anchor, helping to hold together an assortment of microbes. The bacteria, which resemble strands of string under the microscope, are usually found in hot springs, since they enjoy temperatures above 100 degrees Fahrenheit.

    Wright’s team performed a series of synthetic chemical steps to alter three vitamins that C. aurantiacus needs to survive: vitamin B1 (thiamine), vitamin B2 (riboflavin), and vitamin B7 (biotin). While the bacteria recognized the substances as normal vitamins, the researchers can monitor the mimics much more easily than their natural counterparts.

    Wright’s team used the mimics to relay a treasure trove of information about how vitamins enter the cell and interact within the cell, by analyzing the precise location of the molecules’ activity in living cells. Through a system called affinity-based protein profiling, Wright’s group effectively tagged these molecules where they’re active, then used techniques such as mass spectrometry to sort and measure proteins of interest.

    One of the team’s findings suggests multiple vitamins may share the same molecular machinery to gain entry into the cell. The team is still investigating these data. These findings can provide a road map for scientists like Wright who are trying to direct microbes as part of broad efforts to create clean, renewable fuels and reduce the effects of climate change.

    The work was funded by the U.S. Department of Energy Office of Science. The mass spectrometry-based measurements and microscopy were performed at EMSL, the Environmental Molecular Sciences Laboratory, a DOE Office of Science User Facility at PNNL.

    Reference: Lindsey N. Anderson, Phillip K. Koech, Andrew E. Plymale, Elizabeth V. Landorf, Allan Konopka, Frank R. Collart, Mary S. Lipton, Margaret F. Romine and Aaron T. Wright, Live cell discovery of microbial vitamin transport and enzyme-cofactor interactions, ACS Chemical Biology, Dec. 15, 2015, DOI: 10.1021/acschembio.5b00918.

    EMSL, the Environmental Molecular Sciences Laboratory, is a national scientific user facility sponsored by the Department of Energy’s Office of Science. Located at Pacific Northwest National Laboratory in Richland, Wash., EMSL offers an open, collaborative environment for scientific discovery to researchers around the world. Its integrated computational and experimental resources enable researchers to realize important scientific insights and create new technologies. Follow EMSL on Facebook, LinkedIn and Twitter.

    See the full article here .

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    Pacific Northwest National Laboratory (PNNL) is one of the United States Department of Energy National Laboratories, managed by the Department of Energy’s Office of Science. The main campus of the laboratory is in Richland, Washington.

    PNNL scientists conduct basic and applied research and development to strengthen U.S. scientific foundations for fundamental research and innovation; prevent and counter acts of terrorism through applied research in information analysis, cyber security, and the nonproliferation of weapons of mass destruction; increase the U.S. energy capacity and reduce dependence on imported oil; and reduce the effects of human activity on the environment. PNNL has been operated by Battelle Memorial Institute since 1965.


  • richardmitnick 11:23 am on September 5, 2015 Permalink | Reply
    Tags: , Bacteria,   

    From NYT: “Can the Bacteria in Your Gut Explain Your Mood?” 

    New York Times

    The New York Times

    July 12, 2015


    Eighteen vials were rocking back and forth on a squeaky mechanical device the shape of a butcher scale, and Mark Lyte was beside himself with excitement. ‘‘We actually got some fresh yesterday — freshly frozen,’’ Lyte said to a lab technician. Each vial contained a tiny nugget of monkey feces that were collected at the Harlow primate lab near Madison, Wis., the day before and shipped to Lyte’s lab on the Texas Tech University Health Sciences Center campus in Abilene, Tex.

    Lyte’s interest was not in the feces per se but in the hidden form of life they harbor. The digestive tube of a monkey, like that of all vertebrates, contains vast quantities of what biologists call gut microbiota. The genetic material of these trillions of microbes, as well as others living elsewhere in and on the body, is collectively known as the microbiome. Taken together, these bacteria can weigh as much as six pounds, and they make up a sort of organ whose functions have only begun to reveal themselves to science. Lyte has spent his career trying to prove that gut microbes communicate with the nervous system using some of the same neurochemicals that relay messages in the brain.

    Inside a closet-size room at his lab that afternoon, Lyte hunched over to inspect the vials, whose samples had been spun down in a centrifuge to a radiant, golden broth. Lyte, 60, spoke fast and emphatically. ‘‘You wouldn’t believe what we’re extracting out of poop,’’ he told me. ‘‘We found that the guys here in the gut make neurochemicals. We didn’t know that. Now, if they make this stuff here, does it have an influence there? Guess what? We make the same stuff. Maybe all this communication has an influence on our behavior.’’

    Since 2007, when scientists announced plans for a Human Microbiome Project to catalog the micro-organisms living in our body, the profound appreciation for the influence of such organisms has grown rapidly with each passing year. Bacteria in the gut produce vitamins and break down our food; their presence or absence has been linked to obesity, inflammatory bowel disease and the toxic side effects of prescription drugs. Biologists now believe that much of what makes us human depends on microbial activity. The two million unique bacterial genes found in each human microbiome can make the 23,000 genes in our cells seem paltry, almost negligible, by comparison. ‘‘It has enormous implications for the sense of self,’’ Tom Insel, the director of the National Institute of Mental Health, told me. ‘‘We are, at least from the standpoint of DNA, more microbial than human. That’s a phenomenal insight and one that we have to take seriously when we think about human development.’’

    Given the extent to which bacteria are now understood to influence human physiology, it is hardly surprising that scientists have turned their attention to how bacteria might affect the brain. Micro-organisms in our gut secrete a profound number of chemicals, and researchers like Lyte have found that among those chemicals are the same substances used by our neurons to communicate and regulate mood, like dopamine, serotonin and gamma-aminobutyric acid (GABA). These, in turn, appear to play a function in intestinal disorders, which coincide with high levels of major depression and anxiety. Last year, for example, a group in Norway examined feces from 55 people and found certain bacteria were more likely to be associated with depressive patients.

    At the time of my visit to Lyte’s lab, he was nearly six months into an experiment that he hoped would better establish how certain gut microbes influenced the brain, functioning, in effect, as psychiatric drugs. He was currently compiling a list of the psychoactive compounds found in the feces of infant monkeys. Once that was established, he planned to transfer the microbes found in one newborn monkey’s feces into another’s intestine, so that the recipient would end up with a completely new set of microbes — and, if all went as predicted, change their neurodevelopment. The experiment reflected an intriguing hypothesis. Anxiety, depression and several pediatric disorders, including autism and hyperactivity, have been linked with gastrointestinal abnormalities. Microbial transplants were not invasive brain surgery, and that was the point: Changing a patient’s bacteria might be difficult but it still seemed more straightforward than altering his genes.

    When Lyte began his work on the link between microbes and the brain three decades ago, it was dismissed as a curiosity. By contrast, last September, the National Institute of Mental Health awarded four grants worth up to $1 million each to spur new research on the gut microbiome’s role in mental disorders, affirming the legitimacy of a field that had long struggled to attract serious scientific credibility. Lyte and one of his longtime colleagues, Christopher Coe, at the Harlow primate lab, received one of the four. ‘‘What Mark proposed going back almost 25 years now has come to fruition,’’ Coe told me. ‘‘Now what we’re struggling to do is to figure out the logic of it.’’ It seems plausible, if not yet proved, that we might one day use microbes to diagnose neurodevelopmental disorders, treat mental illnesses and perhaps even fix them in the brain.

    In 2011, a team of researchers at University College Cork, in Ireland, and McMaster University, in Ontario, published a study in Proceedings of the National Academy of Science that has become one of the best-known experiments linking bacteria in the gut to the brain. Laboratory mice were dropped into tall, cylindrical columns of water in what is known as a forced-swim test, which measures over six minutes how long the mice swim before they realize that they can neither touch the bottom nor climb out, and instead collapse into a forlorn float. Researchers use the amount of time a mouse floats as a way to measure what they call ‘‘behavioral despair.’’ (Antidepressant drugs, like Zoloft and Prozac, were initially tested using this forced-swim test.)

    For several weeks, the team, led by John Cryan, the neuroscientist who designed the study, fed a small group of healthy rodents a broth infused with Lactobacillus rhamnosus, a common bacterium that is found in humans and also used to ferment milk into probiotic yogurt. Lactobacilli are one of the dominant organisms babies ingest as they pass through the birth canal. Recent studies have shown that mice stressed during pregnancy pass on lowered levels of the bacterium to their pups. This type of bacteria is known to release immense quantities of GABA; as an inhibitory neurotransmitter, GABA calms nervous activity, which explains why the most common anti-anxiety drugs, like Valium and Xanax, work by targeting GABA receptors.

    Cryan found that the mice that had been fed the bacteria-laden broth kept swimming longer and spent less time in a state of immobilized woe. ‘‘They behaved as if they were on Prozac,’’ he said. ‘‘They were more chilled out and more relaxed.’’ The results suggested that the bacteria were somehow altering the neural chemistry of mice.

    Until he joined his colleagues at Cork 10 years ago, Cryan thought about microbiology in terms of pathology: the neurological damage created by diseases like syphilis or H.I.V. ‘‘There are certain fields that just don’t seem to interact well,’’ he said. ‘‘Microbiology and neuroscience, as whole disciplines, don’t tend to have had much interaction, largely because the brain is somewhat protected.’’ He was referring to the fact that the brain is anatomically isolated, guarded by a blood-brain barrier that allows nutrients in but keeps out pathogens and inflammation, the immune system’s typical response to germs. Cryan’s study added to the growing evidence that signals from beneficial bacteria nonetheless find a way through the barrier. Somehow — though his 2011 paper could not pinpoint exactly how — micro-organisms in the gut tickle a sensory nerve ending in the fingerlike protrusion lining the intestine and carry that electrical impulse up the vagus nerve and into the deep-brain structures thought to be responsible for elemental emotions like anxiety. Soon after that, Cryan and a co-author, Ted Dinan, published a theory paper in Biological Psychiatry calling these potentially mind-altering microbes ‘‘psychobiotics.’’

    It has long been known that much of our supply of neurochemicals — an estimated 50 percent of the dopamine, for example, and a vast majority of the serotonin — originate in the intestine, where these chemical signals regulate appetite, feelings of fullness and digestion. But only in recent years has mainstream psychiatric research given serious consideration to the role microbes might play in creating those chemicals. Lyte’s own interest in the question dates back to his time as a postdoctoral fellow at the University of Pittsburgh in 1985, when he found himself immersed in an emerging field with an unwieldy name: psychoneuroimmunology, or PNI, for short. The central theory, quite controversial at the time, suggested that stress worsened disease by suppressing our immune system.

    By 1990, at a lab in Mankato, Minn., Lyte distilled the theory into three words, which he wrote on a chalkboard in his office: Stress->Immune->Disease. In the course of several experiments, he homed in on a paradox. When he dropped an intruder mouse in the cage of an animal that lived alone, the intruder ramped up its immune system — a boost, he suspected, intended to fight off germ-ridden bites or scratches. Surprisingly, though, this did not stop infections. It instead had the opposite effect: Stressed animals got sick. Lyte walked up to the board and scratched a line through the word ‘‘Immune.’’ Stress, he suspected, directly affected the bacterial bugs that caused infections.

    To test how micro-organisms reacted to stress, he filled petri plates with a bovine-serum-based medium and laced the dishes with a strain of bacterium. In some, he dropped norepinephrine, a neurochemical that mammals produce when stressed. The next day, he snapped a Polaroid. The results were visible and obvious: The control plates were nearly barren, but those with the norepinephrine bloomed with bacteria that filigreed in frostlike patterns. Bacteria clearly responded to stress.

    Then, to see if bacteria could induce stress, Lyte fed white mice a liquid solution of Campylobacter jejuni, a bacterium that can cause food poisoning in humans but generally doesn’t prompt an immune response in mice. To the trained eye, his treated mice were as healthy as the controls. But when he ran them through a plexiglass maze raised several feet above the lab floor, the bacteria-fed mice were less likely to venture out on the high, unprotected ledges of the maze. In human terms, they seemed anxious. Without the bacteria, they walked the narrow, elevated planks.

    Each of these results was fascinating, but Lyte had a difficult time finding microbiology journals that would publish either. ‘‘It was so anathema to them,’’ he told me. When the mouse study finally appeared in the journal Physiology & Behavior in 1998, it garnered little attention. And yet as Stephen Collins, a gastroenterologist at McMaster University, told me, those first papers contained the seeds of an entire new field of research. ‘‘Mark showed, quite clearly, in elegant studies that are not often cited, that introducing a pathological bacterium into the gut will cause a change in behavior.’’

    Lyte went on to show how stressful conditions for newborn cattle worsened deadly E. coli infections. In another experiment, he fed mice lean ground hamburger that appeared to improve memory and learning — a conceptual proof that by changing diet, he could change gut microbes and change behavior. After accumulating nearly a decade’s worth of evidence, in July 2008, he flew to Washington to present his research. He was a finalist for the National Institutes of Health’s Pioneer Award, a $2.5 million grant for so-called blue-sky biomedical research. Finally, it seemed, his time had come. When he got up to speak, Lyte described a dialogue between the bacterial organ and our central nervous system. At the two-minute mark, a prominent scientist in the audience did a spit take.

    ‘‘Dr. Lyte,’’ he later asked at a question-and-answer session, ‘‘if what you’re saying is right, then why is it when we give antibiotics to patients to kill bacteria, they are not running around crazy on the wards?’’

    Lyte knew it was a dismissive question. And when he lost out on the grant, it confirmed to him that the scientific community was still unwilling to imagine that any part of our neural circuitry could be influenced by single-celled organisms. Lyte published his theory in Medical Hypotheses, a low-ranking journal that served as a forum for unconventional ideas. The response, predictably, was underwhelming. ‘‘I had people call me crazy,’’ he said.

    But by 2011 — when he published a second theory paper in Bioessays, proposing that probiotic bacteria could be tailored to treat specific psychological diseases — the scientific community had become much more receptive to the idea. A Canadian team, led by Stephen Collins, had demonstrated that antibiotics could be linked to less cautious behavior in mice, and only a few months before Lyte, Sven Pettersson, a microbiologist at the Karolinska Institute in Stockholm, published a landmark paper in Proceedings of the National Academy of Science that showed that mice raised without microbes spent far more time running around outside than healthy mice in a control group; without the microbes, the mice showed less apparent anxiety and were more daring. In Ireland, Cryan published his forced-swim-test study on psychobiotics. There was now a groundswell of new research. In short order, an implausible idea had become a hypothesis in need of serious validation.

    Late last year, Sarkis Mazmanian, a microbiologist at the California Institute of Technology, gave a presentation at the Society for Neuroscience, ‘‘Gut Microbes and the Brain: Paradigm Shift in Neuroscience.’’ Someone had inadvertently dropped a question mark from the end, so the speculation appeared to be a definitive statement of fact. But if anyone has a chance of delivering on that promise, it’s Mazmanian, whose research has moved beyond the basic neurochemicals to focus on a broader class of molecules called metabolites: small, equally druglike chemicals that are produced by micro-organisms. Using high-powered computational tools, he also hopes to move beyond the suggestive correlations that have typified psychobiotic research to date, and instead make decisive discoveries about the mechanisms by which microbes affect brain function.

    Two years ago, Mazmanian published a study in the journal Cell with Elaine Hsiao, then a graduate student and now a neuroscientist at Caltech, and others, that made a provocative link between a single molecule and behavior. Their research found that mice exhibiting abnormal communication and repetitive behaviors, like obsessively burying marbles, were mollified when they were given one of two strains of the bacterium Bacteroides fragilis.

    The study added to a working hypothesis in the field that microbes don’t just affect the permeability of the barrier around the brain but also influence the intestinal lining, which normally prevents certain bacteria from leaking out and others from getting in. When the intestinal barrier was compromised in his model, normally ‘‘beneficial’’ bacteria and the toxins they produce seeped into the bloodstream and raised the possibility they could slip past the blood-brain barrier. As one of his colleagues, Michael Fischbach, a microbiologist at the University of California, San Francisco, said: ‘‘The scientific community has a way of remaining skeptical until every last arrow has been drawn, until the entire picture is colored in. Other scientists drew the pencil outlines, and Sarkis is filling in a lot of the color.’’

    Mazmanian knew the results offered only a provisional explanation for why restrictive diets and antibacterial treatments seemed to help some children with autism: Altering the microbial composition might be changing the permeability of the intestine. ‘‘The larger concept is, and this is pure speculation: Is a disease like autism really a disease of the brain or maybe a disease of the gut or some other aspect of physiology?’’ Mazmanian said. For any disease in which such a link could be proved, he saw a future in drugs derived from these small molecules found inside microbes. (A company he co-founded, Symbiotix Biotherapies, is developing a complex sugar called PSA, which is associated with Bacteroides fragilis, into treatments for intestinal disease and multiple sclerosis.) In his view, the prescriptive solutions probably involve more than increasing our exposure to environmental microbes in soil, dogs or even fermented foods; he believed there were wholesale failures in the way we shared our microbes and inoculated children with these bacteria. So far, though, the only conclusion he could draw was that disorders once thought to be conditions of the brain might be symptoms of microbial disruptions, and it was the careful defining of these disruptions that promised to be helpful in the coming decades.

    The list of potential treatments incubating in labs around the world is startling. Several international groups have found that psychobiotics had subtle yet perceptible effects in healthy volunteers in a battery of brain-scanning and psychological tests. Another team in Arizona recently finished an open trial on fecal transplants in children with autism. (Simultaneously, at least two offshore clinics, in Australia and England, began offering fecal microbiota treatments to treat neurological disorders, like multiple sclerosis.) Mazmanian, however, cautions that this research is still in its infancy. ‘‘We’ve reached the stage where there’s a lot of, you know, ‘The microbiome is the cure for everything,’ ’’ he said. ‘‘I have a vested interest if it does. But I’d be shocked if it did.’’

    Lyte issues the same caveat. ‘‘People are obviously desperate for solutions,’’ Lyte said when I visited him in Abilene. (He has since moved to Iowa State’s College of Veterinary Medicine.) ‘‘My main fear is the hype is running ahead of the science.’’ He knew that parents emailing him for answers meant they had exhausted every option offered by modern medicine. ‘‘It’s the Wild West out there,’’ he said. ‘‘You can go online and buy any amount of probiotics for any number of conditions now, and my paper is one of those cited. I never said go out and take probiotics.’’ He added, ‘‘We really need a lot more research done before we actually have people trying therapies out.’’

    If the idea of psychobiotics had now, in some ways, eclipsed him, it was nevertheless a curious kind of affirmation, even redemption: an old-school microbiologist thrust into the midst of one of the most promising aspects of neuroscience. At the moment, he had a rough map in his head and a freezer full of monkey fecals that might translate, somehow, into telling differences between gregarious or shy monkeys later in life. I asked him if what amounted to a personality transplant still sounded a bit far-fetched. He seemed no closer to unlocking exactly what brain functions could be traced to the same organ that produced feces. ‘‘If you transfer the microbiota from one animal to another, you can transfer the behavior,’’ Lyte said. ‘‘What we’re trying to understand are the mechanisms by which the microbiota can influence the brain and development. If you believe that, are you now out on the precipice? The answer is yes. Do I think it’s the future? I think it’s a long way away.’

    See the full article here .

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  • richardmitnick 2:43 pm on September 3, 2015 Permalink | Reply
    Tags: , Bacteria,   

    From Weizmann: “How Does Your Microbiome Grow?” 

    Weizmann Institute of Science logo

    Weizmann Institute of Science

    01 Sep 2015
    No Writer Credit

    It is increasingly clear that the thousands of different bacteria living in our intestinal tract – our microbiome– have a major impact on our health. But the details of the microbiome’s effects are still fairly murky. A Weizmann Institute study that recently appeared in Science suggests approaching this topic from a new angle: Assess how fast the various bacteria grow. This approach is already revealing intriguing links between bacterial growth rates and such conditions as type II diabetes and inflammatory bowel disease. The new computational method can illuminate a dynamic process such as growth from a static “snapshot” of a single sample, and thus it may have implications for both diagnostics and new avenues of research.

    Tal Korem and David Zeevi, research students in the lab of Prof. Eran Segal of the Computer Science and Applied Mathematics Department, led this research and collaborated with Jotham Suez, a research student in the lab of Dr. Eran Elinav in the Immunology Department, and Dr. Adina Weinberger, a research associate in Segal’s lab. The study began with the advanced genomic sequencing techniques used in many current microbiome studies, which sequence all of the bacterial DNA in a sample. From the short sequences, they construct a picture of the types of bacteria and their relative abundance. But the Weizmann Institute team realized that this sequencing technique held another type of information.

    Bacterial growth rates computed with the new method (top, average; bottom, for specific species, red represents faster replication) for a human subject that underwent a radical dietary change. Compared are days in which only white boiled rice was consumed (grey area) and days of normal diet (white area). A global change in bacterial growth dynamics was observed between dietary regimens

    “The sample’s bacteria are doing what bacteria do best: making copies of their genomes so they can divide,” says Segal. “So most of the bacterial cells contain more than one genome – a genome and a half, for example, or a genome and three quarters.” Since most bacterial strains have pre-programmed “start” and “finish” codes, the team was able to identify the “start” point as the short sequence that was most prevalent in the sample. The least prevalent, at the other end of the genome, was the DNA that gets copied last. The researchers found that analyzing the relative amounts of starting DNA and ending DNA could be translated into the growth rate for each strain of bacteria.

    The group tested this formulation experimentally, first in single-strain cultures for which the growth rate could be controlled and observed, then in multiple animal model systems, and finally in the DNA sequences of human microbiomes, in their full complexity.

    Their method worked even better than expected: The estimated bacterial growth rates turned out to be nearly identical to observed growth rates. “Now we can finally say something about how the dynamics of our microbiome are associated with a propensity to disease. Microbial growth rate reveals things about our health that cannot be seen with any other analysis method,” says Elinav.

    In their examination of human microbiome data, for example, the group found that particular changes in bacterial growth rates are uniquely associated with type II diabetes; others are tied to inflammatory bowel disease. These associations were not observed in the static microbiome “population” studies. Thus the method could be used in the future as a diagnostic tool to detect disease or pathogen infection early on, or to determine the effects of probiotic or antibiotic treatment. In addition, the scientists hope this new understanding of the microbiome will spur further research into the connections between the complex, dynamic ecosystem inside of us and our health.

    Also participating in this research were Tali Avnit-Sagi, Maya Pompan-Lotan, Nadav Cohen and Elad Matot in Segal’s lab; Christoph A. Thaiss and Dr. Meirav Pevsner-Fischer in Elinav’s lab; Dr. Ghil Jona and Prof. Alon Harmelin of the Weizmann Institute; Dr. Alexandra Sirota-Madi and Prof. Ramnik Xavier of Harvard Medical School and the Broad Institute; and Prof. Rotem Sorek of the Weizmann Institute.

    Dr. Eran Elinav’s research is supported by the Abisch Frenkel Foundation for the Promotion of Life Sciences; the Gurwin Family Fund for Scientific Research; the Leona M. and Harry B. Helmsley Charitable Trust; the Crown Endowment Fund for Immunological Research; the Adelis Foundation; the Rising Tide Foundation; the Vera Rosenberg Schwartz Research Fellow Chair; Yael and Rami Ungar, Israel; John L. and Vera Schwartz, Pacific Palisades, CA; Alan Markovitz, Canada; Leesa Steinberg, Canada; Andrew and Cynthia Adelson, Canada; the estate of Jack Gitlitz; the estate of Lydia Hershkovich; and Mr. and Mrs. Donald L. Schwarz, Sherman Oaks, CA. Dr. Elinav is the incumbent of the Rina Gudinski Career Development Chair.

    Prof. Eran Segal’s research is supported by the Adelis Foundation; the Cecil and Hilda Lewis Charitable Trust; the European Research Council; Mr. and Mrs. Donald L. Schwarz, Sherman Oaks, CA; and Leesa Steinberg, Canada.

    See the full article here.

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    Weizmann Institute Campus

    The Weizmann Institute of Science is one of the world’s leading multidisciplinary research institutions. Hundreds of scientists, laboratory technicians and research students working on its lushly landscaped campus embark daily on fascinating journeys into the unknown, seeking to improve our understanding of nature and our place within it.

    Guiding these scientists is the spirit of inquiry so characteristic of the human race. It is this spirit that propelled humans upward along the evolutionary ladder, helping them reach their utmost heights. It prompted humankind to pursue agriculture, learn to build lodgings, invent writing, harness electricity to power emerging technologies, observe distant galaxies, design drugs to combat various diseases, develop new materials and decipher the genetic code embedded in all the plants and animals on Earth.

    The quest to maintain this increasing momentum compels Weizmann Institute scientists to seek out places that have not yet been reached by the human mind. What awaits us in these places? No one has the answer to this question. But one thing is certain – the journey fired by curiosity will lead onward to a better future.

  • richardmitnick 9:57 am on August 31, 2015 Permalink | Reply
    Tags: , Bacteria,   

    From Cornell: “Antibody-making bacteria promise drug development” 

    Cornell Bloc

    Cornell University

    August 31, 2015
    Anne Ju

    Monoclonal antibodies, proteins that bind to and destroy foreign invaders in our bodies, routinely are used as therapeutic agents to fight a wide range of maladies including breast cancer, leukemia, asthma, arthritis, psoriasis, Crohn’s disease and transplant rejection. Humira, a treatment for arthritis and Crohn’s disease, was among the first lab-engineered antibody drugs.

    A general representation of the method used to produce monoclonal antibodies

    Typically, monoclonal antibodies are manufactured in animal cell lines, such as Chinese hamster ovary (CHO) cells, with long development times that can drive up cost. A team of Cornell chemical engineers and New England Biolabs scientists have devised a shortcut. They’ve done it using an engineered E. coli bacterium that carries machinery for human antibody production and can churn out complex proteins, including many of today’s blockbuster, life-saving antibody drugs, in as little as a week.

    A Nature Communications paper published Aug. 27 details the feat, led by co-senior author Matthew DeLisa, the William L. Lewis Professor of Engineering, and first author Michael-Paul Robinson, a graduate student in the field of chemical engineering. They worked with a team led by co-senior author Mehmet Berkmen, a staff scientist at New England Biolabs.

    The work built on a previously commercialized E. coli strain invented by Berkmen, called “SHuffle,” which could make shorter, simpler proteins such as antibody fragments that had less therapeutic value than their full-sized, monoclonal antibody counterparts. Now, the researchers report producing full-length antibodies using the specially engineered SHuffle bacterium, including ones that fight the avian flu virus, the anthrax pathogen Bacillus anthracis, and a replica of the therapeutic antibody Herceptin that is used to treat breast cancer.

    “We can engineer new antibodies in SHuffle almost as quickly as our bodies can. Customizing an antibody requires only simple edits to the bacterium’s DNA, which opens up a low-effort way to prototype new ideas for future therapeutics,” Berkmen said.

    The SHuffle bacterium harbors genetic modifications that allow it, unlike other bacteria, to assemble antibodies and other human proteins into their natural, functional shape. A unique aspect of the method is the “all-in-one-pot” manner in which the large, complicated antibody molecules are assembled, taking place exclusively in the cytoplasmic compartment of the bacterium.

    This method effectively bypasses some of the key bottlenecks in the multi-compartment biosynthesis inherent to such production hosts as CHO cells. Preliminary experiments indicate the SHuffle-made antibodies could be recognized by the human immune system as robustly as the originals.

    “We think this is going to be a very powerful way of biomanufacturing existing antibodies, or even developing entirely new ones from scratch, that is much faster than current methods,” DeLisa said.

    While immunotherapeutics invented in bacteria may one day become useful medicines, other uses may abound.

    “Many diagnostic tests, such as those performed on tumor biopsies, depend on finely-tuned antibodies,” DeLisa said. “Scientists also depend upon antibodies to make the molecular mechanics of living organisms visible, but sometimes they lack antibodies that work well enough for their experiments.”

    The paper is titled “Efficient expression of full-length antibodies in the cytoplasm of engineered bacteria,” and the work was supported by the National Institutes of Health, the Ford Foundation and the National Science Foundation.

    See the full article here.

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    Once called “the first American university” by educational historian Frederick Rudolph, Cornell University represents a distinctive mix of eminent scholarship and democratic ideals. Adding practical subjects to the classics and admitting qualified students regardless of nationality, race, social circumstance, gender, or religion was quite a departure when Cornell was founded in 1865.

    Today’s Cornell reflects this heritage of egalitarian excellence. It is home to the nation’s first colleges devoted to hotel administration, industrial and labor relations, and veterinary medicine. Both a private university and the land-grant institution of New York State, Cornell University is the most educationally diverse member of the Ivy League.

    On the Ithaca campus alone nearly 20,000 students representing every state and 120 countries choose from among 4,000 courses in 11 undergraduate, graduate, and professional schools. Many undergraduates participate in a wide range of interdisciplinary programs, play meaningful roles in original research, and study in Cornell programs in Washington, New York City, and the world over.

  • richardmitnick 8:33 am on August 31, 2015 Permalink | Reply
    Tags: , Bacteria,   

    From COSMOS: “Fighting superbugs with supercomputers” 

    Cosmos Magazine bloc


    31 Aug 2015
    Viviane Richter

    Doctors need new ways to attack the antibiotic-resistant bacterium MRSA, shown here growing on a blood agar plate.Credit: By R Parulan Jr./getty images

    We’re losing the arms race against superbugs. Now with the aid of a supercomputer, Alan Grossfield at the University of Rochester is refining a new battlefield strategy. Instead of attacking their proteins, which bacteria can disguise, the new weapons attack the membrane which is much harder to hide. Grossfield and his team’s findings were published in Biophysical Journal in August.

    In this arms race “the cell membrane is like the final frontier”, says University of Queensland microbiologist Matt Cooper.

    Last year, the UK Review on Antimicrobial Resistance estimated that antibiotic resistant bacteria account for at least 700,000 deaths each year and could grow to 10 million worldwide by 2050. If we want to avoid entering a post-antibiotic era we need new armaments.

    Most antibiotics are designed to latch on to and deactivate a single protein target in the cell. Penicillin, for example, blocks an enzyme bacteria need to hold their cell wall together. However, bacteria can rapidly mutate these protein targets making them unrecognisable to the antibiotics.

    But bacteria are far less able to mutate the structure of their membranes; their basic life chemistry relies on it. So drugs that attack the bacterial membrane should be harder to beat.

    Tree frogs discovered this trick long ago. Their skin contains a host of antimicrobial and antifungal defences – including a group called lipopeptides that slice bacterial membranes, making them leaky. Medicinal chemists are now developing lipopeptides of their own, to be used as antimicrobial drugs. The first, daptomycin, is the only new antibiotic to be approved by the US Food and Drug Administration in the past 15 years.

    Researchers hope to make other lipopeptide drugs that are even more potent that daptomycin. The problem is that human cells also have membranes – so when designing membrane-slicing drugs, it’s important that bacteria remain their sole target. Grossfield looked more closely at one lipopeptide drug in development, already shown to clear bacterial infections in mice, in order to understand how the drug worked.

    Antimicrobial lipopeptides clump together in roughly spherical clusters known as micelles. They float through the bloodstream with their weapons hidden – like a Swiss army knife with all its blades folded away. Only when a clump reaches a target do the blades flip out to pierce the membrane.

    With the help of a supercomputer, Grossfield’s team simulated how the drug responded when stuck to a bacterial and mammalian membrane. This drug’s action takes less than 500th of a second, but the simulations took an entire year of number crunching.

    It turns out the drug has a slight positive charge. Luckily mammalian membranes are neutral, so the drug doesn’t stick. But bacterial membranes are negatively charged. Once stuck, the drug’s “blades” quickly flick out and slice into the membrane. The team found the drug stabbed bacterial membranes 50 orders of magnitude faster than mammalian membranes. “This was really cool,” Grossfield says.

    In this computer simulation, the lipopeptide cluster (green and yellow) sticks to the bacterium’s surface (blue), and then all of a sudden (12 seconds through the video) slices its way into the bacterium’s membrane. Credit: Dejun Lin, University of Rochester Medical Centre

    He also found there’s a sweet spot to the drug’s blade length. If they’re too long, they tend to get jammed in the clump. Too short, and they don’t inflict enough damage to kill the bacterium.

    He hopes his work will help chemists design better lipopeptides in the future: “I hope I can explain to the medicinal chemists what drug properties they should think about.”

    The new drugs will buy us more time, but even this strategy is not likely to last. Some bacteria have already found a defence against daptomycin, first membrane-stabbing drug, which was rolled out in 2003.

    Cooper believes over-prescription of antibiotics is the biggest contributor to resistance. But “attacking the membrane gives us more time”, he says. “We want to find drugs that give us a couple of decades.”

    See the full article here.

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  • richardmitnick 1:36 pm on July 22, 2015 Permalink | Reply
    Tags: , Bacteria, ,   

    From Rockefeller: “Atomic view of cellular pump reveals how bacteria send out proteins” 

    Rockefeller U bloc

    Rockefeller University

    July 22, 2015
    Wynne Parry | 212-327-7789

    A watery passage: The pump, a single-molecule machine, (yellow coils) carries proteins through the cell membrane (pink and dark blue). Within the pump, the researchers found a strikingly large water-filled channel (light blue), a natural environment for hydrophilic proteins. No image credit

    Bacteria have plenty of things to send out into world beyond their own boundaries: coordinating signals to other members of their species, poisons for their enemies, and devious instructions to manipulate host cells they have infected. Before any of this can occur, however, they must first get the shipments past their own cell membranes, and many bacteria have evolved specialized structures and systems for launching the proteins that do these jobs.

    Researchers at The Rockefeller University have determined the structure of a simple but previously unexamined pump that controls the passage of proteins through a bacterial cell membrane, an achievement that offers new insight into the mechanics that allow bacteria to manipulate their environments. The results were published in Nature on July 23.

    “This pump, called PCAT for peptidase-containing ATP-binding cassette transporter, is composed of a single protein, a sort of all-in-one machine capable of recognizing its cargo, processing it, then burning chemical fuel to pump that cargo out of the cell,” says study author Jue Chen, William E. Ford Professor and head of the Laboratory of Membrane Biology and Biophysics. “This new atomic-level structure explains for the first time the links between these three functions.”

    Of the many types of molecules cells need to move into and out of their membranes, proteins are the largest. PCATs specialize in pumping proteins out of the cell, and, because they are single-molecule machines that work alone, or with two partner proteins in some bacteria, they are the simplest such systems.

    Each PCAT molecule has three domains, each in duplicate: one recognizes the cargo by a tag it carries, and cuts off that tag; another binds to and burns ATP, a molecule that contains energy stored within its atomic bonds; and the third forms a channel that spans the cells membrane. Previous work had examined the structure of the first two domains, but the structure of the third, had remained a mystery, along with the details of how the components function together.

    “At this point, we have no idea how many PCATs exist, although we expect they are numerous, because each specializes in a specific type of cargo. For this study, we focused on one we called PCAT1, which transports a small protein of unknown function,” says first author David Yin-wei Lin, a postdoc in the lab. “To get a sense of how PCAT1 changes shape when powered by energy from ATP, we examined the structure in two states, both with and without ATP.”

    The team, which also included Shuo Huang, a research technician who is now a graduate student at Georgia Institute of Technology, purified and crystalized the PCAT1 protein from the heat-loving bacterium Clostridium thermocellum. To determine the structure of the crystals, they used a technique called X-ray diffraction analysis, in which a pattern produced by X-rays bounced off the crystallized protein can be used to infer the structure of the molecule.

    The first structure, determined without ATP, revealed a striking feature: a large, water-filled central channel, a natural environment for a water-loving, or hydrophilic, protein. Two side openings into this channel were guarded by the cargo-recognizing domain, acting as a sort of ticket taker. Sites on this domain would recognize and clip off the cargo’s tag, before ushering the protein into the channel.

    When ATP is present, they found that the side entrances close, freeing the cargo-recognizing domain to move from its station outside of them. In addition, the ATP-binding domains at the bottom of the channel inside the cell come together. The researchers also saw the water channel shrink, leading them to hypothesize that energy from ATP allows PCAT1 to change conformation in such a way that it pushes its cargo out. This suggests that PCAT1 uses a strategy commonly seen in transport proteins known as alternate access, in which one end of the channel is open while the other closes. However, they qualify that PCATs that transport much larger proteins may function differently.

    “By visualizing the structure of this pump, we have been able to determine the details of a transport pathway that, in its simplicity, is fundamentally different from the more complex systems that have been closely studied before. This new information adds to the understanding of how cells send out proteins in order to interact with their environment,” Chen says.

    See the full article here.

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    Rockefeller U Campus

    The Rockefeller University is a world-renowned center for research and graduate education in the biomedical sciences, chemistry, bioinformatics and physics. The university’s 76 laboratories conduct both clinical and basic research and study a diverse range of biological and biomedical problems with the mission of improving the understanding of life for the benefit of humanity.

    Founded in 1901 by John D. Rockefeller, the Rockefeller Institute for Medical Research was the country’s first institution devoted exclusively to biomedical research. The Rockefeller University Hospital was founded in 1910 as the first hospital devoted exclusively to clinical research. In the 1950s, the institute expanded its mission to include graduate education and began training new generations of scientists to become research leaders around the world. In 1965, it was renamed The Rockefeller University.

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