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  • richardmitnick 8:46 am on January 21, 2017 Permalink | Reply
    Tags: , , , Pancreatic tumors rely on signals from surrounding cells, Salk Institute   

    From SALK: “Pancreatic tumors rely on signals from surrounding cells” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    January 19, 2017

    Salk scientists find that targeting the interaction between a pancreatic tumor and its microenvironment could weaken cancer.

    1
    Tumor cells stained with a marker for cancer (green) appear near stromal cells (red). Credit: Salk Institute.

    Just as an invasive weed might need nutrient-rich soil and water to grow, many cancers rely on the right surroundings in the body to thrive. A tumor’s microenvironment—the nearby tissues, immune cells, blood vessels and extracellular matrix—has long been known to play a role in the tumor’s growth.

    Now, Salk scientists have pinned down how signals from this microenvironment encourage pancreatic tumors to grow by altering their metabolism. Blocking the pathways involved, they reported in Proceedings of the National Academy of Sciences the week of January 16, 2017, can slow the growth of a pancreatic cancer.

    “Pancreatic cancer is a deadly disease and is very understudied when it comes to how it communicates with the microenvironment,” says senior author Ronald Evans, director of Salk’s Gene Expression Laboratory, a Howard Hughes Medical Institute investigator and holder of the March of Dimes Chair in Molecular and Developmental Biology. “Our findings open up a lot of avenues for future study.”

    Pancreatic cancer has the worst five-year survival rate of any major cancer and is expected to be the second leading cause of cancer deaths by the year 2030. It’s notoriously resistant to both chemotherapies and emerging immunotherapies, Evans says, emphasizing the importance of new treatment paradigms.

    2
    A marker for cancer (green) appears near stomal cells (red) in tumor cells. Credit: Salk Institute.

    Previous research has shown that the signals coming from surrounding stromal cells include both supportive signals—which help pancreatic tumors grow—and suppressive signals—which try to fight the cancer. To understand specifically how pancreatic cancer cells take advantage of any supportive signals, Evans’s team first had to come up with a method to mimic how pancreatic cancer cells grow so closely integrated with the stroma.

    “We worked out a culture system so that we could grow human pancreatic cells in a three-dimensional system in both the presence and absense of stromal signals,” says first author Mara Sherman, a former Salk postdoctoral research fellow now at Oregon Health & Science University.

    When stromal signaling molecules—isolated from patients or generated in the lab—were present, the metabolism of pancreatic cancer cells changed, the researchers found. Not only were levels of metabolic compounds different, but the expression of certain genes involved in metabolism was turned up, and the epigenome of the cells—molecular markers on DNA that change gene expression on a broader scale—was altered.

    “The tumor is essentially hacking into that stromal microenvironment and grabbing what it needs to up its metabolism,” says Michael Downes, a Salk senior scientist involved in the research.

    3
    From left: Ronald Evans, Mara Sherman, Ruth Yu, Ann Atkins, Tiffany Tseng and Michael Downes. Credit: Salk Institute.

    To try to block this “hacking” of the microenvironment by the cancer cells, the team turned to a drug called JQ1, which is known to block the epigenome changes that they’d observed. Indeed, when JQ1 was added to the 3D culture system, it reversed the genetic changes to the pancreatic cancer cells that the stromal signals had caused. Moreover, when mice with pancreatic tumors were treated with JQ1, tumor growth was slowed.

    More work is needed to reveal whether JQ1, or similar compounds, can shrink or slow the growth of pancreatic tumors in humans and what other pathways in the cancer cells may be responding to the tumor microenvironment, but the findings pave the way for that research.

    Other researchers on the study were Ruth T. Yu, Tiffany W. Tseng, Sihao Liu, Morgan Truitt, Nanhai He, Ning Ding, Annette Atkins, and Mathias Leblanc of the Salk Institute; Cristovao Sousa of Harvard Medical School; Christopher Liddle of the University of Sydney; Eric Collisson of the University of California, San Francisco; John Asara of Beth Israel Deaconess Medical Center; and Alec Kimmelman of the Dana-Farmer Cancer Institute.

    The work and the researchers involved were supported by grants from the National Institutes of Health, the Glenn Foundation for Medical Research, the Leona M. and Harry B. Helmsley Charitable Trust, and Ipsen/Biomeasure.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    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 8:59 pm on September 12, 2016 Permalink | Reply
    Tags: , , Salk Institute   

    From Salk: “The brain’s stunning genomic diversity revealed” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    September 9, 2016
    No writer credit found

    Multi-institutional collaboration led by the Salk Institute shows that half of our healthy neurons contain huge insertions or deletions in DNA

    1
    Using postmortem human brains and human embryonic stem cell models of brain development, Salk Institute researchers discover a new mechanism to generate DNA variation in human neurons. Here, human embryonic cell- derived neurons stained for a neurons specific marker (Tuj1, green, DNA show in red) show remarkable diversity. No image credit.

    Our brains contain a surprising diversity of DNA. Even though we are taught that every cell in our body has the same DNA, in fact most cells in the brain have changes to their DNA that make each neuron a little different.

    Now researchers at the Salk Institute and their collaborators have shown that one source of this variation—called long interspersed nuclear elements or L1s—are present in 44 to 63 percent of healthy neurons and can not only insert DNA but also remove it. Previously, these L1s were known to be small bits of DNA called “jumping genes” that copy and paste themselves throughout the genome, but the researchers found that they also cause large deletions of entire genes. What’s more, such variations can influence the expression of genes that are crucial for the developing brain.

    The findings, published September 12, 2016 in the journal Nature Neuroscience, may help explain what makes us each unique—why even identical twins can be so different from one other, for example—and how jumping genes can go awry and cause disease.

    “In 2013, we discovered that different neurons within the same brain have various complements of DNA, suggesting that they function slightly differently from each other even within the same person,” says the study’s senior investigator Rusty Gage, a professor in Salk’s Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases. “This recent study reveals a new and surprising form of variation that will help us understand the role of L1s, not only in healthy brains but in those affected by schizophrenia and autism.”

    In 2005, Gage’s team discovered L1s as a mechanism of genome diversity in the brain. However, it was not until it became possible to sequence the entire genome of a single cell that scientists could get a handle on the amount and nature of these variations. Using single-cell sequencing detailed in a 2013 Science paper, Gage’s group showed that large chunks of DNA were inserted—or deleted—into the genomes of the cells.

    2
    The “jumping gene” L1 cuts DNA in human cells to generate neuronal genomic diversity. Cells expressing L1 (genomic DNA shown in red) have high levels of DNA breaks as visualized by 53BP1 staining (green) which repairs broken DNA. Credit: Salk Institute

    But even in that study the mechanisms responsible for causing insertions and deletions were unclear, making it difficult to decipher whether specific regions of the genome were more or less likely to be altered, as well as whether jumping genes were related to the deletions.

    In the new study, Gage, co-first authors Jennifer Erwin and Apuã Paquola, and collaborators developed a method to better capture the L1-associated variants in healthy neurons for sequencing and created a computational algorithm to distinguish the variations with greater accuracy than before.

    Using stem cells that are coaxed to differentiate into neurons in a dish, the team found that L1s are prone to DNA breaks. That’s because a specific enzyme that chews through L1 spots in the genome is particularly active during differentiation. People inherit some L1s from their parents, and the enzyme appears to cut near these spots, the group found.

    “The surprising part was that we thought all L1s could do was insert into new places. But the fact that they’re causing deletions means that they’re affecting the genome in a more significant way,” says Erwin, a staff scientist in Gage’s group.

    Gage believes that diversity can be good for the brain—after all, about half of our brain cells have large chunks of missing or inserted DNA caused by L1s alone—but that too much of it can cause disease.

    Recent evidence has shown that neurons derived from individuals with schizophrenia or the rare autism-associated disorder Rett syndrome harbor more than normal amounts of L1 variations in their genomes. In the new study, the team examined a schizophrenia-associated gene called DLG2, in which introducing L1 variations can change the gene’s expression and subsequent maturation of neurons. The group plans to explore the role of L1 variations in other genes and their effects on brain activity and disease.

    Other authors on the study are Tatjana Singer, Iryna Gallina, Carolina Quayle, Tracy Bedrosian, Cheyenne Butcher, Joseph Herdy and Anindita Sarkar of Salk; Mark Novotny and Roger Lasken of the J. Craig Venter Institute; Francisco Alves of the University of São Paulo in Brazil; and Alysson Muotri of the University of California, San Diego.

    The research was supported by George E. Hewitt Foundation for Medical Research, the California Institute for Regenerative Medicine, the National Institutes of Health (MH095741, MH088485), the G. Harold & Leila Y. Mathers Foundation, the Engman Foundation, the Leona M. and Harry B. Helmsley Charitable Trust, the Paul G. Allen Family Foundation, the Glenn Center for Aging Research at the Salk Institute, and JPB Foundation.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    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 1:42 pm on August 31, 2016 Permalink | Reply
    Tags: , , , Salk Institute, Unravel bipolar disorder and schizophrenia   

    From Salk: “Johns Hopkins and Salk co-lead $15 million initiative to unravel bipolar disorder and schizophrenia” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    August 31, 2016
    No writer credit found

    Partnership of government, academics and industry will develop new ways of studying and screening drugs for major psychiatric illnesses.

    The Johns Hopkins University School of Medicine and the Salk Institute for Biological Studies will co-lead a $15.4 million effort to develop new systems for quickly screening libraries of drugs for potential effectiveness against schizophrenia and bipolar disorder, the National Institute of Mental Health (NIMH) has announced. The consortium, which includes four academic or nonprofit institutions and two industry partners, will be led by Hongjun Song, PhD, of Johns Hopkins and Rusty Gage, PhD, of Salk.

    Bipolar disorder affects more than 5 million Americans, and treatments often help only the depressive swings or the opposing manic swings, not both. And though schizophrenia is a devastating disease that affects about 3 million Americans and many more worldwide, scientists still know very little about its underlying causes—which cells in the brain are affected and how—and existing treatments target symptoms only.

    With the recent advance of induced pluripotent stem cell (iPSC) technology, researchers are able to use donated cells, such as skin cells, from a patient and convert them into any other cell type, such as neurons. Generating human neurons in a dish that are genetically similar to patients offers researchers a potent tool for studying these diseases and developing much-needed new therapies.

    A major aim of this collaboration is to improve the quality of iPSC technology, which has been limited in the past by a lack of standards in the field and inconsistent practices among different laboratories. “There has been a bottleneck in stem cell research,” says Song, a professor of neurology and neuroscience at Johns Hopkins. “Every lab uses different protocols and cells from different patients, so it’s really hard to compare results. This collaboration gathers the resources needed to create robust, reproducible tests that can be used to develop new drugs for mental health disorders.”

    “IPSCs are a powerful platform for studying the underlying mechanisms of disease,” says Gage, a professor of genetics at Salk. “Collaborations that bring together academic and industry partners, such as this one enabled by NIMH, will greatly facilitate the improvement of iPSC approaches for high-throughput diagnostic and drug discovery.”

    The teams will use iPSCs generated from more than 50 patients with schizophrenia or bipolar disorder so that a wide range of genetic differences is taken into account. By coaxing iPSCs to become four different types of brain cells, the teams will be able to see which types are most affected by specific genetic differences and when those effects may occur during development.

    First the researchers must figure out, at the cellular level, what features characterize a given illness in a given brain cell type. To do that, they will assess the cells’ shapes, connections, energy use, division and other properties. They will then develop a way of measuring those characteristics that works on a large scale, such as recording the activity of cells under hundreds of different conditions simultaneously.

    Once a reliable, scalable and reproducible test system has been developed, the industry partners will have the opportunity to use it to identify or develop drugs that might combat mental illness. “This exciting new research has great potential to expedite drug discovery by using human cells from individuals who suffer from these devastating illnesses. Starting with a deeper understanding of each disorder should enable the biopharmaceutical industry to design drug discovery strategies that are focused on molecular pathology,” says Husseini K. Manji, M.D., F.R.C.P.C., global therapeutic area head of neuroscience for Janssen Research & Development.

    The researchers also expect to develop a large body of data that will shed light on the molecular and genetic differences between bipolar disorder and schizophrenia. And, since other mental health disorders share some of the genetic variations found in schizophrenia and bipolar disorder, the data will likely inform the study of many illnesses.

    The National Cooperative Reprogrammed Cell Research Groups program, which is funding the research, was introduced by the National Institute of Mental Health in 2013 to overcome barriers to collaboration by creating precompetitive agreements that harness the unique strengths of academic and industry research. The federal-academic-industry collaboration will bring together leading experts in the fields of stem cells and neuropsychiatric disorders:

    Academic Partners:

    Hongjun Song, Professor, the Johns Hopkins University School of Medicine
    Rusty Gage, Professor, Laboratory of Genetics at the Salk Institute
    Sue O’Shea, Director, Michigan Pluripotent Stem Cell Core and Professor, University of Michigan
    Anne Bang, Director, Conrad Prebys Center for Chemical Genomics at the Sanford Burnham Prebys Medical Discovery Institute

    Industry Partners:

    Guang Chen, Janssen fellow, Scientific Director of Neuroscience, Janssen Research & Development
    Jeffrey S. Nye, Vice President, Neuroscience Innovation and Partnership Strategy, Janssen Research & Development, J&J Innovation
    Husseini K. Manji, Global Therapeutic Area Head of Neuroscience, Janssen Research & Development
    Paul Doran, Strategic Alliance Manager, Cellular Dynamics International

    Funding Announcement: http://grants.nih.gov/grants/guide/pa-files/PAR-13-225.html
    Supported by NIMH Cooperative Agreement Number U19MH106434

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    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 5:25 pm on August 25, 2016 Permalink | Reply
    Tags: , , Salk Institute   

    From Salk: “Salk scientists map brain’s action center” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    August 25, 2016
    No writer credit found

    New work dispels long-held notions about area involved in Parkinson’s and addiction

    1
    Salk Institute researchers employed novel genetic tools to map the connectivity of neurons within a part of the brain, called the striatum, that controls movement toward a goal or reward. The matrix neurons, highlighted in green, appear to avoid the patch neurons (in red), which are smaller clusters of neurons in the striatum. Credit: Salk Institute

    When you reach for that pan of brownies, a ball-shaped brain structure called the striatum is critical for controlling your movement toward the reward. A healthy striatum also helps you stop yourself when you’ve had enough.

    But when the striatum doesn’t function properly, it can lead to disorders such as Parkinson’s disease, obsessive-compulsive disorder or addiction.

    In fact, the exact functions of the striatum are by no means resolved, and it’s also a mystery how the structure can coordinate many diverse functions. Now, a new study published August 25, 2016 by Salk Institute researchers and their colleagues in the journal Neuron, delves into the anatomy and function of the striatum by employing cutting-edge strategies to comprehensively map one of the brain’s lesser-known forms of organization.

    “The most exciting result from this research is that we now have a new avenue to study long-standing questions about how the striatum controls movement in both healthy and diseased brains,” says the study’s senior investigator Xin Jin, an assistant professor in the Molecular Neurobiology Laboratory at Salk.

    Forty years ago, researchers discovered a unique way that the striatum is organized. It is dotted with patch neurons, which under the microscope look like tiny islands of cells. The ocean surrounding them is made up of neurons scientists collectively refer to as “matrix” cells.

    Over the course of four decades, scientists hypothesized about the role of patch and matrix neurons in neurodegenerative diseases. One idea was that patch cells were fed by the brain’s higher thought centers, suggesting they could play a role in cognition, whereas the matrix cells seemed to play a role in sensing and movement.

    2
    Using genetic engineering, cutting-edge neuronal tracing and electrophysiology, researchers decipher a lesser known form of organization in a deep, ball-shaped brain area that helps control movement toward a goal. In this artistic interpretation, patch neurons (red) sit as separate, small islands amid matrix neurons (green), but each cell type is well connected with the rest of the brain. Credit: Salk Institute

    In contrast, the new study dispels that idea, showing that both types of information are sent to the patch and matrix neurons, though patch cells tend to receive slightly more information from the brain’s emotion centers (these are included in the higher thought centers). But those results could help explain why, in the brains of patients with neurological disorders like Huntington’s disease (a progressive neurodegenerative disease affecting movement and other functions), patch cells and matrix cells are both affected, Jin says.

    “This is an elegant example demonstrating that we are in a new era of studying brain circuits in ever more refined detail,” said Daofen Chen, Ph.D., program director at the NIH’s National Institute of Neurological Disorders and Stroke. “As a result of emerging technologies and novel tools, we are gaining new insights into mechanisms of brain disorders.”

    Jin, together with the paper’s first authors Jared Smith, Jason Klug and Danica Ross, drew upon several technologies to uncover these new findings. The first was genetic engineering to selectively and precisely target the patch versus matrix neurons; traditionally, researchers used staining methods that were not as exact. Secondly, new neural tracing methods, including one generated by collaborator Edward Callaway and his group at Salk, allowed Jin’s team to chart the entire brain’s input to the patch and matrix cells and the output of each of the cell types as well. A third major approach, from the field of electrophysiology, enabled the scientists to confirm the connections they had mapped and to understand their strength.

    “Much of the previous work on patch and matrix cells inferred their functions based on connectivity with the rest of the brain, but most of those hypotheses were incorrect,” Smith says. “With a more precise map of the input and output of patch and matrix cells, we can now make more informed hypotheses.”

    Patch and matrix neurons are not the only way that neuroscientists understand the striatum. The striatum also contains cells that take two opposing routes—the direct and indirect pathways—that are thought to provide the gas and brakes on movement, so to speak. Those indirect and direct pathways are also crucial for certain behaviors, such as the formation of new habits.

    Interestingly, both patch and matrix groups contain both indirect and direct pathway cells. That makes the story of the striatum more complicated, Jin says, but in future studies his team can study the intersection of these two types of organization in the context of how the striatum controls actions in health and disease.

    Other authors on the study are Jason Klug, Danica Ross, Christopher Howard, Nick Hollon, Vivian Ko, Hilary Hoffman and Edward Callaway of the Salk Institute; and Charles Gerfen of the National Institute of Mental Health in Bethesda, Maryland.

    The research was supported by grants from the National Institutes of Health, the Dana Foundation, the Ellison Medical Foundation, and the Whitehall Foundation.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    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 1:38 pm on August 25, 2016 Permalink | Reply
    Tags: , , Neuregulin-1, Salk Institute   

    From Salk: “Elevating brain protein allays symptoms of Alzheimer’s and improves memory” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    August 25, 2016
    No writer credit found

    Salk Institute tests drug that could boost levels of critical protective protein in brain

    1
    In a mouse model of Alzheimer’s disease, Salk Institute researchers show that raising levels of neuregulin-1 (right) lowers a marker of disease pathology in a part of the brain that controls memory compared with controls (left). Credit: Salk Institute

    LA JOLLA—Boosting levels of a specific protein in the brain alleviates hallmark features of Alzheimer’s disease in a mouse model of the disorder, according to new research published online August 25, 2016 in Scientific Reports.

    The protein, called neuregulin-1, has many forms and functions across the brain and is already a potential target for brain disorders such as Parkinson’s disease, amyotrophic lateral sclerosis and schizophrenia.

    “Neuregulin-1 has broad therapeutic potential, but mechanistically, we are still learning about how it works,” says the study’s senior investigator Kuo-Fen Lee, a professor in the Salk Institute’s Clayton Foundation Laboratories for Peptide Biology and holder of the Helen McLoraine Chair in Molecular Neurobiology. “We’ve shown that it promotes metabolism of the brain plaques that are characteristic of Alzheimer’s disease.”

    Previously, researchers have shown that treating cells with neuregulin-1, for example, dampens levels of amyloid precursor protein, a molecule that generates amyloid beta, which aggregate and form plaques in the brains of Alzheimer’s patients. Other studies suggest that neuregulin-1 could protect neurons from damage caused by blockage of blood flow.

    In the new study, Lee’s team tested this idea in a mouse model of Alzheimer’s disease by raising the levels of one of two forms of neuregulin-1 in the hippocampus, an area of the brain responsible for learning and memory. Both forms of the protein seemed to improve performance on a test of spatial memory in the models.

    What’s more, the levels of cellular markers of disease—including the levels of amyloid beta and plaques—were noticeably lower in mice with more neuregulin-1 compared to controls.

    The group’s experiments suggest that neuregulin-1 breaks up plaques by raising levels of an enzyme called neprilysin, shown to degrade amyloid-beta. But that is probably not the only route through which neuregulin-1 confers its benefits, and the group is exploring other possible mechanisms—such as whether the protein improves signaling between neurons, which is impaired in Alzheimer’s—says the study’s first author Jiqing Xu, a research associate in Lee’s group

    A neuregulin-1 treatment is not available on the market, though it is being explored in clinical trials as a potential treatment for chronic heart failure and Parkinson’s disease. One advantage of neuregulin-1 as a potential drug is that it can cross the blood brain barrier, which means that it could be administered relatively noninvasively even though the efficiency is not clear. On the other hand, other research suggests too much of the protein impairs brain function. Working with chemists at Salk, Lee’s team has come up with a small molecule that can raise levels of existing neuregulin-1 (rather than administering it directly) and are testing it in cells. This alternative therapy could be a better way to prevent plaques from forming because small molecules more readily cross the blood brain barrier.

    The group is also interested in neuregulin-1 for its ties to schizophrenia. An alteration in the neuregulin-1 gene—a single change in one letter of the DNA code for the protein—has been found in families with schizophrenia and linked to late-onset Alzheimer’s disease with psychosis. The protein may be a way to understand the overlap between Alzheimer’s and other brain disorders, Lee says.

    An important caveat is that the new research was conducted in a single type of mouse model of Alzheimer’s. Lee’s group is testing neuregulin-1’s affects across other models. “There’s much more work ahead before neuregulin-1 could become a treatment, but we are excited about its potential, possibly in combination with other therapeutics for Alzheimer’s disease,” Lee says.

    Other authors on the study are Fred DeWinter, Catherine Farrokhi, Jonathan Cook and Xin Jin of Salk’s Clayton Foundation for Peptide Biology Laboratories; and Edward Rockenstein, Michael Mante, Anthony Adame and Eliezer Masliah of the University of California, San Diego.

    The research was supported by the National Institutes of Health, the Clayton Foundation, The Albert G. and Olive H. Schlink Foundation, the Gemcon Family Foundation and the Brown Foundation.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    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 2:49 pm on August 15, 2016 Permalink | Reply
    Tags: , Disregarded plant molecule actually a treasure, Phaseic acid, Salk Institute   

    From Salk: “Disregarded plant molecule actually a treasure” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    August 11, 2016

    The best natural chemists out there are not scientists—they’re plants. Plants have continued to evolve a rich palette of small natural chemicals and receptors since they began to inhabit land roughly 450 million years ago.

    Now, research by Salk Institute scientists published August 11, 2016 in the journal Cell reveals an unexpected role for a small, often overlooked molecule called phaseic acid, which has historically been cast as an inactive byproduct in plants—a metabolic dead end of sorts. The new findings suggest that phaseic acid and its receptors probably co-evolved to become crucial for drought resistance and other survival traits and may inform the development of new, hardier crops that can weather natural disasters wrought by climate change.

    1
    Seed plants evolved a dedicated enzyme to degrade phaseic acid and keep its level in check. A plant lacking this enzyme accumulates more phaseic acid, and is more resistant to long-term drought conditions (right) compared with a normal plant (left). Credit: Salk Institute

    “There had been some hints that phaseic acid was not just an inactive bystander but a plant hormone with an important role,” says the study’s senior investigator Joseph Noel, holder of the Arthur and Julie Woodrow Chair and professor in the Jack H. Skirball Center for Chemical Biology and Proteomics at Salk. “But now, by using an array of cutting-edge biological approaches, we’ve shown more convincingly, that phaseic acid is likely important for survival.”

    Phaseic acid has long lived in the shadows of its precursor—abscisic acid or ABA—which is a big deal in plant research. ABA is a plant hormone that’s present in all land plants and is key for responding to environmental stress and pathogens, in particular alerting the plant to drought conditions. ABA is also known for its connection to the good stuff in fruits and vegetables: carotenoids, such as beta-carotene and lycopene.

    Like all small natural molecules, ABA is produced through intricate metabolic pathways that transform simple carbon-based building blocks into structurally complex natural chemicals that collectively convey a substantial amount of information. Some plants are equipped with more than a handful of receptors for ABA, each of which carries out various functions in the plant. But paradoxically for its role as a master regulator, ABA itself seemed have equal preference for all its receptors, which would not be ideal for the fine-tuned control of plant function.

    In the new study, Noel’s team used a commonly studied plant called Arabidopsis thaliana and obtained varieties that lacked the enzyme that processes phaseic acid, in effect accumulating large amounts of phaseic acid.

    To the group’s surprise, the plants showed changes to the timing of seed germination and they survived without water for a longer time period. “This suggested to us that maybe we should be thinking of phaseic acid not as an inactive degradation product but actually as a molecule that had its own capacity to cause changes like other plant hormones,” says Noel.

    2
    The enzyme that degrades phaseic acid (blue) appears briefly in response to light during early seed germination. The picture on the left was taken one day after plant seeds were taken from a dark environment to light; the picture on the right was taken on the second day. Credit: Salk Institute

    The scientists carried out a series of studies pointing to phaseic acid’s role as a plant hormone, showing for example that the addition of phaseic acid to normal seedlings triggered changes to the expression of numerous specific genes, especially genes coding for metabolic enzymes, that were overlapping but also distinct from those activated by ABA.

    In addition, using a high-resolution imaging technique called x-ray crystallography, the group showed that phaseic acid bound to ABA’s receptors, solidifying evidence that ABA’s receptors can sense more than just ABA.

    The new study suggests more broadly that there could be more hidden complexity to how organisms make use of small chemicals to bring about a variety of different responses. Evolution may well have repurposed other so-called end products of metabolism, Noel says.

    The study’s first author, Jing-Ke Weng, formerly a postdoctoral researcher in Noel’s lab, has set up an independent research group within Massachusetts Institute of Technology’s Whitehead Institute for Biomedical Research and Department of Biology that will continue to explore plant chemicals with previously unappreciated roles. “We hope to discover and understand the complexity of the hormones’, their metabolites and their collective interplay with receptors in various plants,” says Weng.

    Noel’s team will study the role of the hormones in the roots of plants. There is evidence that the phaseic acid and ABA play a role in moving carbon from a plant’s leaves and stems into its roots to protect them during periods of drought, overwintering and during pathogen attacks in the soil, Noel says. “Understanding this area of plant biology offers new ways to think about how we might mitigate climate change.”

    This research was supported by the National Science Foundation, the Pioneer Foundation, the Pew Charitable Trusts, the Searle Scholars Program and the Howard Hughes Medical Institute.

    Other authors on the study are Mingli Ye of the Salk Institute and Bin Li of the University of California, San Diego School of Medicine.

    See the full article here .

    Please help promote STEM in your local schools.

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    Stem Education Coalition

    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 5:43 am on February 6, 2016 Permalink | Reply
    Tags: , , Salk Institute   

    From Salk: “Memory capacity of brain is 10 times more than previously thought” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    January 20, 2016
    No writer credit found
    Office of Communications
    Tel: (858) 453-4100
    press@salk.edu

    Data from the Salk Institute shows brain’s memory capacity is in the petabyte range, as much as entire Web

    Brain

    Salk researchers and collaborators have achieved critical insight into the size of neural connections, putting the memory capacity of the brain far higher than common estimates. The new work also answers a longstanding question as to how the brain is so energy efficient and could help engineers build computers that are incredibly powerful but also conserve energy.

    “This is a real bombshell in the field of neuroscience,” says Terry Sejnowski, Salk professor and co-senior author of the paper, which was published in eLife. “We discovered the key to unlocking the design principle for how hippocampal neurons function with low energy but high computation power. Our new measurements of the brain’s memory capacity increase conservative estimates by a factor of 10 to at least a petabyte, in the same ballpark as the World Wide Web.”

    Our memories and thoughts are the result of patterns of electrical and chemical activity in the brain. A key part of the activity happens when branches of neurons, much like electrical wire, interact at certain junctions, known as synapses. An output ‘wire’ (an axon) from one neuron connects to an input ‘wire’ (a dendrite) of a second neuron. Signals travel across the synapse as chemicals called neurotransmitters to tell the receiving neuron whether to convey an electrical signal to other neurons. Each neuron can have thousands of these synapses with thousands of other neurons.


    Download mp4 video here .

    “When we first reconstructed every dendrite, axon, glial process, and synapse from a volume of hippocampus the size of a single red blood cell, we were somewhat bewildered by the complexity and diversity amongst the synapses,” says Kristen Harris, co-senior author of the work and professor of neuroscience at the University of Texas, Austin. “While I had hoped to learn fundamental principles about how the brain is organized from these detailed reconstructions, I have been truly amazed at the precision obtained in the analyses of this report.”

    Synapses are still a mystery, though their dysfunction can cause a range of neurological diseases. Larger synapses—with more surface area and vesicles of neurotransmitters—are stronger, making them more likely to activate their surrounding neurons than medium or small synapses.

    The Salk team, while building a 3D reconstruction of rat hippocampus tissue (the memory center of the brain), noticed something unusual. In some cases, a single axon from one neuron formed two synapses reaching out to a single dendrite of a second neuron, signifying that the first neuron seemed to be sending a duplicate message to the receiving neuron.

    At first, the researchers didn’t think much of this duplicity, which occurs about 10 percent of the time in the hippocampus. But Tom Bartol, a Salk staff scientist, had an idea: if they could measure the difference between two very similar synapses such as these, they might glean insight into synaptic sizes, which so far had only been classified in the field as small, medium and large.

    To do this, researchers used advanced microscopy and computational algorithms they had developed to image rat brains and reconstruct the connectivity, shapes, volumes and surface area of the brain tissue down to a nanomolecular level.

    The scientists expected the synapses would be roughly similar in size, but were surprised to discover the synapses were nearly identical.

    “We were amazed to find that the difference in the sizes of the pairs of synapses were very small, on average, only about eight percent different in size. No one thought it would be such a small difference. This was a curveball from nature,” says Bartol.

    Because the memory capacity of neurons is dependent upon synapse size, this eight percent difference turned out to be a key number the team could then plug into their algorithmic models of the brain to measure how much information could potentially be stored in synaptic connections.

    It was known before that the range in sizes between the smallest and largest synapses was a factor of 60 and that most are small.

    But armed with the knowledge that synapses of all sizes could vary in increments as little as eight percent between sizes within a factor of 60, the team determined there could be about 26 categories of sizes of synapses, rather than just a few.

    “Our data suggests there are 10 times more discrete sizes of synapses than previously thought,” says Bartol. In computer terms, 26 sizes of synapses correspond to about 4.7 “bits” of information. Previously, it was thought that the brain was capable of just one to two bits for short and long memory storage in the hippocampus.

    “This is roughly an order of magnitude of precision more than anyone has ever imagined,” says Sejnowski.

    What makes this precision puzzling is that hippocampal synapses are notoriously unreliable. When a signal travels from one neuron to another, it typically activates that second neuron only 10 to 20 percent of the time.

    “We had often wondered how the remarkable precision of the brain can come out of such unreliable synapses,” says Bartol. One answer, it seems, is in the constant adjustment of synapses, averaging out their success and failure rates over time. The team used their new data and a statistical model to find out how many signals it would take a pair of synapses to get to that eight percent difference.

    The researchers calculated that for the smallest synapses, about 1,500 events cause a change in their size/ability (20 minutes) and for the largest synapses, only a couple hundred signaling events (1 to 2 minutes) cause a change.

    “This means that every 2 or 20 minutes, your synapses are going up or down to the next size. The synapses are adjusting themselves according to the signals they receive,” says Bartol.

    “Our prior work had hinted at the possibility that spines and axons that synapse together would be similar in size, but the reality of the precision is truly remarkable and lays the foundation for whole new ways to think about brains and computers,” says Harris. “The work resulting from this collaboration has opened a new chapter in the search for learning and memory mechanisms.” Harris adds that the findings suggest more questions to explore, for example, if similar rules apply for synapses in other regions of the brain and how those rules differ during development and as synapses change during the initial stages of learning.

    “The implications of what we found are far-reaching,” adds Sejnowski. “Hidden under the apparent chaos and messiness of the brain is an underlying precision to the size and shapes of synapses that was hidden from us.”

    The findings also offer a valuable explanation for the brain’s surprising efficiency. The waking adult brain generates only about 20 watts of continuous power—as much as a very dim light bulb. The Salk discovery could help computer scientists build ultraprecise, but energy-efficient, computers, particularly ones that employ “deep learning” and artificial neural nets—techniques capable of sophisticated learning and analysis, such as speech, object recognition and translation.

    “This trick of the brain absolutely points to a way to design better computers,” says Sejnowski. “Using probabilistic transmission turns out to be as accurate and require much less energy for both computers and brains.”

    Other authors on the paper were Cailey Bromer of the Salk Institute; Justin Kinney of the McGovern Institute for Brain Research; and Michael A. Chirillo and Jennifer N. Bourne of the University of Texas, Austin.

    The work was supported by the NIH and the Howard Hughes Medical Institute.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    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 3:59 pm on January 21, 2016 Permalink | Reply
    Tags: , , Salk Institute, Salk scientists discover how mitochondria recover after damage   

    From Salk: “How the cell’s power station survives attacks” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    January 14, 2016
    No writer credit found

    Salk scientists discover how mitochondria recover after damage, offering clues to cancer, diabetes and brain disease

    Mitochondria, the power generators in our cells, are essential for life. When they are under attack—from poisons, environmental stress or genetic mutations—cells wrench these power stations apart, strip out the damaged pieces and reassemble them into usable mitochondria.

    Now, scientists at the Salk Institute have uncovered an unexpected way in which cells trigger this critical response to threats, offering insight into disorders such as mitochondrial disease, cancer, diabetes and neurodegenerative disease—particularly Parkinson’s disease, which is linked to dysfunctional mitochondria. The work appears January 15, 2016 in Science.

    “Outside marauders come into these power stations of the cell—the mitochondria—and in response, the power stations break into smaller fragments,” says Reuben Shaw, senior author and Salk professor in the Molecular and Cell Biology Laboratory.

    In an average human cell, anywhere from 100 to 500 mitochondria churn out energy in the form of ATP molecules, which act like batteries to carry power to the rest of the cell. At any given time, one or two mitochondria fragment (fission) or reform (fusion) to cycle out any damaged parts. But when a poison—like cyanide or arsenic—or other dangers threaten the mitochondria, a mass fragmentation takes place.

    Researchers have known for years that mitochondria undergo this fragmentation when treated with drugs that affect the mitochondria, but the biochemical details of how the mitochondria damage is sensed and how that triggers the rapid fission response has not been clear until now.

    In the new work, the Salk team found that when cells are exposed to mitochondria damage, a central cellular fuel gauge, the enzyme AMPK, sends an emergency alert to mitochondria instructing them to break apart into many tiny mitochondrial fragments. Interestingly, AMPK is activated by the widely used diabetes therapeutic metformin, as well as exercise and a restricted diet. The new findings suggest that some of the benefits from these therapies may result from their effects in promoting mitochondrial health.

    Temp 1
    Scientists at the Salk Institute (from left: Reuben Shaw, Sebastien Herzig and Erin Toyama) have uncovered an unexpected way in which cells trigger a critical response to mitochondrial threats, offering insight into disorders such as mitochondrial disease, cancer, diabetes and neurodegenerative disease—particularly Parkinson’s disease, which is linked to dysfunctional mitochondria. Credit: Salk Institute

    Prior research by Shaw’s group and others had uncovered AMPK’s role in helping to recycle damaged mitochondrial pieces as well as signaling to the cell to make new mitochondria. But this new role of rapidly triggering mitochondrial fragmentation “really places AMPK at the heart of mitochondria health and long-term well-being,” says Shaw, who is also holder of the William R. Brody Chair.

    To uncover exactly what happens in those first few minutes, the team used the gene editing technique CRISPR to delete AMPK in cells and showed that, even when poison or other threats are introduced to the mitochondria, they do not fragment without AMPK. This indicates that AMPK somehow directly acts on mitochondria to induce fragmentation.

    The group then looked at a way to chemically turn on AMPK without sending attacks to mitochondria. To their surprise, they found that activating AMPK alone was enough to cause the mitochondria to fragment, even without the damage.

    “I could not believe how black and white the results were. Just turning on AMPK by itself gives you as much fragmentation as a mitochondrial poison,” says Shaw.

    The team discovered why this was: when the cell’s power stations are disrupted, the amount of energy floating around a cell—ATP—is lowered. After just a few minutes, AMPK detects this reduction of energy in the cell and hurries to the mitochondria. Like a guard pulling a fire alarm, AMPK activates a receptor on the outside membrane of a mitochondrion to signal it to fragment.

    Drilling down further, the researchers found that AMPK actually acts on two areas of a mitochondrial receptor, called mitochondrial fission factor (MFF), to start the process. MFF calls over a protein, Drp1, that binds and wraps around the mitochondrion like a beaded noose to twist and break it apart.


    Watch mp4 video here .

    “We discovered that the modification of MFF by AMPK is needed for MFF to call over more Drp1 to the mitochondria,” says Erin Quan Toyama, one of the first authors of the paper and a Salk research associate. “Without AMPK sending the alarm, MFF cannot call over to Drp1 and there is no new fragmentation of mitochondria after damage.”

    In the future, the team is interested in addressing what other consequences this signaling pathway has for specific cell types, according to Sébastien Herzig, the other first author of the paper and a Salk research associate. “We want to see what a defect in communication between the mitochondria and AMPK would do to different tissues, particularly ones very dependent on healthy mitochondria, such as brain, muscle and heart,” says Herzig.

    Temp 2
    Scientists at the Salk Institute demonstrated how a molecular sensor detects damage in mitochondria (green) and induces reorganization of the entire mitochondrial network (nuclei in blue). Normal mitochondria (left) undergo massive reorganization (right) after exposure to the toxin rotenone. Credit: Salk Institute

    Adds Toyama, “On one hand, AMPK is known to be important for type 2 diabetes, immune disease and cancer. On the other hand, mitochondrial dysfunction is becoming increasing connected to metabolic diseases and neurodegenerative diseases. We’re making some of the first steps in connecting these two things that have major disease implications.”

    Other authors of the work were Kristina Hellberg and Nathan P. Young of the Salk Institute; Julien Courchet, Tommy L. Lewis Jr. and Franck Polleux of Columbia University; and Oliver C. Losón, Hsiuchen Chen and David C. Chan of the California Institute of Technology.

    The work was funded in part by the Howard Hughes Medical Institute, NIH and The Leona M. and Harry B. Helmsley Charitable Trust.

    PUBLICATION INFORMATION

    JOURNAL

    Science

    TITLE

    AMP-activated Protein Kinase mediates mitochondrial fission in response to energy stress

    AUTHORS

    Erin Quan Toyama, Sébastien Herzig, Julien Courchet, Tommy L. Lewis Jr., Oliver C. Losón, Kristina Hellberg, Nathan P. Young, Hsiuchen Chen, Franck Polleux, David C. Chan, Reuben J. Shaw

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    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 5:42 pm on January 10, 2016 Permalink | Reply
    Tags: , , Glioblastoma multiforme studies, Salk Institute   

    From Salk: “Scientists find key driver for treatment of deadly brain cancer” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    January 8, 2016
    AUTHORS
    Dinorah Friedmann-Morvinski, Rajesh Narasimamurthy, Yifeng Xia, Chad Myskiw, Yasushi Soda, Inder M. Verma

    Temp 1
    Scientists at the Salk Institute have discovered how a protein helps glioblastoma proliferate so quickly and how to turn off this engine of tumor growth using a peptide called NBD. A tumor in an untreated mouse brain (left) grew much more than a tumor treated with the NBD peptide (right). Image: Courtesy of the Salk Institute for Biological Studies

    Glioblastoma multiforme is a particularly deadly cancer. A person diagnosed with this type of brain tumor typically survives 15 months, if given the best care. The late Senator Ted Kennedy succumbed to this disease in just over a year.

    But scientists at the Salk Institute have discovered a key to how these tumor cells proliferate so quickly —and ways to turn this engine of tumor growth into a target for cancer treatment.

    “This is a disease for which there has been practically no improvement in treatment outcome for years,” said Inder Verma, professor in the Salk Institute’s Laboratory of Genetics and senior author of the paper published January 8, 2016 in the journal Science Advances. “It is clear that even if a surgeon removes 99.99 percent of a glioblastoma multiforme tumor, what is left behind will come back and grow into more tumor.”

    To study how glioblastoma multiforme spreads, Verma’s team focused on a transcription factor called nuclear factor kB (or NF-kB). A transcription factor is a protein that binds to DNA and controls the fate of gene expression for a particular set of genes. Several known factors can trigger NF-kB activity in a cell, including ultraviolet and ionizing radiation, immune proteins (cytokines) and DNA damage.

    In the case of glioblastoma multiforme, Verma and colleagues ran a battery of tests to show how overzealous NF-kB activity pushed the cancer cells to proliferate, and how stopping NF-kB slowed cancer growth and increased survival in mice.

    “Our experiments confirmed that NF-kB is required for the cancer cell to proliferate,” says Dinorah Friedmann-Morvinski, first author of the paper and currently a researcher in the department of biochemistry and molecular biology at Tel Aviv University in Israel. “But now we have finally found a way to ameliorate the tumor to increase lifespan.”

    Verma’s team started with a mouse model of glioblastoma multiforme and used genetic tools to manipulate cells into shutting down NF-kB activity in two ways. The team ramped up the presence of a protein called IkBaM, which inhibits NF-kB activity. They also eliminated an enzyme that increases NF-kB activity. With less NF-kB activity, tumor growth slowed and mice lived significantly longer then mice whose NF-kB activity was left alone. But while these genetic experiments demonstrated the role of NF-kB in glioblastoma multiforme, they aren’t a feasible treatment in humans.

    “So we asked how could we manipulate the system using pharmacology rather than genetics,” says Verma.

    Scientists have long suspected that one reason why glioblastoma multiforme comes back so quickly after surgery is the so-called tumor microenvironment. In other words, a tumor changes the environment of its surroundings (nearby tissues) to make it easier for cancer cells to thrive, Verma explains.

    Temp 2
    Dinorah Friedmann-Morvinski and Inder Verma
    Image: Courtesy of the Salk Institute for Biological Studies

    Instead of using genetic tools, Verma and colleagues sought to treat the brain tumors in a way that also changed the tumor microenvironment. The scientists fed mice a peptide (called NBD) that is known to block NF-kB activity when NF-kB is triggered by cytokines (proteins produced by the immune system). The NBD peptide easily travels across the central nervous system, and can successfully penetrate glioblastoma tumor cells. Treating mice with the NBD peptide doubled their typical survival time compared to mice that didn’t get the NBD peptide.

    “We could increase survival time from one month without treatment to three months with treatment,” says Verma. “That’s a profound increase in life expectancy, especially considering a mouse only lives for two years.” Yet, while the NBD peptide kept the tumors at bay, the peptide treatment eventually causes toxicity, most likely in the liver. So researchers explored another tactic to slow NF-kB activity.

    Curbing NF-kB activity can be tricky because NF-kB has many important roles: it helps regulate cell survival, inflammation and immunity among many other functions in the cell.

    “The ultimate goal is to block NF-kB, but because it turns on many genes—at least 100—our aim became finding the handful of genes that directly affect tumor growth,” says Verma. “Then we can be more selective in treatment.”

    Salk scientists tracked which genes were influenced by NF-kB and found one, Timp1, which has been previously implicated in lung cancer. Targeting the Timp1 gene in treatment also slowed tumor growth and increased survival time in mice by a few months.

    “In the future we want to focus on ways to reduce the toxicity of anti-NF-kB drugs,” said Friedmann-Morvinski. “We may do this by specifically targeting these drugs to the tumor, or by identifying downstream targets of the NF-kB pathway, like Timp1, that also prolong survival.” Further experiments may identify treatments that target NF-kB activity in a safe, but effective way.

    Other authors on the paper included Rajesh Narasimamurthy, Yifeng Xia, Chad Myskiw and Yasushi Soda of the Salk Institute for Biological Studies.

    The work was funded by the National Institutes of Health, the H.N. and Frances C. Berger Foundation, and the Leona M. and Harry B. Helmsley Charitable Trust.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    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 12:35 pm on December 28, 2015 Permalink | Reply
    Tags: , , Salk Institute   

    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

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    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.

     
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