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  • richardmitnick 7:38 pm on February 3, 2016 Permalink | Reply
    Tags: , Biology, , Senescence   

    From SA: “Destroying Worn-Out Cells Makes Mice Live Longer” 

    Scientific American

    Scientific American

    February 3, 2016
    Ewen Callaway

    Mice in lab
    Mice whose senescent cells were killed off over six months were healthier, in several ways, than a control group of transgenic mice in which these cells were allowed to build up. Credit: ©iStock

    Eliminating worn-out cells extends the healthy lives of lab mice — an indication that treatments aimed at killing off these cells, or blocking their effects, might also help to combat age-related diseases in humans.

    As animals age, cells that are no longer able to divide — called senescent cells — accrue all over their bodies, releasing molecules that can harm nearby tissues. Senescent cells are linked to diseases of old age, such as kidney failure and type 2 diabetes.

    To test the cells’ role in ageing, Darren Baker and Jan van Deursen, molecular biologists at the Mayo Clinic in Rochester, Minnesota, and their colleagues engineered mice so that their senescent cells would die off when the rodents were injected with a drug.

    The work involved sophisticated genetic tinkering and extensive physiological testing, but the concept has an elegant simplicity to it. “We think these cells are bad when they accumulate. We remove them and see the consequences,” says Baker. “That’s how I try to explain it to my kids.”

    Live long and prosper

    Mice whose senescent cells were killed off over six months were healthier, in several ways, than a control group of transgenic mice in which these cells were allowed to build up. Their kidneys worked better and their hearts were more resilient to stress, they tended to explore their cages more and they developed cancers at a later age. Eliminating senescent cells also extended the lifespans of the mice by 20–30%, Baker and van Deursen report in Nature on February 3.

    The research is a follow-up to a 2011 study, in which their team also found that eliminating senescent cells delayed the onset of diseases of old age in mice, although that work had been done in mice which had a mutation that causes premature ageing.


    download mp4 video here .

    In the hope of discovering therapies for diseases of old age, researchers are already looking for drugs that can directly eliminate senescent cells or stop them from churning out factors that damage neighbouring tissue. They include Baker and van Deursen, who have have licensed patents to develop such drugs to a company van Deursen has co-founded.

    The team’s experiment “gives you confidence that senescent cells are an important target,” says Dominic Withers, a clinician-scientist who studies ageing at Imperial College London and who co-wrote a News and Views article for Nature that accompanies the Mayo Clinic report. “I think that there is every chance this will be a viable therapeutic option.”

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    Scientific American, the oldest continuously published magazine in the U.S., has been bringing its readers unique insights about developments in science and technology for more than 160 years.

     
  • richardmitnick 2:31 pm on January 13, 2016 Permalink | Reply
    Tags: , Biology, , ,   

    From MIT Tech Review: “CRISPR Dispute to Be Decided by Patent Office” 

    MIT Technology Review
    M.I.T Technology Review

    January 12, 2016
    Jacob S. Sherkow

    A “patent interference” proceeding will determine who controls foundational patents on gene editing.

    As this magazine and others have detailed, CRISPR-Cas9—the powerful gene-editing technology being hailed as molecular biology’s “holy grail”—is the subject of a contentious dispute between the widely celebrated Jennifer Doudna at the University of California, Berkeley, and wunderkind Feng Zhang at the Broad Institute and MIT.

    The central question: who invented it first?

    Yesterday, that dispute became official in the eyes of the U.S. Patent and Trademark Office when an administrative patent judge officially declared an “interference” between Doudna’s pending patent application and a dozen of Zhang’s already issued patents. The interference proceeding sets up a legal showdown that may strip Zhang of his patents and see the two scientists deposed under oath.

    Even among patent attorneys—generally, friends of the arcane and hypertechnical—interference proceedings are famous for their complexity. The U.S. patent office now grants patents on a “first to file” basis. But before 2013 this was not the case. Historically, U.S. patent law instead recognized that patent rights should go to whoever could prove they were “first to invent” an idea. Because there is a lag between when patent applications are filed and when they are issued—roughly, three years—this gave rise to the possibility that a later inventor could be awarded a patent before the patent office had time to process an earlier inventor’s application. In that circumstance, the later inventor’s patent “interferes” with the earlier inventor’s ability to rightfully obtain theirs.

    This is precisely what occurred between Doudna and Zhang, whose patents are covered by the older rule. Doudna, with colleagues in Europe, filed a provisional patent application on her early iteration of the CRISPR editing technology on May 25, 2012; Zhang did the same on December 12, 2012. But Zhang’s attorneys requested that the patent office expedite its review of his application under a procedure—funnily named a Petition to Make Special—that allows inventors a quick up-or-down vote on simplified patent applications. As a result, Zhang was awarded his first patent on April 15, 2014, while Doudna’s patent application remained in limbo. Shortly thereafter, Zhang was awarded over a dozen patents on various forms of the technology.

    Perhaps fearing that they were losing the great biotech patent race of the century, Doudna’s attorneys amended her application in order to directly conflict with Zhang’s patents. Specifically, Doudna’s attorneys claimed that her patent application covered gene-editing in mammalian cells—including humans—even though her original filing didn’t detail that aspect of the technology. Yesterday, to the delight of watchers of patent dockets everywhere, an administrative patent judge with a PhD in molecular biology, Judge Deborah Katz, officially declared the interference.

    Despite these seemingly dry technicalities, the CRISPR patent dispute has been spiced with intrigue. During the examination of Doudna’s patent application, several unidentified third parties filed papers with the patent office seeking to block it, arguing that she was not the first to invent her CRISPR technique, while the Broad Institute unleashed its own volley of legal papers, lab notebooks, even copies of private e-mails between scientists. If Doudna’s original application did not command the focus of patent office supervisors when it was filed, it sure does now.

    What comes next? A panel of three patent judges will get to decide who gets the patent rights to CRISPR-Cas9 editing in animal cells. Their decision is likely to center on a few core issues. One is whether Doudna’s original patent application really covered working with human cells. Another is the earliest date either scientist can prove they performed their breakthrough work.

    Yesterday’s declaration of an interference proceeding already provides a few hints. First, it lists Doudna as the “senior party” and Zhang as the “junior party”—an initial determination that the administrative patent judge agrees that Doudna was the first inventor. This means that the burden of proof rests on Zhang, much like how, in a criminal trial, the government—not a criminal defendant—must prove its case beyond a reasonable doubt. Second, the declaration puts at issue all of the patent claims; none are left out. This suggests that the interference proceeding—assuming it retains its current scope—will be an all-or-nothing affair: Zhang will either get to keep all of his patents or lose all of them. This may mean that there is little room, legally, for the patent office to keep both sides happy. But as the dispute has shown us thus far, there is always room for surprises.

    See the full article here .

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  • richardmitnick 12:35 pm on December 28, 2015 Permalink | Reply
    Tags: , Biology,   

    From Salk: “Here comes the sun: cellular sensor helps plants find light” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    December 24, 2015
    No writer credit
    Office of Communications
    Tel: (858) 453-4100
    press@salk.edu

    Temp 1
    No image credit found

    Despite seeming passive, plants wage wars with each other to outgrow and absorb sunlight. If a plant is shaded by another, it becomes cut off from essential sunlight it needs to survive.

    To escape this deadly shade, plants have light sensors that can set off an internal alarm when threatened by the shade of other plants. Their sensors can detect depletion of red and blue light (wavelengths absorbed by vegetation) to distinguish between an aggressive nearby plant from a passing cloud.

    2
    Image: Courtesy of the Salk Institute for Biological Studies

    Scientists at the Salk Institute have discovered a way by which plants assess the quality of shade to outgrow menacing neighbors, a finding that could be used to improve the productivity of crops. The new work, published December 24, 2015 in Cell, shows how the depletion of blue light detected by molecular sensors in plants triggers accelerated growth to overcome a competing plant.

    “With this knowledge and discoveries like it, maybe you could eventually teach a plant to ignore the fact that it’s in the shade and put out a lot of biomass anyway,” says Joanne Chory, senior author and director of Salk’s Plant Molecular and Cellular Biology.

    3
    Ullas V. Pedmale and Joanne Chory
    Image: Courtesy of the Salk Institute for Biological Studies

    The new work upends previously held notions in the field. It was known that plants respond to diminished red light by activating a growth hormone called auxin to outpace its neighbors. However, this is the first time researchers have shown that shade avoidance can happen through an entirely different mechanism: instead of changing the levels of auxin, a cellular sensor called cryptochrome responds to diminished blue light by turning on genes that promote cell growth.

    This revelation could help researchers learn how to modify plant genes to optimize growth to, for example, coerce soy or tomato crops (which are notoriously fickle) grow more aggressively and give a greater yield even in a crowded, shady field.

    The focus of the team’s research efforts was cryptochromes, blue light-sensitive sensors that are responsible for telling a plant when to grow and when to flower. Cryptochromes were first identified in plants and later found in animals, and in both organisms they are associated with circadian rhythm (the body’s biological clock). The protein’s role in sensing depletion of blue light had been known, but this study is the first to show how cryptochromes promote growth in a shaded environment.

    The team placed normal and mutant Arabidopsis plants in a light-controlled room where blue light was limited. The mutant plants lacked either cryptochromes or a PIF transcription factor, a type of protein that binds to DNA to control when genes are switched on or off. PIFs typically make direct contact with red light sensors, called phytochromes, to initiate shade avoidance growth. The researchers compared the responses of the mutant and normal plants in the varying blue light conditions by monitoring the growth rate of the stems and looking at contacts between cryptochromes, PIFs and chromosomes.

    “We found that cryptochromes contact these transcription factors on DNA, activating genes completely different than what other photoreceptors activate,” says Ullas Pedmale, first author of the work and a Salk research associate. “This is also a very short pathway so plants can rapidly respond to their light environment.”

    The next step for the work is to understand how to manipulate the growth response. “Ultimately, we could help farmers grow crops very close together by changing how plants put out leaves, how fast the leaves grow and at what angles the leaves grow relative to each other and the stem. This will help increase yield in the next few generations of crop plants,” says Chory, who is also a Howard Hughes Medical Institute investigator and holds the Howard H. and Maryam R. Newman Chair in Plant Biology.

    “Shade avoidance and the response of plants to increases in temperature look similar and in fact share many common molecular components,” adds Pedmale. “Therefore, studying shade avoidance will not only lead to increases in yield in shaded environments, but may explain how to increase yield in a warming climate.”

    Other authors on the paper were Shao-shan Carol Huang, Mark Zander, Benjamin Cole, Jonathan Hetzel, Pedro Reis, Kazumasa Nito, Joseph Nery and Joseph Ecker of the Salk Institute; Karin Ljung of the Umeå Plant Science Centre in the Swedish University of Agricultural Sciences; and Priya Sridevi of the University of California, San Diego.

    The work was supported by the NIH, Rose Hills Foundation, the H.A. and Mary K. Chapman Charitable Trust, DOE, the NSF, the Gordon and Betty Moore Foundation and the Howard Hughes Medical Institute.

    PUBLICATION INFORMATION

    JOURNAL

    Cell

    TITLE

    Cryptochromes interact directly with PIFs to control plant growth in limiting blue light

    AUTHORS

    Ullas V. Pedmale, Shao-shan Carol Huang, Mark Zander, Benjamin J. Cole, Jonathan Hetzel, Karin Ljung, Pedro A. B. Reis, Priya Sridevi, Kazumasa Nito, Joseph R. Nery, Joseph R. Ecker and Joanne Chory

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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 1:55 pm on December 22, 2015 Permalink | Reply
    Tags: , Biology,   

    From Brown: “Blocking fat transport linked to longevity” 

    Brown University
    Brown University

    December 22, 2015
    David Orenstein

    1
    Fat finding. Fat transport and storage matters to longevity, according to a new study. Here a store of mouse fat cells (red) is permeated by blood vessels (green).Image: Daniela Malide, NHLBI/NIH

    Animals from tiny worms to human beings have a love-hate relationship with fats and lipids. Cholesterol is a famous example of how they are both essential for health and often have a role in death. A new study reveals another way that may be true. Researchers working in nematodes and mice found that a naturally occurring protein responsible for transporting fats like cholesterol around the body also hinders essential functions in cells that increase life span.

    When the scientists genetically blocked production of the worms’ yolk lipoprotein, called vitellogenin (VIT), the nematodes lived up to 40 percent longer, the study showed. Mice, humans and other mammals produce a directly analogous protein called apolipoprotein B (apoB), and therapies have been developed to reduce apoB to prevent cardiovascular disease.

    The new research suggests that there might be a whole other benefit to reducing apoB. Data from the nematodes indicate that apoB’s evolutionary cousin VIT prevents long life span by impairing the ability of cells to use and remodel fats for healthier purposes.

    “That protein, which has an ortholog in humans, is a major decider of what happens to fat inside intestinal cells,” said Louis Lapierre, assistant professor of molecular biology, cell biology and biochemistry at Brown University and senior author of the study in the journal Autophagy. “If you reduce the production of these lipoproteins you allow the fat to be reused in different ways.”

    Lipophagy is the process of breaking down large quantities of built-up fats and reusing them for other purposes. The new study showed that the longevity benefits associated with increased lipophagy are hindered by too much VIT.

    2
    Louis Lapierre “Since we see in the worm that we can extend life span by silencing this protein, we reason that that it could be a promising strategy to prevent age-related disease in humans.” Photo: Nicole Seah

    Lapierre’s team, including lab manager and co-lead author Nicole Seah, demonstrated the link directly. Some experiments, for example, showed that the life span benefits of blocking VIT didn’t occur if autophagy was blocked in other ways. They also showed that VIT hinders a related process called lysosomal lipolysis, the endpoint of lipophagy which catalyzes fat breakdown.

    In mice the team connected this effect to another well-known model of increased longevity: dietary restriction. Many studies have shown that animals that eat less live longer. In this study the researchers showed that calorie-restricted mice produced less apoB.

    In nematodes, the normal purpose of VIT is thought primarily to involve the transport of fats from the intestine to the reproductive system to nourish eggs and to aid in reproduction. Similarly in mammals, Lapierre said, a purpose of apoB is to transfer fats away from the intestine and liver toward other tissues where they can either be used or stored.

    “Altogether our data supports a model in which lipoprotein biogenesis prevents life span extension by distributing lipids away from the intestine and by negatively regulating the induction of autophagy-related and lysosomal lipase genes, thereby challenging the animal’s ability to maintain lipid homeostasis and somatic maintenance,” the authors wrote in the study.

    Help for humans?

    Of course nematodes and mice are not people, but Lapierre said he is optimistic that these findings could eventually matter to human health. He’s not alone. Other labs are currently investigating the relationships between lipoproteins, autophagy, and life span.

    “Since we see in the worm that we can extend life span by silencing this protein, we reason that that it could be a promising strategy to prevent age-related disease in humans,” Lapierre said.

    Earlier this year Lapierre earned a grant from the American Federation for Aging Research to continue his work. His lab group is now looking at the global effects of limiting VIT and apoB in animals.

    In humans, he said, a major unanswered question is what effect silencing apoB would have on fat remodeling in the liver and the intestine.

    The new research finds that at least in nematodes, keeping fats in the intestine allows cells to carry out processes that are linked to longer life span.

    The paper’s other co-lead author is C. Daniel de Magalhaes Filho of the Howard Hughes Medical Institute and Salk Institute. The study’s other authors are Anna Petrashen, Hope Henderson, Jade Laguer, Julissa Gonzalez, Andrew Dillin, and Malene Hansen.

    In addition to AFAR, the National Institutes of Health provided funding for the study (grants K99AG042494 and R00AG042494).

    See the full article here .

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    Welcome to Brown

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

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

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

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

     
  • richardmitnick 6:44 am on October 26, 2015 Permalink | Reply
    Tags: , Biology,   

    From Weizmann: “Awakenings” 

    Weizmann Institute of Science logo

    Weizmann Institute of Science

    10.26.15

    1
    Prof. Atan Gross revealed a mechanism for waking up sleeping stem cells

    An energy supply is important for any undertaking; but in stem cells, energy-producing structures sometimes determine the very fate of the cell. A new Weizmann Institute study, reported in Nature Communications, reveals how cellular power plants called mitochondria can wake up blood-forming stem cells from their sleep, causing them to proliferate and mature into different cell types.

    Blood-forming stem cells, which give rise to the entire immune system, lie sleeping in niches in the bone marrow. They are continuously woken up to replenish the blood with mature cells, which have a finite life span. The wake-up call can come in the form of reactive oxygen molecules called free radicals, which are produced in the mitochondria as a byproduct of the manufacture of cellular fuel. A team of Weizmann Institute scientists headed by Prof. Atan Gross of the Biological Regulation Department has now discovered a mechanism by which the wake-up message is sent to these stem cells via their mitochondria.

    2
    Mitochondria (dark gray), viewed under an electron microscope, are significantly enlarged in blood-forming stem cells lacking MTCH2 (right) compared with regular blood-forming stem cells (left)

    The heart of the message is a protein known as MTCH2 – or “Mitch,” as the scientists call it – which sits on the membranes of mitochondria and acts as a molecular switch. When Gross discovered MTCH2 more than a decade ago, he and his team showed that this protein can regulate cell suicide: Under conditions of severe stress, “Mitch” conveys a self-destruct message that prompts the mitochondria to develop holes and disintegrate, ultimately causing the cell to die. In the new study, postdoctoral fellow Dr. Maria Maryanovich and other members of Gross’s lab – Dr. Yehudit Zaltsman and PhD students Antonella Ruggiero and Andres Goldman – found that in blood-forming stem cells, MTCH2 has an additional role: It suppresses the activity of the mitochondria for as long as the cells need to remain in their dormant state.

    When the scientists created genetically engineered mice that lacked MTCH2 throughout their blood system, the mitochondria in the blood-forming stem cells underwent major changes. These organelles more than doubled in size, and their activity increased almost four-fold. As a result, the stem cells became activated, apparently woken from their sleep by the free radicals generated in the hyper-busy mitochondria. The cells left their niches and began to mature in such large numbers that their supply in the bone marrow was exhausted. These findings suggest that enhancing the activity of the mitochondria – by decreasing MTCH2 – can awaken the stem cells when needed.

    This clever control mechanism of the stem cell cycle – awakening the cells by enhancing their metabolism – ensures that the cells have sufficient energy for growing and maturing. “Like travelers waking up in the morning and stocking up on essential provisions before undertaking a long journey, sleepy stem cells need the energy to survive their new journey after they awaken,” says Gross. “We found that turning on mitochondria metabolism supplies the cells with precisely such energy.” Taking part in the study were Dr. Smadar Levin Zaidman of Chemical Research Support, Dr. Ziv Porat of the Biological Services Unit, and Prof. Tsvee Lapidot and Dr. Karin Golan of the Immunology Department.

    3
    A three-dimensional reconstruction of the mitochondrial volume: The volume is larger (yellow and red) in blood-forming stem cells lacking MTCH2 (right), and relatively smaller (blue and green) in regular blood-forming stem cells

    In addition to shedding new light on the basic biology of the stem cell cycle, the Weizmann Institute study may lead to new ways of controlling the activity of stem cells in research as well as in the clinic. The findings suggest that it may be possible to awaken stem cells by altering their metabolism, rather than by manipulating their genes, as is done today. In addition, the findings open up a new avenue of research into leukemia. They suggest that defects in the control of cellular metabolism in blood-forming stem cells at various stages of their maturation may lead to the abnormal cellular proliferation observed in leukemia. If this is indeed found to be the case, it may be possible to treat leukemia by correcting the cells’ metabolic defects.

    Prof. Atan Gross’s research is supported by the Yeda-Sela Center for Basic Research; the Adelis Foundation; the Lubin-Schupf Fund for Women in Science; the Pearl Welinsky Merlo Foundation Scientific Progress Research Fund; the Louis and Fannie Tolz Collaborative Research Project; the Hymen T. Milgrom Trust donation fund; the Rising Tide Foundation; Lord David Alliance, CBE; the estate of Tony Bieber; and the estate of John Hunter. Prof Gross is the incumbent of the Marketa and Frederick Alexander Professorial Chair.

    See the full article here .

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    Weizmann Institute Campus

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

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

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

     
  • richardmitnick 6:46 am on October 15, 2015 Permalink | Reply
    Tags: , Biology, Circadian clocks,   

    From Weizmann: “Natural Metabolite Might Reset Aging Biological Clocks” 

    Weizmann Institute of Science logo

    Weizmann Institute of Science

    12 Oct 2015
    No Writer Credit

    1

    Weizmann Institute researchers show that our daily rhythms are governed by a substance that declines with age

    As we age, our biological clocks tend to wind down. A Weizmann Institute research team has now revealed an intriguing new link between a group of metabolites whose levels drop as our cells age and the functioning of our circadian clocks – mechanisms encoded in our genes that keep time to cycles of day and night. Their results, which appeared in Cell Metabolism, suggest that the substance, which is found in many foods, could possibly help keep our internal timekeepers up to speed.

    Dr. Gad Asher’s lab in the Weizmann Institute’s Biological Chemistry Department investigates circadian clocks, trying to understand how these natural timekeepers help regulate, and are affected by, everything from nutrition to metabolism. In the present study, he and his research student Ziv Zwighaft were following clues that certain metabolites called polyamines could be tied to the functioning of circadian clocks. We get polyamines from food, but our cells manufacture them as well. These substances are known to regulate a number of essential processes in the cell, including growth and proliferation. And the levels of polyamines have been found to naturally drop as we age.

    Working with mice and cultured cells, they found that, indeed, enzymes that are needed to manufacture polyamines undergo cycles that are tied to both feeding and circadian rhythms of day and night. In mice engineered to lack a functional circadian clock, these fluctuations did not occur.

    As the researchers continued to investigate, they discovered a sort of feedback loop, so that polyamine production is not only regulated by circadian clocks, these substances also regulate the ticking of those clocks, in turn. In cell cultures, adding high levels of polyamines more or less obliterated the circadian rhythm while maintaining low levels slowed the clock by around two hours. “The polyamines are actually an embedded part of the circadian clockwork,” says Asher.

    The scientists then asked how this plays out in younger and older mice, with naturally higher or lower polyamine levels. It is known that the circadian clocks of elderly mice and run slower; concomitantly, their polyamine levels decline. The team found they could slow down the clocks in the young mice by administering a drug to inhibit polyamine synthesis. In contrast, adding a polyamine to the older mice’s drinking water made their clocks run faster than others of their age group and actually restored their function, similar to that of the young mice.

    Asher and his team intend to continue investigating the function of polyamines in circadian systems. “This discovery demonstrates the tight intertwining between circadian clocks and metabolism,” says Zwighaft. “Our findings today rely on experiments with mice, but we think they might hold true in humans. If so, they will have broad clinical implications,” Asher says. “The ability to repair the clock simply, through nutritional intervention with polyamine supplementation, is exciting and obviously of great clinical potential.”

    See the full article here .

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    Weizmann Institute Campus

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

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

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

     
  • richardmitnick 10:33 am on October 11, 2015 Permalink | Reply
    Tags: , Biology, ,   

    From Weizmann: “Getting to the Center” 

    Weizmann Institute of Science logo

    Weizmann Institute of Science

    14-06-2015
    No Writer Credit

    1
    The nucleus (red) in the cell center is surrounded by the disorganized actin network in the cytoplasm, on which the myosin-v motors move the vesicles around in the “active random motion” No image credit.

    Before an egg – whether mouse or human – can be fertilized, it must get its “internal affairs” in order. That includes moving its nucleus into position in the exact center of the cell. Under a microscope, the nucleus appears to do a little dance, jigging its way from the edge of the cell to the middle. What is really going on?

    “This is a question that physics can answer,” says Prof. Nir Gov of the Weizmann Institute’s Chemical Physics Department. “We examine the physics of the biological molecules in the cell to see whether the means of motion that are proposed are mechanically possible.” Gov, a theoretical physicist, worked with physicists and biologists led by Prof. Marie-Helen Verlhac at the College de France in Paris, observing what happens to the nuclei in mouse egg cells.

    The nucleus dance, they found, is the result of bumping: Tiny motorized sacs called vesicles continually collide with the nucleus. These vesicles run on tracks – the long, thin actin filaments that provide the cell with support – and they are transported by molecular motors made of a kind of myosin – a relative of the myosin that makes our muscles contract. (“The vesicles with their myosin motors underneath look like little people running on a track,” says Gov.)

    But the actin fibers form a disorganized network in the cell’s cytoplasm, and the movement of the vesicles is random as well. How does this random motion turn into the directed movement of the nucleus? This is where the physics came in. The mechanism that indeed explains the movement turned out to be subtle but effective.

    2
    Prof. Nir Gov

    The researchers found that the motors carrying the vesicles move more vigorously at the cell’s outer edges and more slowly in its center. Since there is about the same number of vesicles everywhere, this means that the bumping is more intense from one side. As the nucleus moves in toward the center, however, the force of the vesicles striking it gradually drops until it reaches the point at which the pressure is equally low all around. The physical model for this motion also reveals that the myosin motors stir up the cytoplasm, making it more fluid so that the nucleus can slide through it more easily.

    Further investigations showed that, unlike the active motion of the vesicles, “random thermal motion” – the heat-induced movement that makes molecules “jumpy” – cannot give rise to this type of movement, and would not be able to direct the nucleus to the center of the cell.

    How does the differential velocity of the tiny motors arise in the cell? This open question is under further study. “This is the first time that we have seen such ‘active random motion’ perform work in biological systems,” says Gov. “Since almost all cells contain actin transport systems, we think it could play a role in other types of intracellular movements. As well as solving a biological puzzle, we have learned something new about basic physics by researching movement in cells,” he adds.

    See the full article here .

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    Weizmann Institute Campus

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

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

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

     
  • richardmitnick 4:00 pm on September 19, 2015 Permalink | Reply
    Tags: , Biology, Optics and Biology,   

    From NSF: “Year of Light: The brilliance of mixing physics with biology” 

    nsf
    National Science Foundation

    September 18, 2015
    No Writer Credit

    1
    Photo credit: Matthew Comstock

    If you thought fluorescence was just meant for eye-shocking crayons, paints, t-shirts and shoelaces, think again. When physics and biology come together to better understand molecules like DNA, using a mixture of techniques known as fluorescence microscopy and optical traps allows researchers to see and learn so much more.

    A good deal of biological research today now intertwines physics to better comprehend molecules and their dynamic processes. In modern medicine, for example, this approach enables us to better recognize molecular interactions in living systems, such as the actual mechanisms of cellular components and how they move and interact within a cell or on an even smaller level, parsing how parts – of DNA or other molecules so small they refer to them in piconewtons – ambulate in sickness and health, thereby strengthening our ability to combat critical diseases in the long-term, and simultaneously improving our economy, especially in the field of commercial pharmaceuticals.

    To advance research in this field, two physics professors, Taekjip Ha and Yann Chemla at the University of Illinois at Urbana-Champaign and the NSF-funded Center for Physics of Living Cells, have coupled two unique biophysical techniques – optical traps and fluorescence microscopy – to examine the binding processes that underlie DNA strands. Optical traps, which are also referred to as optical tweezers, use a highly focused laser beam to provide an attractive or repulsive force to physically hold and move microscopic objects that are susceptible to this kind of control. The fluorescence microscope is based on the phenomenon that certain materials emit energy detectable as visible light when irradiated with the light of a specific wavelength. The material can be naturally fluorescent or be treated to make it so. The light then in this kind of microscope “excites” the material, allowing researchers to view molecules, for example, in an active state and observe mechanisms they wouldn’t in a static environment.

    Together, this combined technique paves the foundation for others to clearly visualize protein motion and conformational changes, thereby greatly enhancing our ability to measure how molecules interact with one another. The image displayed above offers a small visual sample of the advanced capabilities their new technique offers the field. DNA (blue double helix) is stretched out between two beads (gray spheres) held by optical traps (red cones) with a bound protein glowing with fluorescence excited by a “confocal” laser (green cones).

    See the full article here .

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    The National Science Foundation (NSF) is an independent federal agency created by Congress in 1950 “to promote the progress of science; to advance the national health, prosperity, and welfare; to secure the national defense…we are the funding source for approximately 24 percent of all federally supported basic research conducted by America’s colleges and universities. In many fields such as mathematics, computer science and the social sciences, NSF is the major source of federal backing.

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  • richardmitnick 12:13 pm on August 23, 2015 Permalink | Reply
    Tags: , Biology, ,   

    From Scripps: “Hands-On Research 101: Internships Introduce Undergrads to Biomedical Science in Action” 

    Scripps

    Scripps Research Institute

    August 24, 2015
    Madeline McCurry-Schmidt

    1
    SURF Intern Joshua David says the internship at TSRI gave him new opportunities to learn about biomedicine. (Photo by Cindy Bruaer.)

    When Joshua David saw scientists from The Scripps Research Institute (TSRI) discussing Ebola virus research on the news last year, he wanted to help.

    “I discovered that Scripps is one of the top places looking at Ebola virus at the molecular level,” said David, an undergraduate chemistry major at Virginia Commonwealth University. “The scientists at Scripps are trying to help people who are suffering and dying right now.”

    David quickly got in touch with Ebola researchers at TSRI and learned about the institute’s Summer Undergraduate Research Fellows (SURF) Program, organized by the TSRI Office of Graduate Studies. The SURF Program is a 10-week internship program at TSRI that has brought 38 undergraduates to TSRI’s California and Florida campuses this year. It’s one of several outreach programs, including a summer high school internship program where another 30 students work side-by-side with researchers.

    As a SURF intern, David flew into San Diego in June and spent his summer in Associate Professor Andrew Ward’s lab.

    Learning New Techniques

    David said the internship gave him new opportunities to learn about biomedicine.

    “I’m very interested in structural biology and virology; however, these courses are not offered at my university,” David explained. “Coming here is a great opportunity because it allows me learn techniques used in these fields and gain general knowledge of each field in the process.”

    Under the guidance of C. Daniel Murin, a graduate student in the Ward lab, David learned how to build 3-D structures of proteins involved in Ebola virus attacks. The SURF program emphasizes hands-on research, so David learned to use a technique called electron microscopy (EM) to study exactly how Ebola virus interacts with antibodies.

    “I wanted to take him through that process, so he can go through it almost independently by the end of the summer,” said Murin.

    David worked with Murin on several projects, including studies involving the experimental Ebola virus treatment ZMapp, which has also been the topic of previous studies at TSRI.

    David said one challenge this summer was tackling how to use a molecular imaging program necessary for research with EM.

    “Then I just had to sit down and figure it out,” he said. “It took me about eight hours, but now I understand how to do it.”

    Helping Patients

    David hopes to bring together research and patient care in a future career as a physician-scientist. As a high school student, David interned in a hospital’s intensive care unit. He watched as patients succumbed to diseases like acute respiratory distress syndrome (ARDS)—where doctors have few treatments to offer.

    A technique like EM could give David and other scientists a better look at the proteins involved in disease—from Ebola to ARDS—and lead to new treatments.

    “You can understand how things work in cells at the atomic level, and that really interests me,” said David.

    Before David headed back to Virginia at the end of the summer, he presented a poster outlining his work to peers and supervisors at TSRI. It was chance to show what he’s learned—and why he wants to be part of the next generation of scientists.

    About the Summer Undergraduate Research Fellows (SURF) Program

    TSRI’s 10-week SURF program provides participants the opportunity to perform cutting-edge research in one of 250 laboratories side-by-side with TSRI’s world-renowned faculty. The goals of the program are to:

    Make program participants feel comfortable in a lab setting and increase their research skills
    Teach participants to think critically about the theory and application of biomedical research
    Increase the participants’ proficiency in communicating scientific concepts
    Increase the number of underrepresented and first-generation to college students who consider careers in biomedical research.

    Students can choose to apply to either the La Jolla campus in California or the Jupiter campus in Florida. Learn more at TSRI’s Education website.

    See the full article here.

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

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

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

     
  • richardmitnick 10:49 pm on August 12, 2015 Permalink | Reply
    Tags: , Biology, , Flippases, Lipids   

    From ETH: “How lipids are flipped” 

    ETH Zurich bloc

    ETH Zurich

    12.08.2015
    Peter Rüegg

    1
    Comparison of cavities (green) in inward-facing (left) and outward-occluded (right) states of PglK, with native LLO (middle) shown as space-filling model for size reference. (Illustration: from Perez et al, 2015)

    A team of researchers at ETH Zurich and the University of Bern has succeeded in determining the structure of a lipid flippase at high resolution, which has provided insight into how this membrane protein transports lipids by flipping.

    Biological membranes have a fundamental role in separating the interior of cells from the extracellular space and in helping determine cellular shape and size. They consist of a double layer (“bilayer”) of lipids that contain a hydrophilic head group and generally two long, hydrophobic tails. Whereas the head groups face outwards, the hydrophobic tail face each other. Numerous other components are embedded in membranes, including pore-forming proteins and transport proteins.

    Countless vital processes occur at membranes, including the transport of various substances. The transport of phospholipids and lipid-linked oligosaccharides (LLO) is particularly difficult to achieve due to the bipolar nature of the lipid bilayer – hydrophobic interior, hydrophilic surface. This is why flippases are required to transport lipids from one side of the membrane to the other, essentially flipping their orientation. Flippases have important roles in maintaining the asymmetry of cellular membranes, i.e. in the different lipid composition of the outer and inner sides. In mammals, this affects various processes such as blood coagulation, immune recognition and programmed cell death, or apoptosis. Flippases are also essential for transporting lipid-linked oligosaccharides (“LLOs”), which are transferred onto acceptor proteins during N-linked protein glycosylation.

    Flippase structure revealed for the first time

    Until now biologists knew neither the high-resolution structures of flippases nor the exact mechanism used to flip LLOs. Three research teams from ETH Zurich and the University of Bern, led by ETH professor Kaspar Locher, have now determined the structure of one such flippase, the PglK protein from the bacterium Campylobacter jejuni. The study has been published in the journal Nature.

    This required the researchers to purify the flippase from bacterial membranes and generate three-dimensional crystals, which were then analysed using X-ray crystallography to determine the positions of all atoms. The scientists determined three distinct structures that corresponded to different states of the flippase during the reaction. Their data allowed the researchers to deduce a molecular mechanism of how PglK flips LLOs.

    The researchers show that PglK consists of two identical subunits that move like a pair of scissors when energy (ATP) is consumed. Similar to a credit card reader, the oligosaccharide moiety of the lipid-linked oligosaccharide is then pulled into a hydrophilic channel within the flippase. The hydrophobic, lipidic tail of the LLO molecule remains exposed to the lipidic membrane, causing the LLO to change its orientation so that the sugar part ends up on the outside of the membrane. The flippase itself does not change its orientation during translocation reaction and therefore acts as a catalyst.

    Fundamentally different mechanism

    The newly-discovered mechanism fundamentally differs from previously known transport processes that catalyze import or export of soluble substrates. “The flipping of lipids in membranes has always fascinated biochemists and cell biologists; the biological solution to this problem thrills us!” says co-author Markus Aebi, Professor of Microbiology at ETH Zurich.

    The research groups from ETH Zurich and the University of Bern are the first to have solved the fundamental biological puzzle of how LLOs are flipped. They developed a novel method for studying the reaction in vitro. ETH Professor Aebi insists that only through the cooperation of structural biologists, chemists and microbiologists was it possible to decipher this basic mechanism. “Every group brought their own expertise from their respective fields. This was the only way we could succeed.”

    Therapeutic applications?

    Although the present work constitutes basic research, there are diseases associated with mutations in a human flippase, explains Aebi. These diseases are termed ‘congenital disorders of glycosylation’. More than 10,000 glycosylation sites in various proteins have been identified in humans, “which is why changes in glycosylation in which flippase plays a crucial role affect so many processes in the body,” says the ETH professor. Examples of this include the development and maturation of the central nervous system.

    Whether the newly acquired knowledge of the bacterial flippase PglK leads to novel therapeutic approaches is unclear at present. However, flippases already form an essential part of biotechnological systems that are used to generate glycoproteins desigend for various uses in diagnostics and potential therapeutic agents.

    2
    LLO synthesis and N-glycosylation in Campylobacter jejuni at a glance: The LLO’s lipidic tail is shown in purple. A polypeptide chain is shown in blue. PglH (red) is the glycosyltransferace that couples the oligosaccharide to the polypeptide chain.

    References

    Perez C, Gerber S, Boilevin J, Bucher M, Darbre T, Aebi M, Reymond J-L, Locher KP. Molecular view of lipid-linked oligosaccharide translocation across biological membranes. Nature, Advanced online publication, 12th August 2015. DOI: 10.1038/nature14953

    See the full article here.

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    ETH Zurich campus
    ETH Zurich is one of the leading international universities for technology and the natural sciences. It is well known for its excellent education, ground-breaking fundamental research and for implementing its results directly into practice.

    Founded in 1855, ETH Zurich today has more than 18,500 students from over 110 countries, including 4,000 doctoral students. To researchers, it offers an inspiring working environment, to students, a comprehensive education.

    Twenty-one Nobel Laureates have studied, taught or conducted research at ETH Zurich, underlining the excellent reputation of the university.

     
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