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  • richardmitnick 9:28 am on July 24, 2017 Permalink | Reply
    Tags: , Biology, , , Native mass spectrometry, Signaling islands in cells: targets for precision drug design, U Washington Health Beat   

    From U Washington: “Signaling islands in cells: targets for precision drug design” 

    U Washington

    University of Washington

    Leila Gray

    A critical component of the cell signaling system, anchored protein kinase A, has some flexible molecular parts, allowing it to both contract and stretch, with floppy arms that can reach out to find appropriate targets. John Scott Lab.

    Research results reported in the journal Science overturn long-held views on a basic messaging system within living cells.

    The findings suggest new approaches to designing precisely targeted drugs for cancer and other serious diseases.

    Dr. John D. Scott, professor and chair of pharmacology at the University of Washington School of Medicine and a Howard Hughes Medical Institute Investigator, along with Dr. F. Donelson Smith of the UW and HHMI, led this study, which also involved Drs. Claire and Patrick Eyers and their group at the University of Liverpool. Visit the Scott lab web site, Cell Signaling in Space and Time.

    The researchers explained that key cellular communication machinery is more regionally constrained inside the cell than was previously thought. Communication via this vital system is akin to social networking on your Snapchat account.

    Within a cell, the precise positioning of such messaging components allows hormones, the body’s chief chemical communicators, to transmit information to exact places inside the cell. Accurate and very local activation of the enzyme that Scott and his group study helps assure a correct response occurs in the right place and at the right time.

    “The inside of a cell is like a crowded city,” said Scott, “It is a place of construction and tearing down, goods being transported and trash being recycled, countless messages, (such as the ones we have discovered), assembly lines flowing, and packages moving. Strategically switching on signaling enzyme islands allows these biochemical activities to keep the cell alive and is important to protect against the onset of chronic diseases such as diabetes, heart disease and certain cancers.”

    Advances in electron microscopy and native mass spectrometry enabled the researchers to determine that a critical component of the signaling system, anchored protein kinase A, remains intact during activation. Parts of the molecule are flexible, allowing it to both contract and stretch, with floppy arms that can reach out to find appropriate targets.

    Still, where the molecule performs its act, space is tight. The distance is, in fact, about the width of two proteins inside the cell.

    Green, circled area show where the enzyme in the signalling study is active in mitochondria, the powerhouses of living cells. John D. Scott.

    “We realize that in designing drugs to reach such targets that they will have to work within very narrow confines, ” Scott said.

    One of his group’s collective goals is figuring out how to deliver precision drugs to the right address within this teeming cytoplasmic metropolis.

    “Insulating the signal so that the drug effect can’t happen elsewhere in the cell is an equally important aspect of drug development because it could greatly reduce side effects,” Scott said.

    An effort to take this idea of precision medicine a step further is part of the Institute for Targeted Therapeutics at UW Medicine in Seattle. The institute is being set up by Scott and his colleagues in the UW Department of Pharmacology.

    The scientists are collaborating with cancer researchers to better understand the molecular causes — and possible future treatments — for a certain liver malignancy. This particular liver cancer arises from a mutation that produces an abnormal form of the enzyme that is the topic of this current work, protein kinase A, and alters the enzyme’s role in cell signaling.

    Other advances that gave the researchers a clearer view of the signaling mechanisms reported in Science include CRISPR gene editing, live-cell imaging techniques, and more powerful ways to look at all components of a protein complex.

    See the full article here .

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  • richardmitnick 6:35 am on July 21, 2017 Permalink | Reply
    Tags: , Biology, ,   

    From Salk: “New method to rapidly map the “social networks” of proteins” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    June 26, 2017
    Office of Communications
    Tel: (858) 453-4100

    Salk scientists improved upon a classic approach to mapping the interactions between proteins.

    A new mapping method let researchers discover new links (gray lines) between two groups of plant proteins (yellow and blue) that have a common structure (the BBX domain), suggesting many different combinations of interactions, rather than a few, are involved in coordinating cellular programs like flowering time and circadian rhythm. Credit: Salk Institute.

    Salk scientists have developed a new high-throughput technique to determine which proteins in a cell interact with each other. Mapping this network of interactions, or “interactome,” has been slow going in the past because the number of interactions that could be tested at once was limited. The new approach, published June 26 in Nature Methods, lets researchers test millions of relationships between thousands of proteins in a single experiment.

    “The power of this new approach is in the ability we now have to scale it up,” says senior author Joseph Ecker, professor and director of Salk’s Genomic Analysis Laboratory and investigator of the Howard Hughes Medical Institute. “This assay has the potential to begin to address questions about fundamental biological interactions that we haven’t been able to address before.”

    The interactome of a cell, like a map of social networks, lets scientists see who’s working with who in the world of proteins. This helps them figure out the roles of different proteins and piece together the different players in molecular pathways and processes. If a newly discovered protein interacts with lots of other proteins involved in cellular metabolism, for instance, researchers can deduce that’s a likely role for the new protein and potentially target it for treatments related to metabolic dysfunction.

    Until now, researchers have typically relied on standard high-throughput yeast two-hybrid (Y2H) assays to determine the interactions between proteins. The system requires using a single known protein—known as the “bait”—to screen against a pool of “prey” proteins. But finding all the interactions between, for instance, 1,000 proteins, would require 1000 separate experiments to screen once for each bait’s interaction partners.

    “Current technologies essentially require that interactions detected in primary screening get retested individually,” says Shelly Trigg, an NSF Graduate Research Fellow at the University of California, San Diego, in the Ecker lab, and first author of the new paper. “That may no longer be necessary with the screening depth this approach achieves.”

    In their new method, Ecker, Trigg and their colleagues added a twist to the standard Y2H assay for a much more effective way of measuring the interactome. The genes for two proteins, each on their own circle of DNA, are added to the same cell. If the proteins of interest interact inside the cell, a gene called Cre is activated. When turned on, Cre physically splices the two individual circles of DNA together, thus pairing the genes of interacting proteins together so the team can easily find them through sequencing. The team can generate a massive library of yeast cells—each containing different pairs of proteins by introducing random combinations of genes on circular DNA called plasmids. When cells are positive for a protein interaction, the researchers can use genetic sequencing to figure out what the two proteins interacting are, using new high-throughput DNA sequencing technologies similar to those used for human genome sequencing. This way, they’re no longer limited to testing one “bait” protein at a time, but could test the interactions between all the proteins in a library at once.

    Joseph Ecker (courtesy of Salk Institute) and Shelly Trigg (courtesy of Austin Trigg)

    Ecker’s group tested the new method, dubbed CrY2H-seq, on all the transcription factors—a large class of proteins—in the plant Arabidopsis.

    “When you take 1,800 proteins and test the interactions among them, that’s nearly 4 million combinations,” says Ecker. “We did that ten times in a matter of a month.”

    They revealed more than 8,000 interactions among those proteins tested, giving them new insight into which Arabidopsis transcription factors interact with each other. The data, they say, helps answer longstanding questions about whether certain groups of transcription factors have set functions. Some of the poorly understood transcription factors, they found, interact with more well-understood factors that regulate the plant’s response to auxin, a hormone involved in coordinating plant growth.

    In the future, the method could be scaled up to test larger sets of proteins—human cells, for instance, contain about 20,000 different proteins. This easier and faster method to determine the entire interactome of a cell also opens up the possibility of studying how the interactome changes under different conditions—an experiment that’s never been possible in the past.

    Other researchers on the study were Renee Garza, Andrew MacWilliams, Joseph Nery, Anna Bartlett, Rosa Castanon, Adeline Goubil, Joseph Feeney, Ronan O’Malley, Shao-shan Carol Huang, Zhuzhu Zhang, and Mary Galli of the Salk Institute.

    See the full article here .

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    Salk Institute Campus

    Every cure has a starting point. Like Dr. Jonas Salk when he conquered polio, Salk scientists are dedicated to innovative biological research. Exploring the molecular basis of diseases makes curing them more likely. In an outstanding and unique environment we gather the foremost scientific minds in the world and give them the freedom to work collaboratively and think creatively. For over 50 years this wide-ranging scientific inquiry has yielded life-changing discoveries impacting human health. We are home to Nobel Laureates and members of the National Academy of Sciences who train and mentor the next generation of international scientists. We lead biological research. We prize discovery. Salk is where cures begin.

  • richardmitnick 1:58 pm on July 20, 2017 Permalink | Reply
    Tags: , Biology, , Methicillin, , St. Andrews, The mecA gene confers resistance by producing a protein called PBP2a   

    From St. Andrews: “MRSA emerged years before methicillin was even discovered” 

    U St Andrews bloc

    University of St Andrews

    20 July 2017
    Christine Tudhope
    01334 467 320
    07526 624 243 or

    No image caption or credit

    Methicillin resistant Staphylococcus aureus (MRSA) emerged long before the introduction of the antibiotic methicillin into clinical practice, according to researchers at the University of St Andrews.

    A new study, in collaboration with the Wellcome Trust Sanger Institute and the University of Dundee, suggests the widespread use of earlier antibiotics such as penicillin rather than of methicillin itself allowed Methicillin resistant Staphylococcus aureus (MRSA) to emerge.

    The findings, published in the open access journal Genome Biology, found that S. aureus acquired the gene that confers methicillin resistance (mecA) as early as the mid-1940s, fourteen years before the first use of methicillin.

    Professor Matthew Holden, molecular microbiologist at the University of St Andrews, the corresponding author said:

    “Our study provides important lessons for future efforts to combat antibiotic resistance. It shows that new drugs which are introduced to circumvent known resistance mechanisms, as methicillin was in 1959, can be rendered ineffective by unrecognized, pre-existing adaptations in the bacterial population. These adaptations happen because, in response to exposure to earlier antibiotics, resistant bacterial strains are selected instead of non-resistant ones as bacteria evolve.”

    The mecA gene confers resistance by producing a protein called PBP2a, which decreases the binding efficiency of antibiotics used against S. aureus to the bacterial cell wall. The introduction of penicillin in the 1940s led to the selection of S. aureus strains that carried the methicillin resistance gene.

    Dr Catriona Harkins, clinical lecturer in dermatology at the University of Dundee, the first author of the study said:

    “Within a year of methicillin being first introduced to circumvent penicillin resistance, strains of S. aureus were found that were already resistant to methicillin. In the years that followed resistance spread rapidly in and outside of the UK. Five decades on from the appearance of the first MRSA, multiple MRSA lineages have emerged which have acquired different variants of the resistance gene.”

    To uncover the origins of the very first MRSA and to trace its evolutionary history, the researchers sequenced the genomes of a unique collection of 209 historic S. aureus isolates. The oldest of these isolates were identified over 50 years ago by the S. aureus reference laboratory of Public Health England and have been stored ever since in their original freeze-dried state. The researchers also found genes in these isolates that confer resistance to numerous other antibiotics, as well as genes associated with decreased susceptibility to disinfectants.

    Professor Holden said:

    “S. aureus has proven to be particularly adept at developing resistance in the face of new antibiotic challenges, rendering many antibiotics ineffective. This remains one of the many challenges in tackling the growing problem of antimicrobial resistance. In order to ensure that future antibiotics retain their effectiveness for as long as possible, it is essential that effective surveillance mechanisms are combined with the use of genome sequencing to scan for the emergence and spread of resistance.”

    Science paper:
    Methicillin-resistant Staphylococcus aureus emerged long before the introduction of methicillin into clinical practice.

    See the full article here .

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    U St Andrews campus

    St Andrews is made up from a variety of institutions, including three constituent colleges (United College, St Mary’s College, and St Leonard’s College) and 18 academic schools organised into four faculties. The university occupies historic and modern buildings located throughout the town. The academic year is divided into two terms, Martinmas and Candlemas. In term time, over one-third of the town’s population is either a staff member or student of the university. The student body is notably diverse: over 120 nationalities are represented with over 45% of its intake from countries outside the UK; about one-eighth of the students are from the rest of the EU and the remaining third are from overseas — 15% from North America alone. The university’s sport teams compete in BUCS competitions, and the student body is known for preserving ancient traditions such as Raisin Weekend, May Dip, and the wearing of distinctive academic dress.

  • richardmitnick 12:46 pm on July 16, 2017 Permalink | Reply
    Tags: , Biology, Broad Institute of MIT and Harvard, , Moran Yassour, The infant microbiome,   

    From Broad: Women in STEM- “Meet a Broadie: Moran Yassour, Microbiome Maven” 

    Broad Institute

    Broad Institute

    No writer credit

    Moran Yassour

    Credit: BroadIgnite

    Moran Yassour, a postdoctoral researcher in the labs of Eric Lander and Ramnik Xavier at the Broad Institute, is a pioneer in one of biology’s hottest fields: the human microbiome. She’s researching how the circumstances of our birth and early life influence the origin and development of the microbes in our gut. Support from the BroadIgnite community has allowed her to investigate the differences in the gut bacteria between children born by C-section and those born vaginally. Here, she shares more about her research. The interview has been condensed and edited for clarity.

    How did you come to study the infant microbiome? My mother is a computer science teacher, and I always loved genetics. When I was looking for undergrad programs, I came across a program that combined computer science and life science. I really enjoyed it and stayed in the same program for my master’s and Ph.D.

    When I started my postdoc, I knew that I wanted to be in a field that’s a little bit more translational—something I could easily explain to my grandmother, or a stranger in the elevator, and they could understand what I’m doing and why it’s cool.

    I started working on gut microbiome samples of adult patients with inflammatory bowel disease (IBD), but we also had a collaboration with a Finnish group with a cohort of children who got lots of antibiotics. I thought that was super interesting, because I had two young children at the time (a third is now on the way).

    One day I was sitting in day care, and I realized that there are so many things that are different between them. Clearly, they’re going to share a lot of microbes because they’re all licking the same toys, but they have so many different eating habits. So it started me thinking about all the diversity that we see among children of the same age group, even among the same classroom in daycare.

    What is the goal of your BroadIgnite project? In the Finnish data, we saw a pattern that was known before: kids born by C-section have a different microbe signature than kids born by vaginal delivery. What was really interesting and novel, though, was that 20 percent of kids born by vaginal delivery had the C-section microbial signature. We didn’t have the data to explain it. At some point, when I kept complaining that we don’t have all the things that could be relevant, I realized that we should just try to establish a new cohort that would have all the data we were missing.

    Together with Dr. Caroline Mitchell (an OBGYN at MGH) we enrolled 190 families that came to deliver at MGH labor and delivery, and we collected samples from the kids and from different niches of the mother’s body. Now that most of the samples have been sequenced, we can get a better understanding of the differences in the microbial signatures. We can investigate questions like: do we see less transmission of bacterial strains from mother to child in C-section births? And can we identify the bacteria impacted the most?

    What else might influence a baby’s microbiome? We have a project looking at breast milk versus infant formula. The third most common component in breast milk is a type of sugar called human milk oligosaccharides. There are 200 different types of these sugars, and each mother can have a different combination of these sugars in her milk. But the baby itself does not have the enzymes to break these down—basically the mother is feeding the baby’s gut bacteria.

    In formula, none of these sugars are present, partly because they’re very expensive to make. But we also don’t know which sugars to add. We want to understand what the minimal and necessary set is that we can use to supplement formula that would best mimic breast milk. And so we’re trying to understand which bacteria could grow on which sugar, and which bacterial genes enable this potential growth for each sugar.

    It also turns out that cow’s milk allergy is almost twice as prevalent in kids who are exclusively formula fed than in kids who are breastfed. Formula is based on cow’s milk, so it could just be that they get a lot of exposure to cow’s milk protein if they’re exclusively eating formula. On the other hand, we know that exclusively formula-fed babies have different gut bacteria. So that’s what we’re investigating with the Food Allergy Science Initiative, with a cohort of 180 kids, 90 of which got milk allergy and 90 of which did not.

    What role did BroadIgnite play? Many young scientists lack confidence, so when other people think what you’re studying is important and that the methods you’re using are interesting, then that’s fun. The BroadIgnite funding was a really nice boost. It’s an honor to belong to such an extraordinary group of scientists.

    Furthermore, I think that two strong advantages of the BroadIgnite funding are that I could get the funding started very fast, which helped me establish my new cohort, and that the preliminary results from these samples were instrumental in receiving a large NIH grant to further support my projects.

    See the full article here .

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    The Eli and Edythe L. Broad Institute of Harvard and MIT is founded on two core beliefs:

    This generation has a historic opportunity and responsibility to transform medicine by using systematic approaches in the biological sciences to dramatically accelerate the understanding and treatment of disease.
    To fulfill this mission, we need new kinds of research institutions, with a deeply collaborative spirit across disciplines and organizations, and having the capacity to tackle ambitious challenges.

    The Broad Institute is essentially an “experiment” in a new way of doing science, empowering this generation of researchers to:

    Act nimbly. Encouraging creativity often means moving quickly, and taking risks on new approaches and structures that often defy conventional wisdom.
    Work boldly. Meeting the biomedical challenges of this generation requires the capacity to mount projects at any scale — from a single individual to teams of hundreds of scientists.
    Share openly. Seizing scientific opportunities requires creating methods, tools and massive data sets — and making them available to the entire scientific community to rapidly accelerate biomedical advancement.
    Reach globally. Biomedicine should address the medical challenges of the entire world, not just advanced economies, and include scientists in developing countries as equal partners whose knowledge and experience are critical to driving progress.

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  • richardmitnick 5:14 pm on July 13, 2017 Permalink | Reply
    Tags: , Biology, Epigenetics between the generations,   

    From Max Planck Gesellschaft: “Epigenetics between the generations” 

    Max Planck Gesellschaft

    July 13, 2017
    Dr. Nicola Iovino
    Max Planck Institute of Immunobiology and Epigenetics, Freiburg

    Marcus Rockoff
    Press and Public Relations
    Max Planck Institute of Immunobiology and Epigenetics, Freiburg
    +49 76 1510-8368

    Max Planck researchers prove that we inherit more than just genes.

    We are more than the sum of our genes. Epigenetic mechanisms modulated by environmental cues such as diet, disease or our lifestyle take a major role in regulating the DNA by switching genes on and off. It has been long debated if epigenetic modifications accumulated throughout the entire life can cross the border of generations and be inherited to children or even grand children. Now researchers from the Max Planck Institute of Immunobiology and Epigenetics in Freiburg show robust evidence that not only the inherited DNA itself but also the inherited epigenetic instructions contribute in regulating gene expression in the offspring. Moreover, the new insights by the Lab of Nicola Iovino describe for the first time biological consequences of this inherited information. The study proves that mother’s epigenetic memory is essential for the development and survival of the new generation.

    Egg-cell of a female fruit fly with the egg cell in which H3K27me3 was made visible through green staining. This cell, together with the sperm, will contribute to the formation of the next generation of flies. In the upper right corner, a maternal and paternal pre-nucleus are depicted before their fusion during fertilization. The green colouration of H3K27me3 appears exclusively in the maternal pre-nucleus, indicating that their epigenetic instructions are inherited into the next generation. © MPI of Immunobiology a. Epigenetics/ F. Zenk

    In our body we find more than 250 different cell types. They all contain the exact same DNA bases in exactly the same order; however, liver or nerve cells look very different and have different skills. What makes the difference is a process called epigenetics. Epigenetic modifications label specific regions of the DNA to attract or keep away proteins that activate genes. Thus, these modifications create, step by step, the typical patterns of active and inactive DNA sequences for each cell type. Moreover, contrary to the fixed sequence of ‘letters’ in our DNA, epigenetic marks can also change throughout our life and in response to our environment or lifestyle. For example, smoking changes the epigenetic makeup of lung cells, eventually leading to cancer. Other influences of external stimuli like stress, disease or diet are also supposed to be stored in the epigenetic memory of cells.

    It has long been thought that these epigenetic modifications never cross the border of generations. Scientists assumed that epigenetic memory accumulated throughout life is entirely cleared during the development of sperms and egg cells. Just recently a handful of studies stirred the scientific community by showing that epigenetic marks indeed can be transmitted over generations, but exactly how, and what effects these genetic modifications have in the offspring is not yet understood. “We saw indications of intergenerational inheritance of epigenetic information since the rise of the epigenetics in the early nineties. For instance, epidemiological studies revealed a striking correlation between the food supply of grandfathers and an increased risk of diabetes and cardiovascular disease in their grandchildren. Since then, various reports suggested epigenetic inheritance in different organisms but the molecular mechanisms were unknown”, says Nicola Iovino, corresponding author in the new study.

    Epigenetics between the generations

    He and his team at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, Germany used fruit flies to explore how epigenetic modifications are transmitted from the mother to the embryo. The team focused on a particular modification called H3K27me3 that can also be found in humans. It alters the so-called chromatin, the packaging of the DNA in the cell nucleus, and is mainly associated with repressing gene expression.

    The Max Planck researchers found that H3K27me3 modifications labeling chromatin DNA in the mother’s egg cells were still present in the embryo after fertilization, even though other epigenetic marks are erased. “This indicates that the mother passes on her epigenetic marks to her offspring. But we were also interested, if those marks are doing something important in the embryo”, explains Fides Zenk, first author of the study.

    Inherited epigenetic marks are important for embryogenesis

    Therefore the researchers used a variety of genetic tools in fruit flies to remove the enzyme that places H3K27me3 marks and discovered that embryos lacking H3K27me3 during early development could not develop to the end of embryogenesis. “It turned out that, in reproduction, epigenetic information is not only inherited from one generation to another but also important for the development of the embryo itself”, says Nicola Iovino.

    When they had a closer look into the embryos, the team found that several important developmental genes that are normally switched off during early embryogenesis were turned on in embryos without H3K27me3. “We assumed that activating those genes too soon during development disrupted embryogenesis and eventually caused the death of the embryo. It seems, virtually, that inherited epigenetic information is needed to process and correctly transcribe the genetic code of the embryo”, explains Fides Zenk.

    Implications for the theory of heredity and human health

    With these results the study by the Max Planck researchers is an important step forward and shows clearly the biological consequences of inherited epigenetic information. Not only by providing evidence that epigenetic modifications in flies can be transmitted down through generations, but moreover by revealing that epigenetic marks transmitted from the mother are a fine-tuned mechanism to control gene activation during the complex process of early embryogenesis.

    The international team in Freiburg is convinced that their findings have far-reaching implications. “Our study indicates that we inherit more than just genes from our parents. It seems to be that we also get a fine-tuned as well as important gene regulation machinery that can be influenced by our environment and individual lifestyle. These insights can provide new ground for the observation that at least in some cases acquired environmental adaptations can be passed over the germ line to our offspring”, explains Nicola Iovino. Further, since the disruption of epigenetic mechanisms may cause diseases such as cancer, diabetes and autoimmune disorders, these new findings could have implications for human health.

    Science paper:

    Zenk F, Loeser E, Schiavo R, Kilpert F, Bogdanović O, Iovino N
    Germ line–inherited H3K27me3 restricts enhancer function during maternal-to-zygotic transition.
    Science; July 13th, 2017

    See the full article here .

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    The Max Planck Society is Germany’s most successful research organization. Since its establishment in 1948, no fewer than 18 Nobel laureates have emerged from the ranks of its scientists, putting it on a par with the best and most prestigious research institutions worldwide. The more than 15,000 publications each year in internationally renowned scientific journals are proof of the outstanding research work conducted at Max Planck Institutes – and many of those articles are among the most-cited publications in the relevant field.

    What is the basis of this success? The scientific attractiveness of the Max Planck Society is based on its understanding of research: Max Planck Institutes are built up solely around the world’s leading researchers. They themselves define their research subjects and are given the best working conditions, as well as free reign in selecting their staff. This is the core of the Harnack principle, which dates back to Adolph von Harnack, the first president of the Kaiser Wilhelm Society, which was established in 1911. This principle has been successfully applied for nearly one hundred years. The Max Planck Society continues the tradition of its predecessor institution with this structural principle of the person-centered research organization.

    The currently 83 Max Planck Institutes and facilities conduct basic research in the service of the general public in the natural sciences, life sciences, social sciences, and the humanities. Max Planck Institutes focus on research fields that are particularly innovative, or that are especially demanding in terms of funding or time requirements. And their research spectrum is continually evolving: new institutes are established to find answers to seminal, forward-looking scientific questions, while others are closed when, for example, their research field has been widely established at universities. This continuous renewal preserves the scope the Max Planck Society needs to react quickly to pioneering scientific developments.

  • richardmitnick 1:42 pm on July 12, 2017 Permalink | Reply
    Tags: Biology, , , , Preventing severe blood loss on the battlefield or in the clinic, Reginald Avery   

    From MIT: “Preventing severe blood loss on the battlefield or in the clinic” Reginald Avery 

    MIT News

    MIT Widget

    MIT News

    July 11, 2017
    Dara Farhadi

    At MIT graduate student Reginald Avery has been conducting research on a biomaterial that could stop wounded soldiers from dying from shock due to severe blood loss. “I wanted to do something related to the military because I grew up around that environment,” he says. “The people, the uniformed soldiers, and the well-controlled atmosphere created a good environment to grow up in, and I wanted to still contribute in some way to that community.” Photo: Ian MacLellan

    PhD student Reginald Avery is developing an injectable material that patches ruptured blood vessels.

    In a tiny room in the sub-basement of MIT’s Building 66 sits a customized, super-resolution microscope that makes it possible to see nanoscale features of a red blood cell. Here, Reginald Avery, a fifth-year graduate student in the Department of Biological Engineering, can be found conducting research with quiet discipline, occasionally fidgeting with his silver watch.

    He spends most of his days either at the microscope, taking high-resolution images of blood clots forming over time, or at the computer, reading literature about super-resolution microscopy. Without windows to approximate the time of day, Avery’s watch comes in handy. Not surprisingly for those who know him, it’s set to military time.

    Avery describes his father as a hard-working inspector general for the U.S. Army Test and Evaluation Command. Avery and his fraternal twin brother, Jeff, a graduate student in computer science at Purdue University, were born in Germany and lived for a portion of their childhoods on military bases in Hawaii and Alabama. Eventually the family moved to Maryland and entered civilian life, but Avery’s experiences on a military base never left him. At MIT he’s been conducting research on a biomaterial that could stop wounded soldiers from dying from shock due to severe blood loss.

    “I wanted to do something related to the military because I grew up around that environment,” he says. “The people, the uniformed soldiers, and the well-controlled atmosphere created a good environment to grow up in, and I wanted to still contribute in some way to that community.”

    Blocking blood loss

    Avery is one of the first graduate students to join the Program in Polymers and Soft Matter (PPSM) from the Department of Biological Engineering. When he first joined the lab of Associate Professor Bradley Olsen in the Department of Chemical Engineering, his focus was on optimizing and testing a material that could be topically applied to wounded soldiers.

    The biomaterial is a hydrogel — a material consisting largely of water — with a viscosity similar to toothpaste. Gelatin proteins and inorganic silica nanoparticles are incorporated into the material and function as a substrate that helps to accelerate coagulation rates and reduce clotting times.

    Co-advised by Ali Khademhosseini at Brigham and Women’s Hospital and in collaboration with others at Massachusetts General Hospital, Avery further developed the material so that it could be injected into ruptured blood vessels. Like a cork on a wine bottle, the biomaterial forms a plug in the leaky vessel and stops any blood loss. Avery’s research was published in Science Translational Medicine and featured on the front cover of the November 2016 issue.

    The current standard for patching blood vessels is imperfect. Surgeons typically use metallic coils, special plastic beads, or compounds also found in super glue. Each technology has limitations that the nanocomposite hydrogel attempts to address.

    “The old techniques don’t take advantage of tissue engineering. It can be difficult for a surgeon to deliver metallic coils and beads to the targeted site, and blood may sometimes still find a path through and result in re-bleeding. It’s also expensive, and some techniques have a finite time period to place the material where it needs to be,” Avery says. “We wanted to use a hydrogel that could completely fill a vessel and not allow any leakage to occur through that injury site.”

    The nanocomposite, which can be injected easily with a syringe or catheter, has been tested in animal models without causing inflammatory side-effects or the formation of clots elsewhere in the animal’s circulatory system. Some in vitro experiments also indicate that the material could be useful for treating aneurysms.

    For the past six months Avery has concentrated on uncovering the physical mechanism by which the nanocomposite material interacts with blood. A super-resolution microscope can achieve a resolution of 250 nanometers; a single red blood cell, for a comparison, is about 8,000 nanometers wide. Avery says the ability to visualize how the physiological molecules and proteins interact with the nanocomposite and other surgical tools may also help him design a better material. Obtaining a comprehensive view of the process, however, can be time-consuming.

    “It’s taking snapshots every 10 or 20 seconds for approximately 30 minutes, and putting all of those pictures together,” he says. “What I want to do is visualize these gels and clots forming over time.”

    Found in translation

    While he is eager to see his material put to use to save lives, Avery is glad to be contributing to the work at the basic and translational research stages. He says he’s driven to appropriately characterize a treatment or biomaterial, ask the right questions, and make sure it functions just as well as, or better than, what is currently used in the clinic.

    “I’m comfortable doing a thorough study in vitro to characterize materials or design some synthetic tests prior to in vivo testing,” he says. “You must be very confident in [the biomaterial] before getting to that step so that you’re effectively utilizing the animals, or even more important, you’re not putting a person at risk if something finally does get to that point.”

    Avery also finds meaning in collaborating and helping others with their research. He has worked on projects using neutron scattering to elucidate the network structure of a homo-polypeptide, performed cell culture on thermoresponsive hydrogels, and developed highly elastic polypeptides, projects that Avery says aren’t directly applicable to his thesis work of treating internal bleeding. However, he was happy to have simply had the experience of learning something new.

    “If I can help somebody with something then I’m going to try to do the best that I can. Whether it’s a homework assignment or something in lab, my goal is not to leave somebody worse off,” Avery says. “If there’s something I’ve done in the past that could help you now, I’m excited to show you and hopefully have it work out well for you. If it doesn’t, we can talk even longer to try to figure out what we could do to make it work better.”

    Of the seven papers that Avery has been involved in over the past three years, almost half were collaborative projects outside the area of his thesis work.

    Avery hopes to finish his PhD thesis by the summer of next year. Afterward, he envisions working for a research institute that is devoted to a single disease or condition, or perhaps for a research center associated with a hospital within the military health system so that he could continue developing biomaterials, diagnostics, or other approaches to help soldiers.

    “I’m usually excited to help somebody get something done or get something done for my project. It’s always exciting to get closer to determining the optimum concentration that you need, seeing that one data point that’s higher than the others, or getting that nice image that shows the effect that you have hypothesized,” Avery says. “That’s still a motivating aspect of coming to lab, to eventually get those results. It can take a long time to get there but once you do, you appreciate the journey.”

    See the full article here .

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    The mission of MIT is to advance knowledge and educate students in science, technology, and other areas of scholarship that will best serve the nation and the world in the twenty-first century. We seek to develop in each member of the MIT community the ability and passion to work wisely, creatively, and effectively for the betterment of humankind.

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  • richardmitnick 9:30 am on July 12, 2017 Permalink | Reply
    Tags: , Biology, How old are your cells? New method determines cell age more accurately, , , The biophysical qualities of cells such as cell movements and structural features make better measures of functional age than other factors including cell secretions and cell energy   

    From Hopkins: “How old are your cells? New method determines cell age more accurately” 

    Johns Hopkins
    Johns Hopkins University

    Arthur Hirsch

    Glandular tissue at 20x magnification. Image credit: Getty Images.

    Sure, you know how old you are, but what about your cells? Are they the same age? Are they older, younger? Why does it matter?

    Led by scientists at Johns Hopkins University, a team of researchers is reporting progress in developing a method to accurately determine the functional age of cells, a step that could eventually help clinicians evaluate and recommend ways to delay some health effects of aging and potentially improve other treatments, including skin graft matching and predicting prospects for wound healing.

    In the current issue of Nature Biomedical Engineering, lead author Jude M. Phillip, who conducted this research while completing his doctorate in chemical and biomolecular engineering at Johns Hopkins, reports success in creating a system that considers a wide array of cellular and molecular factors in one comprehensive aging assessment.

    These results show that the biophysical qualities of cells, such as cell movements and structural features, make better measures of functional age than other factors, including cell secretions and cell energy.

    The multidisciplinary team of engineers and clinicians examined dermal cells from just underneath the surface of the skin taken from both males and females between the ages of 2 and 96.

    The researchers from Johns Hopkins, Yale University, and the National Cancer Institute of the National Institutes of Health hoped to devise a system that, through computational analysis, could take the measure of various factors of cellular and molecular functions. From that information, they hoped to determine the biological age of individuals more accurately using their cells, in contrast to previous studies, which makes use of gross physiology, or examining cellular mechanisms such as DNA methylation.

    “We combined some classic biomolecular hallmarks of aging, and sought to further elucidate the role of biophysical properties of aging cells, all in one study,” said Phillip, now a post-doctoral fellow at Weill Cornell Medicine.

    Researchers trying to understand aging have, up until now, focused on factors such as tissue and organ function and on molecular-level studies of genetics and of epigenetics, meaning heritable traits that are not traced to DNA. The level in between—cells—has received relatively little attention, the researchers wrote.

    This research was meant to correct for that omission by considering the biophysical attributes of cells, including such factors as the cells’ ability to move, maintain flexibility, and structure. This focus emerges from the understanding that changes associated with aging at the physiological level—such as diminished lung capacity, grip strength, and mean pressure in the arteries—”tend to be secondary to changes in the cells themselves, thus advocating the value of cell-based technologies to assess biological age,” the research team wrote.

    For example, older cells are more rigid and do not move as well as younger cells, which, among other consequences, most likely contributes to the slower wound healing commonly seen in older people, said Denis Wirtz, the senior author and Johns Hopkins’ vice provost for research. Wirtz and Phillip conducted their research in the Johns Hopkins Institute for NanoBioTechnology.

    From the analysis, they were able to stratify individuals’ samples into three groups: those whose cells roughly reflected their chronological age, those whose cells were functionally older, and those whose cells were functionally younger. The results also showed that the so-called biophysical factors of cells determined a more accurate measure of age than biomolecular factors such as cell secretions, cell energy, and the organization of DNA.

    Phillip explained that this better accuracy from the biophysical factors most likely results from the orchestration of many biomolecular factors. He compared it to the more complete picture you get looking at a forest from a distance without binoculars.

    “With binoculars you can see details about the individual trees, the color and shapes of the leaves, the roughness of the bark, the type of tree, but without the binoculars you can now see the density of the trees, and whether there is a barren plot, or a group or dying trees,” Phillip said. “This is something you may miss with the binoculars, unless you are looking at the correct spot.”

    The more accurate system could eventually enable clinicians to see aging in cells before a patient experiences age-related health decline. This in turn could allow doctors to recommend treatments or changes in life habits, such as exercise or diet changes, Wirtz said. Phillip said the work could potentially help clinicians produce more successful skin grafts by matching cell characteristics of the donor and the graft site. Other potential applications range from toxicology screening for cosmetics and topical therapeutics to predicting progression of some age-related diseases.

    The researchers acknowledge that the system needs further testing with a larger cell sample, but the results are robust and encouraging. Conducted along with clinicians such as Jeremy Walston, the Raymond and Anna Lublin Professor of Geriatric Medicine, and co-director of the Biology of Healthy Aging program at the Johns Hopkins School of Medicine, this work promises to allow clinicians to measure a person’s health in the present and the future.

    “It opens the door to finally be able to track how a person is doing at the cellular level,” Wirtz said.

    Added Phillip: “This platform is also more than just a cellular age predictor; it has the ability to do so much more in terms of assessing an individual’s cellular health.”

    See the full article here .

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    Johns Hopkins Campus

    The Johns Hopkins University opened in 1876, with the inauguration of its first president, Daniel Coit Gilman. “What are we aiming at?” Gilman asked in his installation address. “The encouragement of research … and the advancement of individual scholars, who by their excellence will advance the sciences they pursue, and the society where they dwell.”

    The mission laid out by Gilman remains the university’s mission today, summed up in a simple but powerful restatement of Gilman’s own words: “Knowledge for the world.”

    What Gilman created was a research university, dedicated to advancing both students’ knowledge and the state of human knowledge through research and scholarship. Gilman believed that teaching and research are interdependent, that success in one depends on success in the other. A modern university, he believed, must do both well. The realization of Gilman’s philosophy at Johns Hopkins, and at other institutions that later attracted Johns Hopkins-trained scholars, revolutionized higher education in America, leading to the research university system as it exists today.

  • richardmitnick 1:21 pm on July 8, 2017 Permalink | Reply
    Tags: , Biology, , , , , , , , UCSD Comet supercomputer   

    From Science Node: “Cracking the CRISPR clock” 

    Science Node bloc
    Science Node

    05 Jul, 2017
    Jan Zverina

    SDSC Dell Comet supercomputer

    Capturing the motion of gyrating proteins at time intervals up to one thousand times greater than previous efforts, a team led by University of California, San Diego (UCSD) researchers has identified the myriad structural changes that activate and drive CRISPR-Cas9, the innovative gene-splicing technology that’s transforming the field of genetic engineering.

    By shedding light on the biophysical details governing the mechanics of CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats) activity, the study provides a fundamental framework for designing a more efficient and accurate genome-splicing technology that doesn’t yield ‘off-target’ DNA breaks currently frustrating the potential of the CRISPR-Cas9- system, particularly for clinical uses.

    Shake and bake. Gaussian accelerated molecular dynamics simulations and state-of-the-art supercomputing resources reveal the conformational change of the HNH domain (green) from its inactive to active state. Courtesy Giulia Palermo, McCammon Lab, UC San Diego.

    “Although the CRISPR-Cas9 system is rapidly revolutionizing life sciences toward a facile genome editing technology, structural and mechanistic details underlying its function have remained unknown,” says Giulia Palermo, a postdoctoral scholar with the UC San Diego Department of Pharmacology and lead author of the study [PNAS].

    See the full article here

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    Science Node is an international weekly online publication that covers distributed computing and the research it enables.

    “We report on all aspects of distributed computing technology, such as grids and clouds. We also regularly feature articles on distributed computing-enabled research in a large variety of disciplines, including physics, biology, sociology, earth sciences, archaeology, medicine, disaster management, crime, and art. (Note that we do not cover stories that are purely about commercial technology.)

    In its current incarnation, Science Node is also an online destination where you can host a profile and blog, and find and disseminate announcements and information about events, deadlines, and jobs. In the near future it will also be a place where you can network with colleagues.

    You can read Science Node via our homepage, RSS, or email. For the complete iSGTW experience, sign up for an account or log in with OpenID and manage your email subscription from your account preferences. If you do not wish to access the website’s features, you can just subscribe to the weekly email.”

  • richardmitnick 2:22 pm on July 7, 2017 Permalink | Reply
    Tags: , Biology, Dendritic cells 'divide and conquer' to elude viral infection while promoting immunity, ,   

    From MedicalXpress: “Dendritic cells ‘divide and conquer’ to elude viral infection while promoting immunity” 

    Medicalxpress bloc


    Infographic depicting a “division of labor” among DC subsets, which protects the body during viral infection. Credit: Carla Schaffer / AAAS

    A research team led by Jackson Laboratory (JAX) Professor Karolina Palucka, M.D., Ph.D., in collaboration with a research team at Institut Curie in France led by Dr. Nicolas Manel, have addressed a long-standing puzzle of immunology: How do dendritic cells (DCs) do their job of promoting adaptive immunity to a virus while avoiding getting infected themselves?

    DCs are the “beat cops” of the immune system. They round up viral antigens (proteins specific to a given virus), and present them to the receptors on T cells, which in turn promote an adaptive immune response to that virus. But along the way the DCs are vulnerable to infection by the virus, presumably compromising their protective powers.

    The research team reports in Science Immunology that two subsets of DCs work together to activate T cells against a virus: one dies and produces the viral antigens that the other then sweeps up and presents to the T cells.

    “We show that one DC subset (CD1c+ DCs) is susceptible to viral infection and produces viral fragments,” Palucka says. “Another DC subset (CD141+ DCs) uses these viral fragments to activate T cells against the virus. This paradigm may allow a better understanding of the induction of protective immunity against viruses and live-attenuated vaccines against viral infections.”

    Silvin et al. found that a molecule called RAB15 can help limit viral infection in DCs, and examined its localization in human monocytes growing in culture. Credit: Silvin et al., Sci. Immunol. 2, eaai8071

    CD141+ DCs are dependent on the productive infection of “bystander” CD1c+ DCs, to effectively activate T cells. Credit: Silvin et al., Sci. Immunol. 2, eaai8071

    See the full article here .

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    Medical Xpress is a web-based medical and health news service that is part of the renowned Science X network. Medical Xpress features the most comprehensive coverage in medical research and health news in the fields of neuroscience, cardiology, cancer, HIV/AIDS, psychology, psychiatry, dentistry, genetics, diseases and conditions, medications and more.

  • richardmitnick 8:42 am on July 7, 2017 Permalink | Reply
    Tags: A Duet of Firsts: Imaging Chemical Building Blocks, , Biology, ,   

    From PNNL: “A Duet of Firsts: Imaging Chemical Building Blocks” 

    PNNL Lab

    July 2017

    The new metallic-organic framework, NU-1301, is made up of uranium oxide nodes and tricarboxylate organic linkers. Image courtesy of Northwestern University.

    Two firsts in science came about because of a near-dare. According to Nigel Browning at Pacific Northwest National Laboratory, “Omar Farha was giving a presentation on MOFs [metal-organic frameworks] and someone said ‘I bet you couldn’t make one out of uranium.’” Farha took the challenge and proved them wrong. In designing the uranium-laden frameworks, PNNL scientists Dr. Nigel Browning and Dr. Layla Mehdi helped Farha and his colleagues at Northwestern University overcome a troubling bottleneck in imaging the material. Before this study, scientists used x-ray analysis and modeling to map out MOF structures. The approaches come with sharp drawbacks. Browning and Mehdi showed that low-dose imaging is a viable option for MOF imaging, allowing for the structure to be resolved at the near-atomic level.

    This collaborative effort produced two notable milestones; it was first MOF made out of uranium, and the first time low-dose electron microscopy was used to map the MOF structure.

    Reference: Li P, NA Vermeulen, CD Malliakas, DA Gómez-Gualdrón, AJ Howarth, BL Mehdi, A Dohnalkova, ND Browning, M O’Keeffe, and OK Farha. 2017. Bottom-up construction of a superstructure in a porous uranium-organic crystal. Science 356(6338):624-627. DOI: 10.1126/science.aam7851

    See the full article here .

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

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


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