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  • richardmitnick 7:23 am on September 27, 2016 Permalink | Reply
    Tags: , Biology, Killing Superbugs with Star-Shaped Polymers instead of Antibiotics, , Shu Lam, U Melbourne   

    From University of Melbourne via Science Alert: Women in STEM – “Killing Superbugs with Star-Shaped Polymers instead of Antibiotics” Shu Lam 

    u-melbourne-bloc

    University of Melbourne

    ScienceAlert

    Science Alert

    The science world is freaking out over this 25-year-old’s answer to antibiotic resistance

    26 SEP 2016
    FIONA MACDONALD

    Could this be the end of superbugs?

    1
    Shu Lam

    A 25-year-old student has just come up with a way to fight drug-resistant superbugs without antibiotics.

    The new approach has so far only been tested in the lab and on mice, but it could offer a potential solution to antibiotic resistance, which is now getting so bad that the United Nations recently declared it a “fundamental threat” to global health.

    Antibiotic-resistant bacteria already kill around 700,000 people each year, but a recent study suggests that number could rise to around 10 million by 2050.

    In addition to common hospital superbug, methicillin-resistant Staphylococcus aureus (MRSA), scientists are now also concerned that gonorrhoea is about to become resistant to all remaining drugs.

    But Shu Lam, a 25-year-old PhD student at the University of Melbourne in Australia, has developed a star-shaped polymer that can kill six different superbug strains without antibiotics, simply by ripping apart their cell walls.

    “We’ve discovered that [the polymers] actually target the bacteria and kill it in multiple ways,” Lam told Nicola Smith from The Telegraph. “One method is by physically disrupting or breaking apart the cell wall of the bacteria. This creates a lot of stress on the bacteria and causes it to start killing itself.”

    The research has been published in Nature Microbiology, and according to Smith, it’s already being hailed by scientists in the field as “a breakthrough that could change the face of modern medicine”.

    Before we get too carried away, it’s still very early days. So far, Lam has only tested her star-shaped polymers on six strains of drug-resistant bacteria in the lab, and on one superbug in live mice.

    But in all experiments, they’ve been able to kill their targeted bacteria – and generation after generation don’t seem to develop resistance to the polymers.

    The polymers – which they call SNAPPs, or structurally nanoengineered antimicrobial peptide polymers – work by directly attacking, penetrating, and then destabilising the cell membrane of bacteria.

    Unlike antibiotics, which ‘poison’ bacteria, and can also affect healthy cells in the area, the SNAPPs that Lam has designed are so large that they don’t seem to affect healthy cells at all.

    “With this polymerised peptide we are talking the difference in scale between a mouse and an elephant,” Lam’s supervisor, Greg Qiao, told Marcus Strom from the Sydney Morning Herald. “The large peptide molecules can’t enter the [healthy] cells.”

    You can see the SNAPPs (green) surrounding and ripping apart bacterial cells below:

    2

    While the results are positive so far, it’s too early to get excited about what this could mean for humans, says Cyrille Boyer from the University of New South Wales in Australia, who wasn’t involved in the research.

    “The main advantage seems to be they can kill bacteria more effectively and selectively [than other peptides]” Boyer told Strom, before adding that the team is a long way off clinical applications.

    But what’s awesome about the new project is that, while other teams are looking for new antibiotics, Lam has found a completely different approach. And it could make all the different in the coming ‘post-antibiotic world’.

    That’s what she’s hoping, anyway.

    “For a time, I had to come in at 4am in the morning to look after my mice and my cells,” she told The Telegraph. “I wanted to be involved in some kind of research that would help solve problems … I really hope that the polymers we are trying to develop here could eventually be a solution.”

    See the full article here .

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    The University of Melbourne (informally Melbourne University) is an Australian public research university located in Melbourne, Victoria. Founded in 1853, it is Australia’s second oldest university and the oldest in Victoria. Times Higher Education ranks Melbourne as 33rd in the world, while the Academic Ranking of World Universities places Melbourne 44th in the world (both first in Australia).

    Melbourne’s main campus is located in Parkville, an inner suburb north of the Melbourne central business district, with several other campuses located across Victoria. Melbourne is a sandstone university and a member of the Group of Eight, Universitas 21 and the Association of Pacific Rim Universities. Since 1872 various residential colleges have become affiliated with the university. There are 12 colleges located on the main campus and in nearby suburbs offering academic, sporting and cultural programs alongside accommodation for Melbourne students and faculty.

    Melbourne comprises 11 separate academic units and is associated with numerous institutes and research centres, including the Walter and Eliza Hall Institute of Medical Research, Florey Institute of Neuroscience and Mental Health, the Melbourne Institute of Applied Economic and Social Research and the Grattan Institute. Amongst Melbourne’s 15 graduate schools the Melbourne Business School, the Melbourne Law School and the Melbourne Medical School are particularly well regarded.

    Four Australian prime ministers and five governors-general have graduated from Melbourne. Nine Nobel laureates have been students or faculty, the most of any Australian university

     
  • richardmitnick 7:36 am on September 24, 2016 Permalink | Reply
    Tags: , Biology, , Research at Princeton   

    From Research at Princeton: “New method identifies protein-protein interactions on basis of sequence alone (PNAS)” 

    Princeton University
    Princeton University

    September 23, 2016
    Catherine Zandonella, Office of the Dean for Research

    1
    Researchers can now identify which proteins will interact just by looking at their sequences. Pictured are surface representations of a histidine kinase dimer (HK, top) and a response regulator (RR, bottom), two proteins that interact with each other to carry out cellular signaling functions. (Image based on work by Casino, et. al. credit: Bitbol et. al 2016/PNAS.)

    Genomic sequencing has provided an enormous amount of new information, but researchers haven’t always been able to use that data to understand living systems.

    Now a group of researchers has used mathematical analysis to figure out whether two proteins interact with each other, just by looking at their sequences and without having to train their computer model using any known examples. The research, which was published online today in the journal Proceedings of the National Academy of Sciences, is a significant step forward because protein-protein interactions underlie a multitude of biological processes, from how bacteria sense their surroundings to how enzymes turn our food into cellular energy.

    “We hadn’t dreamed we’d be able to address this,” said Ned Wingreen, Princeton University‘s Howard A. Prior Professor in the Life Sciences, and a professor of molecular biology and the Lewis-Sigler Institute for Integrative Genomics, and a senior co-author of the study with Lucy Colwell of the University of Cambridge. “We can now figure out which protein families interact with which other protein families, just by looking at their sequences,” he said.

    Although researchers have been able to use genomic analysis to obtain the sequences of amino acids that make up proteins, until now there has been no way to use those sequences to accurately predict protein-protein interactions. The main roadblock was that each cell can contain many similar copies of the same protein, called paralogs, and it wasn’t possible to predict which paralog from one protein family would interact with which paralog from another protein family. Instead, scientists have had to conduct extensive laboratory experiments involving sorting through protein paralogs one by one to see which ones stick.

    In the current paper, the researchers use a mathematical procedure, or algorithm, to examine the possible interactions among paralogs and identify pairs of proteins that interact. The method was able to correctly predict 93% of the protein-protein paralog pairs that were present in a dataset of more than 20,000 known paired protein sequences, without being first provided any examples of correct pairs.

    Interactions between proteins happen when two proteins come into physical contact and stick together via weak bonds. They may do this to form part of a larger piece of machinery used in cellular metabolism. Or two proteins might interact to pass a signal from the exterior of the cell to the DNA, to enable a bacterial organism to react to its environment.

    When two proteins come together, some amino acids on one chain stick to the amino acids on the other chain. Each site on the chain contains one of 20 possible amino acids, yielding a very large number of possible amino-acid pairings. But not all such pairings are equally probable, because proteins that interact tend to evolve together over time, causing their sequences to be correlated.

    The algorithm takes advantage of this correlation. It starts with two protein families, each with multiple paralogs in any given organism. The algorithm then pairs protein paralogs randomly within each organism and asks, do particular pairs of amino acids, one on each of the proteins, occur much more or less frequently than chance? Then using this information it asks, given an amino acid in a particular location on the first protein, which amino acids are especially favored at a particular location on the second protein, a technique known as direct coupling analysis. The algorithm in turn uses this information to calculate the strengths of interactions, or “interaction energies,” for all possible protein paralog pairs, and ranks them. It eliminates the unlikely pairings and then runs again using only the top most likely protein pairs.

    The most challenging part of identifying protein-protein pairs arises from the fact that proteins fold and kink into complicated shapes that bring amino acids in proximity to others that are not close by in sequence, and that amino-acids may be correlated with each other via chains of interactions, not just when they are neighbors in 3D. The direct coupling analysis works surprisingly well at finding the true underlying couplings that occur between neighbors.

    The work on the algorithm was initiated by Wingreen and Robert Dwyer, who earned his Ph.D. in the Department of Molecular Biology at Princeton in 2014, and was continued by first author Anne-Florence Bitbol, who was a postdoctoral researcher in the Lewis-Sigler Institute for Integrative Genomics and the Department of Physics at Princeton and is now a CNRS researcher at Universite Pierre et Marie Curie – Paris 6. Bitbol was advised by Wingreen and Colwell, an expert in this kind of analysis who joined the collaboration while a member at the Institute for Advanced Study in Princeton, NJ, and is now a lecturer in chemistry at the University of Cambridge.

    The researchers thought that the algorithm would only work accurately if it first “learned” what makes a good protein-protein pair by studying ones discovered in experiments. This required that the researchers give the algorithm some known protein pairs, or “gold standards,” against which to compare new sequences. The team used two well-studied families of proteins, histidine kinases and response regulators, which interact as part of a signaling system in bacteria.

    But known examples are often scarce, and there are tens of millions of undiscovered protein-protein interactions in cells. So the team decided to see if they could reduce the amount of training they gave the algorithm. They gradually lowered the number of known histidine kinase-response regulator pairs that they fed into the algorithm, and were surprised to find that the algorithm continued to work. Finally, they ran the algorithm without giving it any such training pairs, and it still predicted new pairs with 93 percent accuracy.

    “The fact that we didn’t need a gold standard was a big surprise,” Wingreen said.

    Upon further exploration, Wingreen and colleagues figured out that their algorithm’s good performance was due to the fact that true protein-protein interactions are relatively rare. There are many pairings that simply don’t work, and the algorithm quickly learned not to include them in future attempts. In other words, there is only a small number of distinctive ways that protein-protein interactions can happen, and a vast number of ways that they cannot happen. Moreover, the few successful pairings were found to repeat with little variation across many organisms. This it turns out, makes it relatively easy for the algorithm to reliably sort interactions from non-interactions.

    Wingreen compared this observation – that correct pairs are more similar to one another than incorrect pairs are to each other – to the opening line of Leo Tolstoy’s Anna Karenina, which states, “All happy families are alike; each unhappy family is unhappy in its own way.”

    The work was done using protein sequences from bacteria, and the researchers are now extending the technique to other organisms.

    The approach has the potential to enhance the systematic study of biology, Wingreen said. “We know that living organisms are based on networks of interacting proteins,” he said. “Finally we can begin to use sequence data to explore these networks.”

    The research was supported in part by the National Institutes of Health (Grant R01-GM082938) and the National Science Foundation (Grant PHY–1305525).

    See the full article here .

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    As a world-renowned research university, Princeton seeks to achieve the highest levels of distinction in the discovery and transmission of knowledge and understanding. At the same time, Princeton is distinctive among research universities in its commitment to undergraduate teaching.

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  • richardmitnick 11:19 am on September 16, 2016 Permalink | Reply
    Tags: , Biology, , , Hyperstable peptides, Institute for Protein Design,   

    From U Washington: “Super-stable peptides might be used to create ‘on-demand’ drugs” 

    U Washington

    University of Washington

    09.14.2016
    Michael McCarthy

    1
    An artist’s conception of a peptide created at the UW Medicine Institute for Protein Design. The backbone structure is shown in pink, and the molecular surface is blue. White indicates the crossbonds that stabilize the peptide’s shape. Vikram Mulligan

    2

    Scientists at the University of Washington’s Institute for Protein Design have shown it is possible to create small, hyperstable peptides that could provide the basis for developing powerful new drugs and diagnostic tests.

    “These super stable peptides provide an ideal molecular scaffold on which it should be possible to design ‘on demand’ a new generation of peptide-based drugs,” said UW Medicine protein engineering pioneer David Baker, who oversaw the research project. He is a UW professor of biochemistry.

    David Baker
    David Baker

    In a study, which appears in the journal Nature, the researchers demonstrate that not only is it possible to design peptides that fold into a wide variety of different conformations, but also that it is possible to incorporate functional groups of chemicals not normally found in peptides.

    3
    Illustrations of designed peptides with different configurations of two structures: tightly wound ribbons and flat, arrow-shaped ribbons.

    Both of these abilities could give designers even greater flexibility to create drugs that act on their molecular targets with high precision. Such drugs should not only be more potent but would also be less likely to have harmful side effects.

    Most drugs work by binding to a key section of a protein in a way that alters how the protein functions, typically by stimulating or inhibiting the protein’s activity. For the binding to occur, the drug must fit into the target site on the protein as a key fits into a lock. How close the lock-and-key fit is can often determine how well the medication works.

    Currently, most prescription drugs are either made of small molecules or much larger proteins. Both classes of drugs have advantages and disadvantages.

    Small molecule drugs, for example, tend to be easy to manufacture, tend to have a long shelf life, and are often easily absorbed. But they often don’t fit the targeted “lock” as selectively as could be hoped. This imperfect fit can result in off-target binding and side-effects that diminish their effectiveness. Protein drugs, on the other hand, often fit their target receptors very well but they are difficult to manufacture, are more unstable, and lose their potency if they are not kept refrigerated. Because of their size and instability, they need to be injected into patients.

    Peptide drugs fall in between these two classes. They are small, so they have many of advantages of small molecule drugs. But they are made of a chain of amino acids, the same components that make up proteins, so they have the potential to achieve the precision of larger protein drugs.

    The power of some tiny peptides can be observed in venomous creatures. A number of poisonous insects and sea creatures produce small peptide toxins. Those are some of the most potent pharmacologically active compounds known. Their potency is among the reasons why medical scientists are interested in tapping into beneficial uses of peptides.

    In the new study, Gaurav Bhardwaj, Vikram Khipple Mulligan, Christopher D. Bahl, senior fellows in the Baker lab, and their colleagues, developed computational methods that are now incorporated in the computer program called Rosetta.

    rosetta-screensaver
    rosettahome
    Rosetta@home, a project running on BOINC software from UC Berkeley
    BOINC WallPaper

    These methods are being used to design peptides ranging from 18 to 47 amino acids in length in 16 different conformations, called topologies.

    Originally developed by Baker and his earlier team, Rosetta uses advanced modelling algorithms to design new proteins by calculating the energies of the biochemical interactions within a protein, and between the protein and its surroundings. Because a protein will assume the shape in which the sum of these interaction energies is at its minimum, the program can calculate which shape a protein will most likely assume in nature.

    The peptides were made hyperstable by designing them to have interior crosslinking structures, called disulfide bonds, which staple together different sections of the peptide. Additional stabilization was secured by tying the two ends of the peptide chain together, a process called cyclization. The resulting constrained peptides were so stable that they were able to survive temperatures to 95 °C, nearly boiling. This survival feat would be impossible for antibody drugs.

    The researchers also showed that the design of these peptides could include amino acids not normally found in proteins. Amino acids have a property called handedness or chirality. Two amino acids can be made of the same atoms but have different arrangements, just as our hands have the same number of fingers but have two mirror-image configurations, right and left. This handedness keeps the right hand from fitting properly into a left-handed glove and vice versa.

    In nature, perhaps due to a chance event billions of years ago, amino acids in living cells are all left-handed. Right-handed amino acids are very rare in naturally occurring proteins. Nevetheless, the researchers were able to insert right-handed amino acids in their designed peptides.

    “Being able to include other types of amino acids allows us to create peptides with a much wider variety of conformations,” said Baker, “and being able to use right-handed amino acids essentially doubles your palette.”

    “By making it possible to create peptides that include ‘unnatural’ amino acids, this approach will allow researchers to explore peptide structures and function that have not been explored by nature through evolution,” Baker said.

    Today’s edition of Nature also has a special supplement, Insight The Protein World. Baker, Po-Ssu, and Scott E. Boyken authored the review article, The coming of age of de novo protein design.

    Also see coverage of the Nature hyperstable peptide design paper in Hutch News by the Fred Hutchinson Cancer Research Center.

    The National Institutes of Health provided partial support for this work through grants P50 AG005136, T32-H600035., GM094597, GM090205, and HHSN272201200025C. Additional funding was provided by The Three Dreamers.

    See the full article here .

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  • richardmitnick 2:23 pm on September 9, 2016 Permalink | Reply
    Tags: , Antibiotic resistance, , Biology, Harvard Medical School, Technion-Israel Institute of Technology   

    From AAAS: “Scientists Build Giant Petri Dish to Film Bacteria Resistance” 

    AAAS

    AAAS

    8 September 2016
    Meagan Phelan

    Researchers have developed a large plate on which to film bacteria as they mutate in the presence of higher and higher concentrations of antibiotics, providing unprecedented insights into the phenomenon of antibiotic resistance.

    “Our device allows us to systematically map the different ways by which bacteria can become resistant to a range of antibiotics and antibiotic combinations,” said co-author Roy Kishony, a professor in the department of systems biology at Harvard Medical School and a principal investigator at Technion-Israel Institute of Technology.

    The ultimate goal, Kishony added, is to develop tools “that can predict the evolution of pathogens under different treatments, and better guide treatment choice.”

    “With our plate device, the evolutionary paths that the bacteria follow to achieve antibiotic resistance appear clearly and visually,” said co-author Michael Baym, a postdoctoral fellow in the Kishony Lab at Harvard Medical School, “and will hopefully let us start tailoring our approaches to treating resistance to different evolutionary modes.”

    The 2-by-4 foot petri dish used by the researchers to grow the bacteria contains nine bands at its base that can support varying concentrations of antibiotic. The results are reported in the 9 September issue of Science.

    Antibiotics have been used to treat patients since the 1940s, greatly reducing illness and death. However, these drugs have been used so frequently that the bacteria they are designed to kill have adapted to them in many cases, making the drugs less effective. At least 2 million people become infected with bacteria resistant to antibiotics each year in the United States, according to the Centers for Disease Control and Prevention, and at least 23,000 of these die as a result.

    “We know quite a bit about the internal defense mechanisms bacteria use to evade antibiotics,” Baym said, “but we don’t really know much about their physical movements across space as they adapt to survive in different environments.”

    To better understand how antibiotic resistance evolves in space and time, Baym and his colleagues developed a device called the microbial evolution growth arena plate, or MEGA-plate. The researchers used the antibiotics trimethoprim and ciprofloxacin in the MEGA plate in concentrations from zero to 10,000 times the original dose.

    On the right side of the plate where antibiotic levels were zero, Baym, Kishony, and colleagues grew Escherichia coli bacteria, which appeared white on the inky black background. Over two weeks, a camera mounted on the ceiling above the plate took periodic snapshots of the bacteria mutating.

    In the band with no antibiotic, the bacteria spread up until the point where they could no longer survive as they mingled with the first traces of antibiotic. Then, a small group of bacteria developed genetic mutations that allowed them to persist.

    1
    Researchers traced the branching patterns of bacterial evolution on the MEGA plate. | Katharine Sutliff/ Science

    As these drug-resistant mutants arose, their descendants migrated to areas of higher and higher antibiotic concentration, developing further mutations to compete with other mutants around them. As they continued their journey to the highest antibiotic concentration level, all remaining bacterial mutants had to evolve further still.

    Through this process of cumulative, successive mutations, the researchers could visualize how bacteria that are normally sensitive to antibiotics can evolve resistance to extremely high concentrations — those up to 100,000-fold higher than the one that killed their predecessors — in just over ten days.

    The bacteria were unable to adapt directly from zero antibiotic to the highest concentrations, for both drugs tested, revealing that exposure to intermediate concentrations of antibiotics is essential for the bacteria to evolve resistance.

    Initial mutations at each new band on the plate led to slower growth, hinting that bacteria adjusting to the antibiotic aren’t able to grow at ideal speed while developing mutations. Once fully resistant, however, such bacteria regained normal growth rates.

    “One of our main objectives in the lab is to reveal such evolutionary tradeoffs,” said Kishony, “whereby a bacterium becoming resistant to a drug confers a cost we might be able to exploit. We might potentially use other drugs to enhance such resistance-associated weakness.”

    Intriguingly, the researchers also found that the location of bacterial species played a role in their success in developing resistance. For example, when the researchers moved the trapped mutants — those behind their fast-moving, fit counterparts — to the “frontlines” of the growing bacteria, they were able to grow into new regions where the frontline bacteria could not.

    “What we saw suggests that evolution is not always led by the most resistant mutants,” said Baym. “The strongest mutants are, in fact, often moving behind more vulnerable strains.”

    This overturns the assumption that mutants that survive the highest concentration of a drug drive the fitness of bacterial populations; rather, it is those mutants that are both sufficiently fit and arise sufficiently close to the advancing front that lead the evolutionary road.

    The work of Baym, Kishony, and colleagues was inspired by Hollywood wizardry, the authors say. Kishony saw a digital billboard advertising the 2011 film Contagion, a grim narrative about a deadly viral pandemic. The marketing tool was built using a giant lab dish to show hordes of painted, glowing microbes creeping slowly across a dark backdrop to spell out the title of the movie.

    “This project was fun and joyful throughout,” Kishony said. “Seeing the bacteria spread for the first time was a thrill. Our MEGA-plate takes complex, often obscure, concepts in evolution, such as mutation selection, lineages, parallel evolution and clonal interference, and provides a visual seeing-is-believing demonstration of these otherwise vague ideas. It’s also a powerful illustration of how easy it is for bacteria to become resistant to antibiotics.”

    See the full article here .

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  • richardmitnick 10:59 am on September 9, 2016 Permalink | Reply
    Tags: , Biology, lncRNA, Long noncoding RNA,   

    From MIT: “Linking RNA structure and function” 

    MIT News
    MIT News
    MIT Widget

    September 8, 2016
    Anne Trafton | MIT News Office

    1
    In a new study, MIT biologists have deciphered the structure of one type of long noncoding RNA and used that information to figure out how it interacts with a cellular protein to control the development of heart muscle cells. Image: Jose-Luis Olivares/MIT

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    MIT biologists have deciphered the structure of a long noncoding RNA known as Braveheart. They found that the AGIL motif, at top left, is critical to the molecule’s function. Courtesy of the researchers

    Biologists have discovered how an enigmatic type of RNA helps to control cell fate.

    Several years ago, biologists discovered a new type of genetic material known as long noncoding RNA. This RNA does not code for proteins and is copied from sections of the genome once believed to be “junk DNA.”

    Since then, scientists have found evidence that long noncoding RNA, or lncRNA, plays roles in many cellular processes, including guiding cell fate during embryonic development. However, it has been unknown exactly how lncRNA exerts this influence.

    Inspired by historical work showing that structure plays a role in the function of other classes of RNA such as transfer RNA, MIT biologists have now deciphered the structure of one type of lncRNA and used that information to figure out how it interacts with a cellular protein to control the development of heart muscle cells. This is one of first studies to link the structure of lncRNAs to their function.

    “Emerging data points to fundamental roles for many of these molecules in development and disease, so we believe that determining the structure of lncRNAs is critical for understanding how they function,” says Laurie Boyer, the Irwin and Helen Sizer Career Development Associate Professor of Biology and Biological Engineering at MIT and the senior author of the study, which appears in the journal Molecular Cell on Sept. 8.

    Learning more about how lncRNAs control cell differentiation could offer a new approach to developing drugs for patients whose hearts have been damaged by cardiovascular disease, aging, or cancer.

    The paper’s lead author is MIT postdoc Zhihong Xue. Other MIT authors are undergraduate Boryana Doyle and Sarnoff Fellow Arune Gulati. Scott Hennelly, Irina Novikova, and Karissa Sanbonmatsu of Los Alamos National Laboratory are also authors of the paper.

    Probing the heart

    Boyer’s lab previously identified a mouse lncRNA known as Braveheart, which is found at higher levels in the heart compared to other tissues. In 2013, Boyer showed that this RNA molecule is necessary for normal development of heart muscle cells.

    In the new study, the researchers decided to investigate which regions of the 600-nucleotide RNA molecule are crucial to its function. “We knew Braveheart was critical for heart muscle cell development, but we didn’t know the detailed molecular mechanism of how this lncRNA functioned, so we hypothesized that determining its structure could reveal new clues,” Xue says.

    To determine Braveheart’s structure, the researchers used a technique called chemical probing, in which they treated the RNA molecule with a chemical reagent that modifies exposed RNA nucleotides. By analyzing which nucleotides bind to this reagent, the researchers can identify single-stranded regions, double-stranded helices, loops, and other structures.

    This analysis revealed that Braveheart has several distinct structural regions, or motifs. The researchers then tested which of these motifs were most important to the molecule’s function. To their surprise, they found that removing 11 nucleotides, composing a loop that represents just 2 percent of the entire molecule, halted normal heart cell development.

    The researchers then searched for proteins that the Braveheart loop might interact with to control heart cell development. In a screen of about 10,000 proteins, they discovered that a transcription factor protein called cellular nucleic acid binding protein (CNBP) binds strongly to this region. Previous studies have shown that mutations in CNBP can lead to heart defects in mice and humans.

    Further studies revealed that CNBP acts as a potential roadblock for cardiac development, and that Braveheart releases this repressor, allowing cells to become heart muscle.

    “This is one of the first studies to relate lncRNA structure to function,” says John Rinn, a professor of stem cell and regenerative biology at Harvard University, who was not involved in the research.

    “It is critical that we move toward understanding the specific functional domains and their structural elements if we are going to get lncRNAs up to speed with proteins, where we already know how certain parts play certain roles. In fact, you can predict what a protein does nowadays because of the wealth of structure-to-function relationships known for proteins,” Rinn says.

    Building a fingerprint

    Scientists have not yet identified a human counterpart to the mouse Braveheart lncRNA, in part because human and mouse lncRNA sequences are poorly conserved, even though protein-coding genes of the two species are usually very similar. However, now that the researchers know the structure of the mouse Braveheart lncRNA, they plan to analyze human lncRNA molecules to identify similar structures, which would suggest that they have similar functions.

    “We’re taking this motif and we’re using it to build a fingerprint so we can potentially find motifs that resemble that lncRNA across species,” Boyer says. “We also hope to extend this work to identify the modes of action of a catalog of motifs so that we can better predict lncRNAs with important functions.”

    The researchers also plan to apply what they have learned about lncRNA toward engineering new therapeutics. “We fully expect that unraveling lncRNA structure-to-function relationships will open up exciting new therapeutic modalities in the near future,” Boyer says.

    See the full article here .

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  • richardmitnick 8:57 am on September 9, 2016 Permalink | Reply
    Tags: , Biology, , , Genetic Engineering to Clash With Evolution,   

    From Quanta: “Genetic Engineering to Clash With Evolution” 

    Quanta Magazine
    Quanta Magazine

    September 8, 2016
    Brooke Borel

    In a crowded auditorium at New York’s Cold Spring Harbor Laboratory in August, Philipp Messer, a population geneticist at Cornell University, took the stage to discuss a powerful and controversial new application for genetic engineering: gene drives.

    Gene drives can force a trait through a population, defying the usual rules of inheritance. A specific trait ordinarily has a 50-50 chance of being passed along to the next generation. A gene drive could push that rate to nearly 100 percent. The genetic dominance would then continue in all future generations. You want all the fruit flies in your lab to have light eyes? Engineer a drive for eye color, and soon enough, the fruit flies’ offspring will have light eyes, as will their offspring, and so on for all future generations. Gene drives may work in any species that reproduces sexually, and they have the potential to revolutionize disease control, agriculture, conservation and more. Scientists might be able to stop mosquitoes from spreading malaria, for example, or eradicate an invasive species.

    The technology represents the first time in history that humans have the ability to engineer the genes of a wild population. As such, it raises intense ethical and practical concerns, not only from critics but from the very scientists who are working with it.

    Messer’s presentation highlighted a potential snag for plans to engineer wild ecosystems: Nature usually finds a way around our meddling. Pathogens evolve antibiotic resistance; insects and weeds evolve to thwart pesticides. Mosquitoes and invasive species reprogrammed with gene drives can be expected to adapt as well, especially if the gene drive is harmful to the organism — it’ll try to survive by breaking the drive.

    “In the long run, even with a gene drive, evolution wins in the end,” said Kevin Esvelt, an evolutionary engineer at the Massachusetts Institute of Technology. “On an evolutionary timescale, nothing we do matters. Except, of course, extinction. Evolution doesn’t come back from that one.”

    Gene drives are a young technology, and none have been released into the wild. A handful of laboratory studies show that gene drives work in practice — in fruit flies, mosquitoes and yeast. Most of these experiments have found that the organisms begin to develop evolutionary resistance that should hinder the gene drives. But these proof-of-concept studies follow small populations of organisms. Large populations with more genetic diversity — like the millions of swarms of insects in the wild — pose the most opportunities for resistance to emerge.

    It’s impossible — and unethical — to test a gene drive in a vast wild population to sort out the kinks. Once a gene drive has been released, there may be no way to take it back. (Some researchers have suggested the possibility of releasing a second gene drive to shut down a rogue one. But that approach is hypothetical, and even if it worked, the ecological damage done in the meantime would remain unchanged.)

    The next best option is to build models to approximate how wild populations might respond to the introduction of a gene drive. Messer and other researchers are doing just that. “For us, it was clear that there was this discrepancy — a lot of geneticists have done a great job at trying to build these systems, but they were not concerned that much with what is happening on a population level,” Messer said. Instead, he wants to learn “what will happen on the population level, if you set these things free and they can evolve for many generations — that’s where resistance comes into play.”

    At the meeting at Cold Spring Harbor Laboratory, Messer discussed a computer model his team developed, which they described in a paper posted in June on the scientific preprint site biorxiv.org. The work is one of three theoretical papers on gene drive resistance submitted to biorxiv.org in the last five months — the others are from a researcher at the University of Texas, Austin, and a joint team from Harvard University and MIT. (The authors are all working to publish their research through traditional peer-reviewed journals.) According to Messer, his model suggests “resistance will evolve almost inevitably in standard gene drive systems.”

    It’s still unclear where all this interplay between resistance and gene drives will end up. It could be that resistance will render the gene drive impotent. On the one hand, this may mean that releasing the drive was a pointless exercise; on the other hand, some researchers argue, resistance could be an important natural safety feature. Evolution is unpredictable by its very nature, but a handful of biologists are using mathematical models and careful lab experiments to try to understand how this powerful genetic tool will behave when it’s set loose in the wild.

    1
    Lucy Reading-Ikkanda for Quanta Magazine

    Resistance Isn’t Futile

    Gene drives aren’t exclusively a human technology. They occasionally appear in nature. Researchers first thought of harnessing the natural versions of gene drives decades ago, proposing to re-create them with “crude means, like radiation” or chemicals, said Anna Buchman, a postdoctoral researcher in molecular biology at the University of California, Riverside. These genetic oddities, she adds, “could be manipulated to spread genes through a population or suppress a population.”

    In 2003, Austin Burt, an evolutionary geneticist at Imperial College London, proposed a more finely tuned approach called a homing endonuclease gene drive, which would zero in on a specific section of DNA and alter it.

    Burt mentioned the potential problem of resistance — and suggested some solutions — both in his seminal paper and in subsequent work. But for years, it was difficult to engineer a drive in the lab, because the available technology was cumbersome.

    With the advent of genetic engineering, Burt’s idea became reality. In 2012, scientists unveiled CRISPR, a gene-editing tool that has been described as a molecular word processor. It has given scientists the power to alter genetic information in every organism they have tried it on. CRISPR locates a specific bit of genetic code and then breaks both strands of the DNA at that site, allowing genes to be deleted, added or replaced.

    CRISPR provides a relatively easy way to release a gene drive. First, researchers insert a CRISPR-powered gene drive into an organism. When the organism mates, its CRISPR-equipped chromosome cleaves the matching chromosome coming from the other parent. The offspring’s genetic machinery then attempts to sew up this cut. When it does, it copies over the relevant section of DNA from the first parent — the section that contains the CRISPR gene drive. In this way, the gene drive duplicates itself so that it ends up on both chromosomes, and this will occur with nearly every one of the original organism’s offspring.

    Just three years after CRISPR’s unveiling, scientists at the University of California, San Diego, used CRISPR to insert inheritable gene drives into the DNA of fruit flies, thus building the system Burt had proposed. Now scientists can order the essential biological tools on the internet and build a working gene drive in mere weeks. “Anyone with some genetics knowledge and a few hundred dollars can do it,” Messer said. “That makes it even more important that we really study this technology.”

    Although there are many different ways gene drives could work in practice, two approaches have garnered the most attention: replacement and suppression. A replacement gene drive alters a specific trait. For example, an anti-malaria gene drive might change a mosquito’s genome so that the insect no longer had the ability to pick up the malaria parasite. In this situation, the new genes would quickly spread through a wild population so that none of the mosquitoes could carry the parasite, effectively stopping the spread of the disease.

    A suppression gene drive would wipe out an entire population. For example, a gene drive that forced all offspring to be male would make reproduction impossible.

    But wild populations may resist gene drives in unpredictable ways. “We know from past experiences that mosquitoes, especially the malaria mosquitoes, have such peculiar biology and behavior,” said Flaminia Catteruccia, a molecular entomologist at the Harvard T.H. Chan School of Public Health. “Those mosquitoes are much more resilient than we make them. And engineering them will prove more difficult than we think.” In fact, such unpredictability could likely be found in any species.

    2
    A sample of malaria-infected blood contains two Plasmodium falciparum parasites. CDC/PHIL

    The three new biorxiv.org papers use different models to try to understand this unpredictability, at least at its simplest level.

    The Cornell group used a basic mathematical model to map how evolutionary resistance will emerge in a replacement gene drive. It focuses on how DNA heals itself after CRISPR breaks it (the gene drive pushes a CRISPR construct into each new organism, so it can cut, copy and paste itself again). The DNA repairs itself automatically after a break. Exactly how it does so is determined by chance. One option is called nonhomologous end joining, in which the two ends that were broken get stitched back together in a random way. The result is similar to what you would get if you took a sentence, deleted a phrase, and then replaced it with an arbitrary set of words from the dictionary — you might still have a sentence, but it probably wouldn’t make sense. The second option is homology-directed repair, which uses a genetic template to heal the broken DNA. This is like deleting a phrase from a sentence, but then copying a known phrase as a replacement — one that you know will fit the context.

    Nonhomologous end joining is a recipe for resistance. Because the CRISPR system is designed to locate a specific stretch of DNA, it won’t recognize a section that has the equivalent of a nonsensical word in the middle. The gene drive won’t get into the DNA, and it won’t get passed on to the next generation. With homology-directed repair, the template could include the gene drive, ensuring that it would carry on.

    The Cornell model tested both scenarios. “What we found was it really is dependent on two things: the nonhomologous end-joining rate and the population size,” said Robert Unckless, an evolutionary geneticist at the University of Kansas who co-authored the paper as a postdoctoral researcher at Cornell. “If you can’t get nonhomologous end joining under control, resistance is inevitable. But resistance could take a while to spread, which means you might be able to achieve whatever goal you want to achieve.” For example, if the goal is to create a bubble of disease-proof mosquitoes around a city, the gene drive might do its job before resistance sets in.

    The team from Harvard and MIT also looked at nonhomologous end joining, but they took it a step further by suggesting a way around it: by designing a gene drive that targets multiple sites in the same gene. “If any of them cut at their sites, then it’ll be fine — the gene drive will copy,” said Charleston Noble, a doctoral student at Harvard and the first author of the paper. “You have a lot of chances for it to work.”

    The gene drive could also target an essential gene, Noble said — one that the organism can’t afford to lose. The organism may want to kick out the gene drive, but not at the cost of altering a gene that’s essential to life.

    The third biorxiv.org paper, from the UT Austin team, took a different approach. It looked at how resistance could emerge at the population level through behavior, rather than within the target sequence of DNA. The target population could simply stop breeding with the engineered individuals, for example, thus stopping the gene drive.

    “The math works out that if a population is inbred, at least to some degree, the gene drive isn’t going to work out as well as in a random population,” said James Bull, the author of the paper and an evolutionary biologist at Austin. “It’s not just sequence evolution. There could be all kinds of things going on here, by which populations block [gene drives],” Bull added. “I suspect this is the tip of the iceberg.”

    Resistance is constrained only by the limits of evolutionary creativity. It could emerge from any spot along the target organism’s genome. And it extends to the surrounding environment as well. For example, if a mosquito is engineered to withstand malaria, the parasite itself may grow resistant and mutate into a newly infectious form, Noble said.

    Not a Bug, but a Feature?

    If the point of a gene drive is to push a desired trait through a population, then resistance would seem to be a bad thing. If a drive stops working before an entire population of mosquitoes is malaria-proof, for example, then the disease will still spread. But at the Cold Spring Harbor Laboratory meeting, Messer suggested the opposite: “Let’s embrace resistance. It could provide a valuable safety control mechanism.” It’s possible that the drive could move just far enough to stop a disease in a particular region, but then stop before it spread to all of the mosquitoes worldwide, carrying with it an unknowable probability of unforeseen environmental ruin.

    Not everyone is convinced that this optimistic view is warranted. “It’s a false security,” said Ethan Bier, a geneticist at the University of California, San Diego. He said that while such a strategy is important to study, he worries that researchers will be fooled into thinking that forms of resistance offer “more of a buffer and safety net than they do.”

    And while mathematical models are helpful, researchers stress that models can’t replace actual experimentation. Ecological systems are just too complicated. “We have no experience engineering systems that are going to evolve outside of our control. We have never done that before,” Esvelt said. “So that’s why a lot of these modeling studies are important — they can give us a handle on what might happen. But I’m also hesitant to rely on modeling and trying to predict in advance when systems are so complicated.”

    Messer hopes to put his theoretical work into a real-world setting, at least in the lab. He is currently directing a gene drive experiment at Cornell that tracks multiple cages of around 5,000 fruit flies each — more animals than past studies have used to research gene drive resistance. The gene drive is designed to distribute a fluorescent protein through the population. The proteins will glow red under a special light, a visual cue showing how far the drive gets before resistance weeds it out.

    Others are also working on resistance experiments: Esvelt and Catteruccia, for example, are working with George Church, a geneticist at Harvard Medical School, to develop a gene drive in mosquitoes that they say will be immune to resistance. They plan to insert multiple drives in the same gene — the strategy suggested by the Harvard/MIT paper.

    Such experiments will likely guide the next generation of computer models, to help tailor them more precisely to a large wild population.

    “I think it’s been interesting because there is this sort of going back and forth between theory and empirical work,” Unckless said. “We’re still in the early days of it, but hopefully it’ll be worthwhile for both sides, and we’ll make some informed and ethically correct decisions about what to do.”

    See the full article here .

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    Formerly known as Simons Science News, Quanta Magazine is an editorially independent online publication launched by the Simons Foundation to enhance public understanding of science. Why Quanta? Albert Einstein called photons “quanta of light.” Our goal is to “illuminate science.” At Quanta Magazine, scientific accuracy is every bit as important as telling a good story. All of our articles are meticulously researched, reported, edited, copy-edited and fact-checked.

     
  • richardmitnick 3:29 pm on September 8, 2016 Permalink | Reply
    Tags: , Biology, Drug Search for Leishmaniasis, ,   

    From Drug Search for Leishmaniasis at WCG: “Researchers Publish Findings on Potential New Treatments for Leishmaniasis” 

    New WCG Logo

    WCGLarge

    World Community Grid (WCG)

    8 Sep 2016
    By: Dr. Carlos Muskus López
    Coordinator, Molecular Biology and Computational Unit, PECET University of Antioquia

    Summary
    The Drug Search for Leishmaniasis team recently published their findings in the Journal of Computer-Aided Molecular Design. Using World Community Grid’s computing power, they have identified several drug compounds which may lead to improved treatments for this neglected and sometimes deadly disease.

    1
    One of the best ligands bound to the dihydrorootate dehydrogenase (DHODH) from Leishmania major. (a) Predicted binding within the crystal structure (b) Superimposition of the ligand conformations predicted to bind to each of the DHODH protein conformations extracted from the MD simulation

    Background

    Leishmaniasis, one of the most neglected tropical diseases in the world, infects more than two million people every year. The disease is caused by a parasite (genus Leishmania) which is transmitted between humans and animals by female sand flies. The number of cases continues to increase in tropical countries such as Bangladesh, India, Sudan, Ethiopia, Brazil, Colombia, Peru and others.

    The existing treatments for leishmaniasis can cause severe side effects. Additionally, drug-resistant parasites are causing major problems in many countries. For these reasons, there is an urgent need for new, safe and inexpensive anti-leishmaniasis drug compounds.

    Overview

    In our paper, we describe the detailed steps we took to identify protein drug targets, which included the screening of 600,000 molecules to determine which might lead to development of new treatments for the disease. Specifically, we searched for drugs which target the proteins which are essential for the survival of the parasite that causes leishmaniasis. By finding molecules that bind to these proteins, they can potentially be disabled, thus stopping the infection and curing the disease.

    The paper describes how some of the protein targets can bend and change shape, which presents some challenges in finding good candidate molecules. We discuss our approach to dealing with these problems.

    Using the results computed on World Community Grid, we selected the ten best drug candidates for test-tube experiments, which yielded very promising results. In particular, one of the compounds appears to be able to kill the leishmaniasis parasite without affecting human cells in vitro. Three additional compounds also showed promising results.

    We now plan to work to modify the three promising identified drug compounds to improve their potency, solubility and to minimize toxicity. We will also evaluate other top candidates depending on the funds we can raise. Furthermore, we are developing an open data platform with World Community Grid´s results so that other researchers can mine our data to detect additional drug hits or leads.

    We are grateful to all the World Community Grid volunteers who made this research possible by donating their computing power to this project.

    See the full article here.

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    World Community Grid (WCG) brings people together from across the globe to create the largest non-profit computing grid benefiting humanity. It does this by pooling surplus computer processing power. We believe that innovation combined with visionary scientific research and large-scale volunteerism can help make the planet smarter. Our success depends on like-minded individuals – like you.”

    WCG projects run on BOINC software from UC Berkeley.
    BOINCLarge

    BOINC is a leader in the field(s) of Distributed Computing, Grid Computing and Citizen Cyberscience.BOINC is more properly the Berkeley Open Infrastructure for Network Computing.

    BOINC WallPaper

    CAN ONE PERSON MAKE A DIFFERENCE? YOU BET!!

    MyBOINC

    “Download and install secure, free software that captures your computer’s spare power when it is on, but idle. You will then be a World Community Grid volunteer. It’s that simple!” You can download the software at either WCG or BOINC.

    Please visit the project pages-

    FightAIDS@home Phase II

    FAAH Phase II
    OpenZika

    Rutgers Open Zika

    Help Stop TB
    WCG Help Stop TB
    Outsmart Ebola together

    Outsmart Ebola Together

    Mapping Cancer Markers
    mappingcancermarkers2

    Uncovering Genome Mysteries
    Uncovering Genome Mysteries

    Say No to Schistosoma

    GO Fight Against Malaria

    Drug Search for Leishmaniasis

    Computing for Clean Water

    The Clean Energy Project

    Discovering Dengue Drugs – Together

    Help Cure Muscular Dystrophy

    Help Fight Childhood Cancer

    Help Conquer Cancer

    Human Proteome Folding

    FightAIDS@Home

    World Community Grid is a social initiative of IBM Corporation
    IBM Corporation
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    IBM – Smarter Planet
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  • richardmitnick 9:04 am on September 7, 2016 Permalink | Reply
    Tags: , Biology, , , Microbe tenants help – and hinder – your immune system   

    From COSMOS: “Microbe tenants help – and hinder – your immune system” 

    Cosmos Magazine bloc

    COSMOS

    07 September 2016
    Dyani Lewis

    1
    Have a propensity for hayfever? The bugs in your gut might have something to do with that. Colin Hawkins / Getty Images

    Obesity isn’t the only condition linked to imbalanced gut microflora. A host of autoimmune and inflammatory conditions – inflammatory bowel disease, coeliac disease, multiple sclerosis, rheumatoid arthritis and lupus – are also associated with changes to gut microbial ecosystems.

    (Indeed, obesity is often described as an inflammatory condition for the widespread immune reaction that accompanies excess weight.)

    Connecting the dots between altered gut microbes and disease is a lively area of research. Scientists are working on the ‘chicken or egg’ problem: does disrupting the gut microflora cause the disease, or does having the disease lead to changes in gut microflora?

    In many cases, it is likely that a complex interplay between genetics and environmental triggers – including the microbes in our guts – is involved.

    One clue seems to lie with the gut’s role as a barrier. The surface of our intestinal tract is larger than a tennis court. This is great for facilitating nutrient absorption. But the flipside is a gargantuan barrier that our immune system needs to defend.

    There’s now compelling evidence that breaching this barrier – a condition known as ‘leaky gut’ – allows bacterial toxins including fragments of bacterial cell wall (lipopolysaccharide) and tail proteins (flagellin) into our bloodstream, triggering inflammation in tissues far removed from the intestine.

    The types of microbes living in our gut can influence how leaky it is. Increasingly, research is showing that just as in obesity, inflammatory conditions could be more a case of protective microbes being wiped out than damaging microbes taking over.

    Several groups of related beneficial bacteria called the ‘clostridial clusters’ seem to be particularly important. (These are not be confused with their distant relative, the extremely harmful diarrhoea-causing Clostridium difficile.)

    Members of these groups are specialist fibre fermenters, pumping out those beneficial short chain fatty acids, which help to keep our gut intact by strengthening the molecular bonds between intestinal cells.

    Without short chain fatty acids, the gut becomes leaky and the immune system pumps out damaging pro-inflammatory signals. But with them, the gut is kept intact and inflammation is quelled by specialised immune cells that multiply in their presence.

    The clostridial clusters are in a prime location for immune-microbe chatter. They hunker down in the thick mucous that lines the gut, stimulating its production and even feeding off it.

    When the mucous layer thins out – perhaps due to a loss of these beneficial microbes – toxins and other microbes that are normally kept at a distance are able to gain access to and cross the delicate gut lining, causing inflammation.

    In 2014, scientists at Keio University in Tokyo found that killing clostridial clusters with antibiotics makes mice more susceptible to bowel inflammation. Conversely, supplementing mice with these microbes prevents or even reverses inflammation. The same year, researchers at the University of Chicago discovered that wiping them out made mice more likely to develop peanut allergy.

    In one mouse study, transferring a single member of the clostridial clusters found to be lacking in people with inflammatory bowel disease – Faecalibacterium prausnitzii – protected mice from induced gut inflammation.

    It’s not yet known whether having fewer clostridia causes inflammatory bowel disease, or whether it simply accompanies and exacerbates the condition. It is also unclear whether a clostridial cocktail could work in people.

    Studies of other probiotic cocktails have seen improvements in some cases of bowel inflammation but not others, suggesting that we haven’t yet hit on a magic formula that will work for everyone.

    The same is true for multiple sclerosis, rheumatoid arthritis and lupus. Changes in gut microbes have been found in all of these autoimmune conditions, but studies in mice – and to a lesser extent, people – are yet to clearly identify which microbes are important for keeping the condition at bay, and which microbes exacerbate the condition.

    Neither probiotics (microbial supplements), nor prebiotics (microbial food supplements) have seen consistent benefits for these conditions.

    2
    Kids who grow up around farms have fewer allergies and lower rates of asthma than city kids. Gigja Einarsdottir / Getty Images

    But it’s become clear that the microbes we are exposed to and colonised by as young children play an outsized role in our future immune health.

    Numerous studies support what has been dubbed the ‘hygiene hypothesis’. Children who grow up in less industrialised settings or on farms, or have older (microbe-sharing) siblings, are less likely to develop hayfever and allergies than their more germ-free counterparts.

    Although the hygiene hypothesis initially focused on childhood infections as the key ingredient in a healthy immune system, it is now understood that exposure to our ‘good’ microbes underpins the relationship.

    Mice raised germ-free fail to develop normal immune systems, with entire components of their immune arsenal missing or underdeveloped.

    And children born via caesarean section are more prone to asthma and allergies, presumably because they are missing some key players necessary for immune development.

    In cancer, too, our microbial companions have a say. At least three species of bacteria have been shown to increase colon tumours in cancer-prone mice. These strains may also play a role in colorectal cancers in people, but research needs to shore up this link.

    Gut microbes can also turbo-charge cancer immunotherapies – drugs that ramp up our immune system to fight cancer.

    In 2015, researchers at the University of Chicago found that fast-growing tumours in mice can be slowed simply by spiking food with beneficial bugs. When combined with an immune-boosting drug, tumour growth was brought to a standstill.

    In another 2015 study, by researchers in France, antibiotics effectively removed all benefits of the immunotherapy drug.

    This research could help to answer the perplexing question of why immune-boosting drugs only work in some people.

    Microbial communities outside of our gut are also important when it comes to immune regulation.

    Psoriasis, atopic dermatitis and eczema have been linked to imbalances in the skin microbiota, and the composition of a woman’s vaginal microbiota has been found to influence how susceptible she is to HIV infection.

    But turning these findings into meaningful treatments or preventative measures needs more investigation.

    See the full article here .

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  • richardmitnick 7:11 am on September 6, 2016 Permalink | Reply
    Tags: , Biology, ,   

    From Max Planck Gesellschaft: “Hungry cells on the move” 

    MPG bloc

    Max Planck Gesellschaft

    September 06, 2016
    rof. Dr. Rüdiger Klein
    Max Planck Institute of Neurobiology, Martinsried
    Phone:+49 89 8578-3151Fax:+49 89 8578-3152
    rklein@neuro.mpg.de

    Dr. Stefanie Merker
    Max Planck Institute of Neurobiology, Martinsried
    Phone:+49 89 8578-3514
    Email:
    merker@neuro.mpg.de

    Researchers discover a signalling pathway that enables cells to reach their destinations through repulsion

    When cells grow and divide, they come into contact with other cells. This happens not only during development and regeneration and after injury, but also during cancer growth and the formation of metastases. When cells come into contact with each other in this way, information is exchanged by proteins, which are embedded in the cell membranes and form tight lock-and-key complexes with each other. These connections must be severed if the cells want to transmit a repulsion signal. It appears that the fastest way to do this is for the cells to engulf the protein complex from the membrane of the neighbouring cell. Scientists from the Max Planck Institute of Neurobiology in Martinsried have now identified the molecules that control this process.

    1
    Ephrins (blue) and Ephs (red) form complexes (yellow) at cell contact points. To enable the cells to separate from each other, they are pulled into one of the cells with the help of the signalling proteins Tiam and Rac.
    © MPI of Neurobiology/Gaitanos

    Development is an extremely rapid process. Increasing numbers of cells are formed which must find their correct position in the body, clearly demarcate themselves from each other to form tissue, or – as is the case in the nervous system – establish contact with partner cells in remote locations. “The crowding is accompanied by orderly pushing and shoving,” says Rüdiger Klein, whose Department at the Max Planck Institute of Neurobiology studies how cells get their bearings. “A popular way for one cell to show another which direction to take is for it to repel the other cell following brief contact.” According to the scientists’ observations, the cells do not exactly treat each other with kid gloves and even go so far as to engulf entire pieces from the membranes of other cells.

    When cells come into contact with each other, ephrin and Eph receptors are often involved. These proteins are located on the surface of almost all cells. When two cells meet, their ephrin and Eph receptors connect to form tight ephrin/Eph complexes. These complexes then trigger the repulsion process through intracellular signalling pathways. “This is where the problem arises, as it appears that the cells then want to separate as quickly as possible – however, the two cells are attached to each other through the tight ephrin/Eph complex,” explains Klein. So the cells do something else: they extend their own cell membranes so far over the individual complexes that the complex and the surrounding membrane detaches from the neighbouring cell and is fully incorporated into the cell.
    Left: Ephrin and Eph receptors are found on the surface of almost all cells. Centre: When cells come into contact with each other, the two proteins form a tight complex. This triggers a signalling chain which causes the cell membrane to protrude. This process is controlled by the Tiam and Rac molecules and results in the reformation of the actin cytoskeleton. Right: The cells separate when one cell fully engulfs the ephrin/Eph complex through endocytosis.

    2
    Left: Ephrin and Eph receptors are found on the surface of almost all cells. Centre: When cells come into contact with each other, the two proteins form a tight complex. This triggers a signalling chain which causes the cell membrane to protrude. This process is controlled by the Tiam and Rac molecules and results in the reformation of the actin cytoskeleton. Right: The cells separate when one cell fully engulfs the ephrin/Eph complex through endocytosis.

    The Max Planck researchers discovered as early as 2003 that cells can use this process, known as endocytosis, to separate from each other. Thanks to progress made in molecular biology since then, they have now managed to show how the process is controlled in detail.

    With the help of a series of genetic modifications and the targeted deactivation of individual cell components, the scientists succeeded in demonstrating that Tiam signalling proteins are activated through the formation of the ephrin/Eph complex. As a result, Rac enzymes become active which, in turn, cause the engulfment of the ephrin/Eph complexes by the cell membrane through the local restructuring of the actin cytoskeleton. If one of these components is missing, this engulfing process through endocytosis is blocked and the cells do not repel each other but remain attached.

    The clarification of this signalling pathway is important, as it provides a better understanding of the development of neuronal networks and other organ systems. The findings are also of considerable interest for cancer research: thanks to their ability to control cell repulsion, ephrin and Eph receptors play a major role in the penetration of tissue by cancer cells and in the formation of metastases. For this reason, receptors and their connection partners are the focus of current medical research. Better understanding of this signalling pathway, through which cell repulsion is controlled, could enable the development of new drugs to combat cancer.

    Original publication:
    Thomas N. Gaitanos, Jorg Koerner, Rüdiger Klein
    Tiam/Rac signaling mediates trans-endocytosis of ephrin receptor EphB2 and is important for cell repulsion.
    Journal of Cell Biology; 5 September, 2016

    See the full article here .

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    MPG campus

    The Max Planck Society for the Advancement of Science (German: Max-Planck-Gesellschaft zur Förderung der Wissenschaften e. V.; abbreviated MPG) is a formally independent non-governmental and non-profit association of German research institutes founded in 1911 as the Kaiser Wilhelm Society and renamed the Max Planck Society in 1948 in honor of its former president, theoretical physicist Max Planck. The society is funded by the federal and state governments of Germany as well as other sources.

    According to its primary goal, the Max Planck Society supports fundamental research in the natural, life and social sciences, the arts and humanities in its 83 (as of January 2014)[2] Max Planck Institutes. The society has a total staff of approximately 17,000 permanent employees, including 5,470 scientists, plus around 4,600 non-tenured scientists and guests. Society budget for 2015 was about €1.7 billion.

    The Max Planck Institutes focus on excellence in research. The Max Planck Society has a world-leading reputation as a science and technology research organization, with 33 Nobel Prizes awarded to their scientists, and is generally regarded as the foremost basic research organization in Europe and the world. In 2013, the Nature Publishing Index placed the Max Planck institutes fifth worldwide in terms of research published in Nature journals (after Harvard, MIT, Stanford and the US NIH). In terms of total research volume (unweighted by citations or impact), the Max Planck Society is only outranked by the Chinese Academy of Sciences, the Russian Academy of Sciences and Harvard University. The Thomson Reuters-Science Watch website placed the Max Planck Society as the second leading research organization worldwide following Harvard University, in terms of the impact of the produced research over science fields.

     
  • richardmitnick 11:39 am on September 2, 2016 Permalink | Reply
    Tags: , , Biology, , , Sterling Chemistry Lab reopens as a catalyst for cutting-edge science,   

    From Yale: “Sterling Chemistry Lab reopens as a catalyst for cutting-edge science” 

    Yale University bloc

    Yale University

    August 31, 2016

    Jim Shelton
    james.shelton@yale.edu
    203-361-8332

    1
    President Salovey addresses the crowd at the SCL ribbon-cutting event. (Photo by Michael Marsland)

    From its gleaming, glass-enclosed teaching labs to the powerful mechanical hubs located in the basement and penthouse, the new Sterling Chemistry Lab (SCL) has all the right elements to be a citadel of science for the next century.

    The 93-year-old building has been transformed from the inside out, and Yale officials celebrated with a grand reopening on Aug. 30. Hundreds of students, faculty, and staff gathered to tour SCL’s new teaching labs, hear more about the building’s history and envision scientific discoveries yet to come.

    “The center of gravity of this campus is shifting north,” Yale President Peter Salovey said at the ribbon cutting, noting the construction of Yale’s newest residential colleges nearby and the resurgence of investment in Science Hill.

    “We are at a moment here at Yale when we will take the excellent science, research, and education we do on campus, especially Science Hill, and move it to a truly outstanding level,” Salovey said. “We should want nothing less for students and for faculty.”

    For the new SCL, that effort required two years of cranes, jackhammers, power saws, and occasional corridor closings. The exterior of the iconic building, designed by architect Williams Adams Delano in a Collegiate Gothic style, remains unchanged. CannonDesign is the architect for the renovation, with HBRA Architects designing the central public corridor areas, and Dimeo Construction guiding the work. SCL renovations encompass 159,000 square feet, of which 31,600 is additional space, and the building will be seeking LEED Gold certification.

    3
    The renovation includes new teaching labs for chemistry, such as this one, as well as labs for physics and biology. (Photo by Michael Marsland)

    “Science is and must be a top priority for Yale,” said Provost Benjamin Polak. “If we think about what great universities will do in the 21st century, they’re going to advance knowledge by their discoveries, they’re going to change the world, and they’re going to move minds. That means science, and Yale has to be part of that — has to lead at that.”

    A trio of teaching labs is central to that goal at the new SCL, both physically and symbolically. Biology teaching labs are located on the second floor, with flexibility allowing for adaptability to a variety of experiments and teaching needs; chemistry teaching labs are on the third floor, with individual venting hoods for each student conducting an experiment and dedicated spaces for teaching general, organic, advanced, and physical chemistry. Physics teaching labs are on the second floor, built with enhanced flexibility for experiments of different durations and sizes.

    “This really is an occasion of coming together,” said Dean of the Faculty of Arts and Sciences (FAS) Tamar Gendler, noting that the renovation merges research and teaching, brings together students and faculty, and involves multiple disciplines. It also combines past and present, knits together different areas of the campus, and blends the abstract with the concrete, Gendler said.

    Scott Miller, the Irénée du Pont Professor of Chemistry, divisional director of sciences for FAS, and former chair of the Department of Chemistry, took note of the many scientific discoveries that have taken place at SCL since 1923. He mentioned Lars Onsager’s work on thermodynamics for irreversible systems; the pioneering chemical biology research of Stuart Schreiber; and emeritus professor Jerome Berson’s research on reactive intermediates.

    “Laboratories are sacred places,” Miller said. “Laboratories are the places where we try very hard to connect observation to explanation; where we try to make things on the basis of our theories and then when we can’t make them the way we’d like to we have to revise our theories. Laboratories are the places where we connect ‘mind to hand.’ These are truly profound things.”

    In order to create teaching labs for today’s students, the SCL renovation involved a major overhaul of the building’s mechanical systems. Prior to renovation, many of the individual labs in SCL required separate services to handle venting, electricity, and other needs. Now there is a centralized system to handle the flow of power, water, and ventilation throughout the building. In addition, SCL has new replacement skylights and windows, switched from steam heat to hot-water baseboards, upgraded its sprinkler system, installed a bigger service elevator, completed masonry work, and conducted structural upgrades.

    The renovation addresses aesthetic needs, as well. Expansive, well-lit corridors connect the labs with communal areas and a landscaped courtyard, for example. Also, the use of glass walls to frame the labs is intended to inspire a more connected, collaborative spirit among students and faculty.

    “I can’t wait to come back in the coming weeks and see students at these benches and classes being taught,” Salovey said.

    See the full article here .

    Please help promote STEM in your local schools.

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    Yale University Campus

    Yale University comprises three major academic components: Yale College (the undergraduate program), the Graduate School of Arts and Sciences, and the professional schools. In addition, Yale encompasses a wide array of centers and programs, libraries, museums, and administrative support offices. Approximately 11,250 students attend Yale.

     
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