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  • richardmitnick 1:34 pm on February 7, 2017 Permalink | Reply
    Tags: Biology, Biomathematics, , , New study is an advance toward preventing a ‘post-antibiotic era’,   

    From UCLA: “New study is an advance toward preventing a ‘post-antibiotic era’ “ 

    UCLA bloc


    February 07, 2017
    Stuart Wolpert

    UCLA biologists identify drug combinations that may be highly effective at reducing growth of deadly bacteria

    UCLA’s Elif Tekin, Casey Beppler, Pamela Yeh and Van Savage are gaining insights into why certain groups of three antibiotics interact well together and others don’t.

    A landmark report by the World Health Organization in 2014 observed that antibiotic resistance — long thought to be a health threat of the future — had finally become a serious threat to public health around the world. A top WHO official called for an immediate and aggressive response to prevent what he called a “post-antibiotic era, in which common infections and minor injuries which have been treatable for decades can once again kill.”

    A team of UCLA biologists has been responding to the challenge, exploring possible ways to defeat life-threatening antibiotic-resistant bacteria. In 2016, they reported that combinations of three different antibiotics can often overcome bacteria’s resistance to antibiotics, even when none of the three antibiotics on its own — or even two of the three together — is effective.

    Their latest work, which is published online and appears in the current print edition of the Journal of the Royal Society Interface, extends their understanding of that phenomenon and identifies two combinations of drugs that are unexpectedly successful in reducing the growth of E. coli bacteria.

    A key to the study is an understanding that using two, three or more antibiotics in combination does not necessarily make the drugs more effective in combating bacteria — in fact, in many cases, their effectiveness is actually reduced when drugs are used together — so the combinations must be chosen carefully and systematically. The new paper also provides the first detailed explanation of how the scientists created a mathematical formula that can help predict which combinations of drugs will be most effective.

    The scientists tested every possible combination of a group of six antibiotics, including 20 different combinations of three antibiotics at a time.

    Among the three-drug combinations, the researchers found two that were noticeably more effective than they had expected. Those groupings used treatments from three different classes of antibiotics, so the combinations used a wide range of mechanisms to fight the bacteria. (Five of the three-drug combinations were less effective than they expected, and the other 13 groupings performed as they predicted.)

    Pamela Yeh. Reed Hutchinson/UCLA

    “So many bacteria are now so resistant to antibiotics,” said Pamela Yeh, the study’s senior author and a UCLA assistant professor of ecology and evolutionary biology. “We have a logical, methodical way to identify three-drug combinations to pursue. We think it’s vital to have this framework for identifying the best possible combinations of antibiotics.”

    The researchers have identified cases where the effects of the interactions are larger than the sum of the parts.

    “Doctors may want to super-efficiently kill the bacteria, and that is what these enhanced interactions make possible,” said lead author Casey Beppler, who was an undergraduate in Yeh’s laboratory and is now a graduate student at UC San Francisco.

    For the current study, the scientists evaluated the drug combinations on plates in a lab. Beppler said a next step will be to test the most effective combinations in mice.

    In addition to reporting on how well various combinations of antibiotics worked, the paper also presents a mathematical formula the biologists developed for analyzing how three or more factors interact and of explaining complex, unexpected interactions. The framework would be useful for solving other questions in the sciences and social sciences in which researchers analyze how three or more components might interact — for example, how climate is affected by the interplay among temperature, rainfall, humidity and ocean acidity.

    The biologists are gaining a deep understanding of why certain groups of three antibiotics interact well together, and others don’t, said Van Savage, a co-author of the paper and a UCLA professor of ecology and evolutionary biology and of biomathematics.

    Beppler said more research is needed to determine which combinations are optimal for specific diseases and for specific parts of the body. And the researchers now are using the mathematical formula to test combinations of four antibiotics.

    Co-authors of the new research are Elif Tekin, a UCLA graduate student in Savage’s laboratory; Zhiyuan Mao, Cynthia White, Cassandra McDiarmid and Emily Vargas, who were undergraduates in Yeh’s laboratory; and Jeffrey H. Miller, a UCLA distinguished professor of microbiology, immunology and molecular genetics.

    Yeh’s research was funded by the Hellman Foundation. Savage’s research was funded by a James S. McDonnell Foundation Complex Systems Scholar Award and from the National Science Foundation. Beppler received funding from the National Institutes of Health Initiative to Maximize Student Development.

    See the full article here .

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    UC LA Campus

    For nearly 100 years, UCLA has been a pioneer, persevering through impossibility, turning the futile into the attainable.

    We doubt the critics, reject the status quo and see opportunity in dissatisfaction. Our campus, faculty and students are driven by optimism. It is not naïve; it is essential. And it has fueled every accomplishment, allowing us to redefine what’s possible, time after time.

    This can-do perspective has brought us 12 Nobel Prizes, 12 Rhodes Scholarships, more NCAA titles than any university and more Olympic medals than most nations. Our faculty and alumni helped create the Internet and pioneered reverse osmosis. And more than 100 companies have been created based on technology developed at UCLA.

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

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

    Brown University
    Brown University


    February 2, 2017
    Kevin Stacey

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    See the full article here .

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    Welcome to Brown

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

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

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

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

  • richardmitnick 3:19 pm on February 4, 2017 Permalink | Reply
    Tags: , Biology, Coxsackievirus B1, Enteroviruses, , , Wyss Institute’s human gut-on-a-chip goes viral   

    From Wyss: “Wyss Institute’s human gut-on-a-chip goes viral” 

    Harvard bloc tiny
    Wyss Institute bloc
    Wyss Institute

    February 1, 2017
    No writer credit found

    Enteroviruses enter the human body through the digestive or respiratory tract and from there spread to other sites in the body where they can cause a variety of serious health threats including meningitis, pancreatitis, myocarditis, the death of motor neurons, and perhaps even help trigger diabetes. However, they remain a challenge to study because they cannot be grown in conventional human cell cultures. Yet, understanding how enteroviruses invade gastrointestinal cells, multiply within them, and are released to other sites in the body could be key to ending the present dearth of specific anti-viral therapies and vaccines.

    As shown in these immunofluorescence images, the research team recapitulated the typical epithelial microvilli architecture of the human gut in a microchannel of a microfluidic chip with cell nuclei shown in blue and the cytoskeleton that enables each cell to assume and maintain its shape in the microvilli structure shown in red (left image). Upon infection with a clinical Coxsackievirus B1 strain (green), the epithelium produced and secreted additional viral particles that induced the break-down of the tissue’s normal architecture. Credit: Wyss Institute at Harvard University.

    Towards solving this problem, a multidisciplinary team of tissue engineers and biologists at Harvard’s Wyss Institute for Biologically Inspired Engineering working alongside scientists from the Molecular Virology Team at the U.S. Food and Drug Administration (FDA)’s Center for Food Safety and Applied Nutrition now have leveraged the Wyss Institute’s previously developed human gut-on-a-chip to mimic the entry, host cell-interaction and multiplication of a pathogenic clinical strain of Coxsackievirus using gut epithelium outside the human body. Their findings are reported in PLoS One.

    “We teamed up with FDA researchers to show for the first time that an enterovirus can be successfully cultured in a microfluidic human Gut Chip system. We were excited to find that the organ-on-a-chip approach offers a potential new way to study these viral pathogens under more physiologically relevant conditions in vitro,” said the Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who led the team. Ingber also is the Judah Folkman Professor of Vascular Biology at Boston Children’s Hospital and Harvard Medical School, and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS).

    “Now that we have a functional minimal system in place that replicates typical host-pathogen interactions, we can start to vary the type of intestinal cells, include immune cells that may contribute to the host response to infection, or create tissues using human stem cell-derived intestinal cells to tease out virus specificities and requirements for infection,” said Ingber.

    First developed in 2012, the Wyss Institute’s human gut-on-a-chip is a transparent, hollow-channeled microfluidic device the size of a computer memory stick that recapitulates the gut microenvironment. Human intestinal epithelial cells are cultured in a microchannel on a porous membrane that separates them from a parallel microchannel that mimics a neighboring capillary blood vessel. Fluid with or without viruses is flowed through both channels and exchanged through the pores of the membrane. Suction forces are also applied to parallel hollow channels, which produce cyclic deformations in the tissue that mimic intestinal peristalsis-like motions. This culture approach results in the growth of a fully differentiated gut epithelium that exhibits three-dimensional finger-like villus structures and that harbors all of the relevant cell types of the small intestine. In 2015, the team added more complexity to their biomimicking device by co-culturing a capillary endothelium on the lower surface of the membrane as well as a bacterial gut microbiome on the lumen of the epithelial channel to model aspects of human intestinal inflammation.

    “We were able to recapitulate how Coxsackievirus B1 enters the epithelium lining the intestinal villi from the gut lumen, and show that the virus replicates inside the cells and exits them again via a specific route to go on to infect cells downstream in the channel,” said Remi Villenave, Ph.D., the study’s first author who did the work when he was a postdoctoral fellow working with Ingber. “Also inflammatory cytokines that likely contribute to intestinal tissue injury in the chip were preferentially secreted into the lumen of the intestinal channel rather than into the media transporting channel, paralleling what is seen in acute infections in people.”

    Besides Villenave and Ingber, the article is also authored by FDA researchers Samantha Wales, Efstathia Papafragkou, Christopher Elkins and Michael Kulka. Additional authors are Tiama Hamkins-Indik, James Weaver, Thomas Ferrante and Anthony Bahinski, who at the time of the study were affiliated with the Wyss Institute.

    See the full article here .

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    Wyss Institute campus

    The Wyss (pronounced “Veese”) Institute for Biologically Inspired Engineering uses Nature’s design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world.

    Working as an alliance among Harvard’s Schools of Medicine, Engineering, and Arts & Sciences, and in partnership with Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Dana Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Tufts University, and Boston University, the Institute crosses disciplinary and institutional barriers to engage in high-risk research that leads to transformative technological breakthroughs.

  • richardmitnick 2:26 pm on February 2, 2017 Permalink | Reply
    Tags: , Biology, , ,   

    From Caltech: “Protein Chaperone Takes Its Job Seriously” 

    Caltech Logo



    Whitney Clavin
    (626) 395-1856

    Structural rendering of a ribosomal protein (yellow and red) bound to its chaperone (blue). By capturing an atomic-resolution snapshot of the pair of proteins interacting with each other, Ferdinand Huber, a graduate student in the lab of André Hoelz revealed that chaperones can protect their ribosomal proteins by tightly packaging them up. The red region illustrates where the dramatic shape alterations occur when the ribosomal protein is released from the chaperone during ribosome assembly. Credit: Huber and Hoelz/Caltech

    A diagram of the cell showing the process by which chaperone proteins (red) transport ribosomal proteins (beige) to the nucleus. The chaperones bind to the ribosomal proteins and usher them into the nucleus, while also protecting the proteins from liquidation machinery. Once a ribosomal protein reaches a growing ribosome (green and purple), the chaperone releases it. The nearly complete ribosome units exit the nucleus where they undergo final assembly. Credit: Huber and Hoelz/Caltech

    For proteins, this would be the equivalent of the red-carpet treatment: each protein belonging to the complex machinery of ribosomes—components of the cell that produce proteins—has its own chaperone to guide it to the right place at the right time and protect it from harm.

    In a new Caltech study, researchers are learning more about how ribosome chaperones work, showing that one particular chaperone binds to its protein client in a very specific, tight manner, almost like a glove fitting a hand. The researchers used X-ray crystallography to solve the atomic structure of the ribosomal protein bound to its chaperone.

    “Making ribosomes is a bit like baking a cake. The individual ingredients come in protective packaging that specifically fits their size and shape until they are unwrapped and blended into a batter,” says André Hoelz, professor of chemistry at Caltech, a Heritage Medical Research Institute (HMRI) Investigator, and Howard Hughes Medical Institute (HHMI) Faculty Scholar.” What we have done is figure out how the protective packaging fits one ribosomal protein, and how it comes unwrapped.” Hoelz is the principal investigator behind the study published February 2, 2017, in the journal Nature Communications. The finding has potential applications in the development of new cancer drugs designed specifically to disable ribosome assembly.

    In all cells, genetic information is stored as DNA and transcribed into mRNAs that code for proteins. Ribosomes translate the mRNAs into amino acids, linking them together into polypeptide chains that fold into proteins. More than a million ribosomes are produced per day in an animal cell.

    Building ribosomes is a formidable undertaking for the cell, involving about 80 proteins that make up the ribosome itself, strings of ribosomal RNA, and more than 200 additional proteins that guide and regulate the process. “Ribosome assembly is a dynamic process, where everything happens in a certain order. We are only now beginning to elucidate the many steps involved,” says Hoelz.

    To make matters more complex, the proteins making up a ribosome are first synthesized outside the nucleus of a cell, in the cytoplasm, before being transported into the nucleus where the initial stages of ribosome assembly take place.

    Chaperone proteins help transport ribosomal proteins to the nucleus while also protecting them from being chopped up by a cell’s protein shredding machinery. The components that specifically aim this machinery at unprotected ribosomal proteins, recently identified by Raymond Deshaies, professor of biology at Caltech and an HHMI Investigator, ensures that equal numbers of the various ribosomal proteins are available for building the massive structure of a ribosome.

    Structural rendering of a chaperone called Acl4 bound to ribosomal protein L4

    Previously, Hoelz and his team, in collaboration with the laboratory of Ed Hurt at the University of Heidelberg, discovered that a ribosomal protein called L4 is bound by a chaperone called “Assembly chaperone of RpL4,” or Acl4. The chaperone ushers L4 through the nucleus, protecting it from harm, and delivers it to a developing ribosome at a precise time and location. In the new study, the team used X-ray crystallography, a process that involves exposing protein crystals to high-energy X-rays, to solve the structure of the bound pair. The technique was performed at Caltech’s Molecular Observatory beamline at the Stanford Synchrotron Radiation Lightsource.

    “This was not an easy structure to solve,” says Ferdinand Huber, a graduate student at Caltech in the Hoelz lab and first author of the new study. “Solving the structure was incredibly exciting because you could see with your eyes, for the very first time, how the chaperone embraces the ribosomal protein to protect it.”

    Hoelz says that the structure was a surprise because it was not known previously that chaperones hold on to their ribosomal proteins so tightly. He says they want to study other chaperones in the future to see if they function in a similar fashion to tightly guard ribosomal proteins. The results may lead to the development of new drugs for cancer therapy by preventing cancer cells from supplying the large numbers of ribosomes required for tumor growth.

    The study, called “Molecular Basis for Protection of Ribosomal Protein L4 from Cellular Degradation,” was funded by a PhD fellowship of the Boehringer Ingelheim Fonds, a Faculty Scholar Award of the Howard Hughes Medical Research Institute, a Heritage Medical Research Institute Principal Investigatorship, a Kimmel Scholar Award of the Sidney Kimmel Foundation for Cancer Research, a Teacher-Scholar Award of the Camille & Henry Dreyfus Foundation, and Caltech startup funds.

    See the full article here .

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    The California Institute of Technology (commonly referred to as Caltech) is a private research university located in Pasadena, California, United States. Caltech has six academic divisions with strong emphases on science and engineering. Its 124-acre (50 ha) primary campus is located approximately 11 mi (18 km) northeast of downtown Los Angeles. “The mission of the California Institute of Technology is to expand human knowledge and benefit society through research integrated with education. We investigate the most challenging, fundamental problems in science and technology in a singularly collegial, interdisciplinary atmosphere, while educating outstanding students to become creative members of society.”
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  • richardmitnick 2:48 pm on January 30, 2017 Permalink | Reply
    Tags: Biology, , , Dr. Miriam Eisenstein, GSK-3, Modeling of molecules on the computer, , ,   

    From Weizmann: Women in STEM – “Staff Scientist: Dr. Miriam Eisenstein” 

    Weizmann Institute of Science logo

    Weizmann Institute of Science

    No writer credit found

    Name: Dr. Miriam Eisenstein
    Department: Chemical Research Support

    “The modeling of molecules on the computer,” says Dr. Miriam Eisenstein, Head of the Macromolecular Modeling Unit of the Weizmann Institute of Science’s Chemical Research Support Department, “is sometimes the only way to understand exactly how such complex molecules as proteins interact.”

    Eisenstein was one of the first to develop molecular docking methods while working with Prof. Ephraim Katzir – over two decades ago – and she has worked in collaboration with many groups at the Weizmann Institute.

    But even with all her experience, protein interactions can still surprise her. This was the case in a recent collaboration with the lab group of Prof. Hagit Eldar-Finkelman of Tel Aviv University, in research that was hailed as a promising new direction for finding treatments for Alzheimer’s disease. Eldar-Finkelman and her group were investigating an enzyme known as GSK-3, which affects the activity of various proteins by clipping a particular type of chemical tag, known as a phosphate group, onto them. GSK-3 thus performs quite a few crucial functions in the body, but it can also become overactive, and this extra activity has been implicated in a number of diseases, including diabetes and Alzheimer’s.

    The Tel Aviv group, explains Eisenstein, was exploring a new way of blocking, or at least damping down, the activity of this enzyme. GSK-3 uses ATP — a small, phosphate-containing molecule — in the chemical tagging process, transferring one of the ATP phosphate groups to a substrate. The ATP binding site on the enzyme is often targeted with ATP-like drug compounds that by themselves binding prevent the ATP from binding, thus blocking the enzyme’s activity. But such compounds are not discriminating enough, often blocking related enzymes in the process, which is an undesired side effect. This is why Eldar-Finkelman and her team looked for molecules that would compete with the substrate and occupy its binding cavity, so that the enzyme’s normal substrates cannot attach to GSK-3 and clip onto the phosphate groups.

    After identifying one molecule – a short piece of protein, or peptide – that substituted for GSK-3’s substrates in experiments, Eldar-Finkelman turned to Eisenstein to design peptides that would be better at competing with the substrate. At first Eisenstein computed model structures of the enzyme with an attached protein substrate and the enzyme with an attached peptide; she then characterized the way in which the enzyme binds either the substrate or the competing peptide. The model structures pinpointed the contacts, and these were verified experimentally by Eldar-Finkelman.

    This led to the next phase, a collaborative effort to introduce alterations to the peptide so as to improve its binding capabilities. One of the new peptides was predicted by Eisenstein to be a good substrate, and Eldar-Finkelman’s experiments showed that it indeed was. Once chemically tagged, the new peptide proved to be excellent at binding to GSK-3 – many times better than the original – and this was the surprise, because normally, once they are tagged, such substrates are repelled from the substrate-binding cavity and end up dissociating from the enzyme. Molecular modeling explained what was happening. After initially binding as a substrate and attaining a phosphate group, the peptide slid within the substrate-binding cavity, changing its conformation in the process, and attached tightly to a position normally occupied by the protein substrate.

    Experiments in Eldar-Finkelman’s group showed that this peptide is also active in vivo and, moreover, was able to reduce the symptoms of an Alzheimer-like condition in mice. The results of this research appeared in Science Signaling.

    “This experiment is a great example of the synergy between biologists and computer modelers,” says Eisenstein. “Hagit understands the function of this enzyme in the body, and she had this great insight on a possible way to control its actions. I am interested in the way that two proteins fit together and influence one another at the molecular and atomic levels, so I can provide the complementary insight.”

    “Molecular modeling is such a useful tool, it has enabled me to work with a great many groups and take part in a lot of interesting, exciting work, over the years,” she adds. “Computers have become much stronger in that time, but the basic, chemical principles of attraction and binding between complex molecules remain the same, and our work is as relevant as ever.”

    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 9:07 am on January 24, 2017 Permalink | Reply
    Tags: Altered DNA, Ants, , Biology, Hypersociality,   

    From NYT: “Gene-Modified Ants Shed Light on How Societies Are Organized” 

    New York Times

    The New York Times

    JAN. 23, 2017

    Dr. Daniel Kronauer, shown in a double exposure, above, studies ants with altered DNA in order to understand complex biological systems. Credit Béatrice de Géa for The New York Times

    Whether personally or professionally, Daniel Kronauer of Rockefeller University is the sort of biologist who leaves no stone unturned. Passionate about ants and other insects since kindergarten, Dr. Kronauer says he still loves flipping over rocks “just to see what’s crawling around underneath.”

    In an amply windowed fourth-floor laboratory on the east side of Manhattan, he and his colleagues are assaying the biology, brain, genetics and behavior of a single species of ant in ambitious, uncompromising detail. The researchers have painstakingly hand-decorated thousands of clonal raider ants, Cerapachys biroi, with bright dots of pink, blue, red and lime-green paint, a color-coded system that allows computers to track the ants’ movements 24 hours a day — and makes them look like walking jelly beans.

    The scientists have manipulated the DNA of these ants, creating what Dr. Kronauer says are the world’s first transgenic ants. Among the surprising results is a line of Greta Garbo types that defy the standard ant preference for hypersociality and instead just want to be left alone.

    The researchers also have identified the molecular and neural cues that spur ants to act like nurses and feed the young, or to act like queens and breed more young, or to serve as brutal police officers, capturing upstart nestmates, spread-eagling them on the ground and reducing them to so many chitinous splinters.

    Dr. Kronauer, who was born and raised in Germany and just turned 40, is tall, sandy-haired, blue-eyed and married to a dentist. He is amiable and direct, and his lab’s ambitions are both lofty and pragmatic.

    “Our ultimate goal is to have a fundamental understanding of how a complex biological system works,” Dr. Kronauer said. “I use ants as a model to do this.” As he sees it, ants in a colony are like cells in a multicellular organism, or like neurons in the brain: their fates joined, their labor synchronized, the whole an emergent force to be reckoned with.

    “But you can manipulate an ant colony in ways you can’t easily do with a brain,” Dr. Kronauer said. “It’s very modular, and you can take it apart and put it back together again.”

    Dr. Kronauer and his co-authors describe their work in a series of recent reports that appear in Proceedings of the National Academy of Sciences, The Journal of Experimental Biology and elsewhere.

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  • richardmitnick 8:50 am on January 24, 2017 Permalink | Reply
    Tags: , Biology, Endoplasmic reticulum, , Snd2, SRP pathway,   

    From Weizman: “Outward-Bound Proteins Have a Third Way” 

    Weizmann Institute of Science logo

    Weizmann Institute of Science

    No writer credit found

    A newly discovered “shuttle” for proteins is a “safety net” for vital communication between cells.

    Snd2 was tagged with a green fluorescent protein, and the endoplasmic reticulum was marked with a red fluorescent protein. The overlap between the green and red microscopy signals indicates that the newly discovered Snd2 is a receptor on the endoplasmic reticulum membrane. No image credit.

    The cells in our bodies must constantly communicate with one another. For many, it is a matter of survival; for others, it is the way they keep our bodies healthy and functioning efficiently. Communications are carried out by proteins – both the numerous proteins that are situated on the cells’ outer membranes to receive the messages and the messengers themselves, which are secreted to the outside of the cell. For most of these proteins, getting to the outside of the cell involves passage through an organelle called the endoplasmic reticulum. This first entails getting across the membrane of this organelle, to which the proteins are targeted, with the help of a special “shuttle” that conducts them to a sort of “transit area,” checking them first to see if they have the proper “passports.”

    How many different shuttles are needed to move all these proteins – in effect, around 30% of all the proteins in each cell? Previous studies of the past few decades have identified two – sort of couriers, like FedEx or DHL for proteins. Now, a new study [Nature], conducted in the lab of Prof. Maya Schuldiner of the Institute’s Molecular Genetics Department, has uncovered a third shuttle, and raised the possibility that more might be awaiting discovery.

    (l-r) Naama Aviram and Prof. Maya Schuldiner describe a ‘safety net’ for communication proteins. No image credit.

    The study was led by research student Naama Aviram, in collaboration with the labs of Prof. Richard Zimmerman of Saarland University, Germany, Prof. Blanche Schwappach of Göttingen University, also inGermany, and Prof. Jonathan Weissman of the University of California, San Francisco. “The first pathway for transferring proteins into the endoplasmic reticulum was discovered in the 1980s,” says Schuldiner. “Scientists found that this shuttle, called SRP, identifies the protein to be transported by reading a tag that is a sort of ‘passport’.”

    But this finding was not the whole story: Although many proteins use the SRP pathway to get to the endoplasmic reticulum membrane, this shuttle system seemed to have trouble identifying other outward-bound proteins. The reason eventually became clear: SRP easily identifies the tag when it is situated at one end of the protein, but has a hard time with tags at the other end. “This suggested that there was another pathway to catch the proteins that SRP misses,” says Schuldiner. “We identified that pathway in 2008 and named it GET.”

    The “shuttles” that lead proteins to the endoplasmic reticulum: the two previously known SRP and GET pathways, together with the newly discovered SND pathway, each caters for proteins with a different position of their “passports”. No image credit.

    But even with two shuttle services, the scientists noted there were still proteins that were not easily recognized by the pathways. “These are proteins that, if they are not efficiently transported to the endoplasmic reticulum, the cell dies. So we undertook a search for yet another pathway,” says Aviram.

    The team began their experiments in yeast cells, whose basic functions are nearly identical to those of human cells, and then tested their results in human cells. To begin, the researchers identified proteins that need to pass through the endoplasmic reticulum transit area, but do not receive assistance from either known pathway.

    Then, using the advanced robotic system in Schuldiner’s lab, they systematically looked at the ability of a protein to reach the endoplasmic reticulum membrane in the absence of each gene in the yeast cell, finding three that appeared to be necessary to the process of transporting these particular “problematic” proteins. When these genes were missing, the researchers observed accumulations of protein within the cell – proteins that had not managed to reach their destination outside of it.

    The three genes, which the team called SND1, SND2 and SND3, work together; one on the ribosome (the cell’s protein-manufacturing complex) and the other two at the “gates” of the endoplasmic reticulum.

    Together with the Weissman lab in San Francisco, the scientists revealed that this third pathway is active when the “passport” is closer to the center of the protein – the region the other two pathways have a hard time reading. “The new pathway functions as a ‘safety net’ for crucial proteins that may need to catch the next shuttle, but have their tags in inconvenient places,” says Schuldiner.

    Together with the Zimmerman lab, the researchers then asked whether this was occurring in a similar way in human cells. The scientists silenced the human SND2 gene – which they found has been conserved throughout evolution – and showed that here, too, the passage into the endoplasmic reticulum was defective, suggesting that this third pathway is at work in human cells as it is in yeast.

    “Many diseases, for example diabetes, involve disruption to intercellular communications,” says Schuldiner. “And we don’t always know just where the message goes astray. Maybe, in the future, understanding this pathway might help us figure out how to treat disease and save lives.”

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

    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.

    See the full article here .

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  • richardmitnick 3:10 pm on January 20, 2017 Permalink | Reply
    Tags: , Biology, , , Telomere length, TZAP   

    From Scripps: “Scientists Discover Master Regulator of Cellular Aging’ 

    Scripps Research Institute

    January 23, 2017
    Madeline McCurry-Schmidt

    “This protein sets the upper limit of telomere length,” says Associate Professor and senior author Eros Lazzerini Denchi (left), pictured here with study first author Graduate Student Julia Su Zhou Li. (Photo by Madeline McCurry-Schmidt.)

    Scientists at The Scripps Research Institute (TSRI) have discovered a protein that fine-tunes the cellular clock involved in aging.

    This novel protein, named TZAP, binds the ends of chromosomes and determines how long telomeres, the segments of DNA that protect chromosome ends, can be. Understanding telomere length is crucial because telomeres set the lifespan of cells in the body, dictating critical processes such as aging and the incidence of cancer.

    “Telomeres represent the clock of a cell,” said TSRI Associate Professor Eros Lazzerini Denchi, corresponding author of the new study, published in the journal Science [link is below]. “You are born with telomeres of a certain length, and every time a cell divides, it loses a little bit of the telomere. Once the telomere is too short, the cell cannot divide anymore.”

    Naturally, researchers are curious whether lengthening telomeres could slow aging, and many scientists have looked into using a specialized enzyme called telomerase to “fine-tune” the biological clock. One drawback they’ve discovered is that unnaturally long telomeres are a risk factor in developing cancer.

    “This cellular clock needs to be finely tuned to allow sufficient cell divisions to develop differentiated tissues and maintain renewable tissues in our body and, at the same time, to limit the proliferation of cancerous cells,” said Lazzerini Denchi.

    In this new study, the researcher found that TZAP controls a process called telomere trimming, ensuring that telomeres do not become too long.

    “This protein sets the upper limit of telomere length,” explained Lazzerini Denchi. “This allows cells to proliferate—but not too much.”

    For the last few decades, the only proteins known to specifically bind telomeres were the telomerase enzyme and a protein complex known as the Shelterin complex. The discovery TZAP, which binds specifically to telomeres, was a surprise since many scientists in the field believed there were no additional proteins binding to telomeres.

    “There is a protein complex that was found to localize specifically at chromosome ends, but since its discovery, no protein has been shown to specifically localize to telomeres,” said study first author Julia Su Zhou Li, a graduate student in the Lazzerini Denchi lab.

    “This study opens up a lot of new and exciting questions,” said Lazzerini Denchi.

    In addition to Lazzerini Denchi and Li, authors of the study, TZAP: a telomere-associated protein involved in telomere length control, were Tatevik Simavorian, Cristina Bartocci and Jill Tsai of TSRI; Javier Miralles Fuste of the Salk Institute for Biological Studies and the University of Gothenburg; and Jan Karlseder of the Salk Institute for Biological Studies.

    See the full article here .

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    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

  • richardmitnick 3:12 pm on January 17, 2017 Permalink | Reply
    Tags: , Biology, , , , The most successful phyla have species that live on land and have a skeleton and are parasites, Three Ways to Be a Winner in the Game of Evolution,   

    From U Arizona: “Three Ways to Be a Winner in the Game of Evolution” 

    U Arizona bloc

    University of Arizona

    Jellyfish, polyps and the like belong to a phylum called Cnidaria, one of about 30 major groups that make up the animal kingdom. (Photo: Chai Seamaker/Shutterstock)

    A new UA study reveals the key traits associated with high species diversity: The most successful phyla have species that live on land, have a skeleton and are parasites.

    A new study by University of Arizona biologists helps explain why different groups of animals differ dramatically in their number of species, and how this is related to differences in their body forms and ways of life.

    For millennia, humans have marveled at the seemingly boundless variety and diversity of animals inhabiting the Earth. So far, biologists have described and catalogued about 1.5 million animal species, a number that many think might be eclipsed by the number of species still awaiting discovery.

    All animal species are divided among roughly 30 phyla, but these phyla differ dramatically in how many species they contain, from a single species to more than 1.2 million in the case of insects and their kin. Animals have incredible variation in their body shapes and ways of life, including the plantlike, immobile marine sponges that lack heads, eyes, limbs and complex organs, parasitic worms that live inside other organisms (nematodes, platyhelminths), and phyla with eyes, skeletons, limbs and complex organs that dominate the land in terms of species numbers (arthropods) and body size (chordates).

    Amid this dazzling array of life forms, one question has remained as elusive as it is obvious: Why is it that some groups on the evolutionary tree of animals have branched into a dizzying thicket of species while others split into a mere handful and called it a day?

    From the beginnings of their discipline, biologists have tried to find and understand the patterns underlying species diversity. In other words, what is the recipe that allows a phylum to diversify into many species, or, in the words of evolutionary biologists, to be “successful”? A fundamental but unresolved problem is whether the basic biology of these phyla is related to their species numbers. For example, does having a head, limbs and eyes allow some groups to be more successful and thus have greater species numbers?

    A simplified evolutionary tree of six representative animal phyla, illustrating differences in body form, habitat, and species numbers among them. (Image: T. Jezkova/Shutterstock/Aaron Ambos/J. Wiens)

    This colorful chocolate chip sea star, along with sea cucumbers and sea urchins, belongs to the Echinoderms, the only phylum with a five-symmetrical body plan. (Photo: Ethan Daniels/Shutterstock)

    n the new study, Tereza Jezkova and John Wiens, both in the University of Arizona’s Department of Ecology and Evolutionary Biology, have helped resolve this problem. They assembled a database of 18 traits, including traits related to anatomy, reproduction and ecology. They then tested how each trait was related to the number of species in each phylum, and how quickly species in each phylum multiplied over time (diversification). The results are published in the journal American Naturalist.

    Jezkova and Wiens found that just three traits explained most variation in diversification and species numbers among phyla: the most successful phyla have a skeleton (either internal or external), live on land (instead of in the ocean) and parasitize other organisms. Other traits, including those that might seem more dramatic, had surprisingly little impact on diversification and species numbers: Evolutionary accomplishments such as having a head, limbs and complex organ systems for circulation and digestion don’t seem to be primary accessories in the evolutionary “dress for success.”

    “Parasitism isn’t correlated with any of the other traits, so it seems to have a strong effect on its own,” Wiens said.

    He explained that when a host species splits into two species, it takes its parasite population(s) with it.

    “You can have a number of parasite species living inside the same host,” he said. “For example, there could be 10 species of nematodes in one host species, and if that host species splits into two, there are 20 species of nematodes. So that really multiplies the diversity.”

    The researchers used a statistical method called multiple regression analysis to tease out whether a trait such as parasitic lifestyle is a likely driver of species diversification.

    “We tested all these unique traits individually,” Wiens explained. “For example, having a head, having eyes, where the species in a phylum tend to live, whether they reproduce sexually or asexually, whether they undergo metamorphosis or not. And from that we picked six traits that each had a strong effect on their own. We then fed those six traits into a multiple regression model. And then we asked, ‘What combination of traits explains the most variation without including any unnecessary variables?’ — and from that we could reduce it down to three key variables.”

    The authors point out that the analysis does not make any assumptions about the fossil record, which is not a true reflection of past biodiversity, as it does not reveal most soft-bodied animals or traits like a parasitic lifestyle.

    “We wanted to know what explains the pattern of diversity in the species we see today,” Wiens said. “Who are the winners, and who are the losers?”

    Marine biodiversity is in jeopardy from human activities such as acidification from carbon emissions, posing an existential threat to many marine animals, Wiens said.

    “Many unique products of animal evolution live only in the oceans and could easily be lost, so groups that have survived for hundreds of millions of years could disappear in our lifetime, which is terrible,” he said. “Many of the animals’ phyla that are losers in terms of present-day species numbers tend to be in the ocean, and because of human activity, they may go completely extinct.”

    The study also suggests that man-made extinction may wage a heavy toll on Earth’s biodiversity because of the effect of secondary extinctions, Wiens explained.

    “When a species goes extinct, all its associated species that live in it or on it are likely to go extinct as well,” he said.

    See the full article here .

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    U Arizona campus

    The University of Arizona (UA) is a place without limits-where teaching, research, service and innovation merge to improve lives in Arizona and beyond. We aren’t afraid to ask big questions, and find even better answers.

    In 1885, establishing Arizona’s first university in the middle of the Sonoran Desert was a bold move. But our founders were fearless, and we have never lost that spirit. To this day, we’re revolutionizing the fields of space sciences, optics, biosciences, medicine, arts and humanities, business, technology transfer and many others. Since it was founded, the UA has grown to cover more than 380 acres in central Tucson, a rich breeding ground for discovery.

    Where else in the world can you find an astronomical observatory mirror lab under a football stadium? An entire ecosystem under a glass dome? Visit our campus, just once, and you’ll quickly understand why the UA is a university unlike any other.

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