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Under Embargo Till: 19:00 UTC March 15, 2010
Posted: 19:00 UTC 03/15/2010

Scientists Demonstrate Mammalian Regeneration Through a Single Gene Deletion

Monday, March 15, 2010

A quest that began over a decade ago with a chance observation has reached a milestone: the identification of a gene that may regulate regeneration in mammals. The absence of this single gene, called p21, confers a healing potential in mice long thought to have been lost through evolution and reserved for creatures like flatworms, sponges, and some species of salamander. In a report published today in the Proceedings of the National Academy of Sciences, researchers from The Wistar Institute demonstrate that mice that lack the p21 gene gain the ability to regenerate lost or damaged tissue.

Unlike typical mammals, which heal wounds by forming a scar, these mice begin by forming a blastema, a structure associated with rapid cell growth and de-differentiation as seen in amphibians. According to the Wistar researchers, the loss of p21 causes the cells of these mice to behave more like embryonic stem cells than adult mammalian cells, and their findings provide solid evidence to link tissue regeneration to the control of cell division.

Much like a newt that has lost a limb, these mice will replace missing or damaged tissue with healthy tissue that lacks any sign of scarring,” said the project’s lead scientist Ellen Heber-Katz, Ph.D., a professor in Wistar’s Molecular and Cellular Oncogenesis program. “While we are just beginning to understand the repercussions of these findings, perhaps, one day we’ll be able to accelerate healing in humans by temporarily inactivating the p21 gene.”

Heber-Katz and her colleagues used a p21 knockout mouse to help solve a mystery first encountered in 1996 regarding another mouse strain in her laboratory. MRL mice, which were being tested in an autoimmunity experiment, had holes pierced in their ears to create a commonly used life-long identification marker. A few weeks later, investigators discovered that the earholes had closed without a trace. While the experiment was ruined, it left the researchers with a new question: Was the MRL mouse a window into mammalian regeneration?

The discovery set the Heber-Katz laboratory off on two parallel paths. Working with geneticists Elizabeth Blankenhorn, Ph.D., at Drexel University, and James Cheverud, Ph.D., at Washington University, the laboratory focused on mapping the critical genes that turn MRL mice into healers.

Meanwhile, cellular studies ongoing at Wistar revealed that MRL cells behaved very differently than cells from “non-healer” mouse strains in culture. Khamilia Bedebaeva, M.D., Ph.D., having studied genetic effects following the Chernobyl reactor radiation accident, noticed immediately that these cells were atypical, showing profound differences in cell cycle characteristics and DNA damage. This led Andrew Snyder, Ph.D., to explore the DNA damage pathway and its effects on cell cycle control.

Snyder found that p21, a cell cycle regulator, was consistently inactive in cells from the MRL mouse ear. P21 expression is tightly controlled by the tumor suppressor p53, another regulator of cell division and a known factor in many forms of cancer. The ultimate experiment was to show that a mouse lacking p21 would demonstrate a regenerative response similar to that seen in the MRL mouse. And this indeed was the case. As it turned out, p21 knockout mice had already been created, were readily available, and widely used in many studies. What had not been noted was that these mice could heal their ears.

In normal cells, p21 acts like a brake to block cell cycle progression in the event of DNA damage, preventing the cells from dividing and potentially becoming cancerous,” Heber-Katz said. “In these mice without p21, we do see the expected increase in DNA damage, but surprisingly no increase in cancer has been reported.”

In fact, the researchers saw an increase in apoptosis in MRL mice – also known as programmed cell death – the cell’s self-destruct mechanism that is often switched on when DNA has been damaged. According to Heber-Katz, this is exactly the sort of behavior seen in naturally regenerative creatures.

The combined effects of an increase in highly regenerative cells and apoptosis may allow the cells of these organisms to divide rapidly without going out of control and becoming cancerous,” Heber-Katz said. “In fact, it is similar to what is seen in mammalian embryos, where p21 also happens to be inactive after DNA damage. The down regulation of p21 promotes the induced pluripotent state in mammalian cells, highlighting a correlation between stem cells, tissue regeneration, and the cell cycle.”

The study was supported by grants from the Harold G. and Leila Y. Mathers Foundation, the F.M. Kirby Foundation, the W.W. Smith Foundation, the National Institute for General Medical Sciences and National Cancer Institute.

Study investigators also include Wistar researchers Paul M. Lieberman, Ph.D.; Dmitri Gourevitch M.D.; Lise Clark D.V.M., Ph.D.; Xiang-Ming Zhang; and John Leferovich. Snyder, formerly of the Lieberman laboratory at Wistar, and Bedebaeva are co-first authors on this paper. James Cheverud of Washington University is also a co-author on this paper.

The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has long held the prestigious Cancer Center designation from the National Cancer Institute. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible.


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Source: Wistar Institute
Time Stamp: 3/15/2010 at 19:00:00 UTC

Developing Weed Resistance in Corn Hybrids

Monday, March 15, 2010

Millions of people in the savannas of west and central Africa rely on maize (corn) as a staple crop, and as an “insurance” food crop at the beginning of the rainy season. A destructive parasitic weed, Striga hermonthica, poses a threat to this valuable crop. Almost 64% of cropland in this area of Africa is affected by the parasite, which causes an average grain yield loss of 68%. Farmers in Striga-infested areas have not yet adopted Striga-resistant hybrids.

Scientists at the International Institute of Tropical Agriculture (IITA) in partnership with scientists in the University of Ibadan in Nigeria and the National Institute of Agricultural Research in Benin Republic investigated the relationship between the genetic diversity of maize inbred lines having different levels of resistance to Striga and the performance of their hybrids under parasite infestation. The results are reported in the March-April 2010 edition of Crop Science, published by the Crop Science Society of America.

The study experimented on all combinations of ten lines of maize with varying levels of resistance to the parasitic weeds in different locations in Africa over three years. Hybrids from two resistant parental lines exhibited the highest level of field resistance, while hybrids from parents with low resistance fared the worst. Hybrids with only one parent with high Striga resistance showed moderate levels of field resistance.

Another important finding was that the genetic diversity of the parental lines did not affect grain yield or other traits among the hybrids. The researchers expect that genetically diverse, Striga-resistant maize crops will provide opportunities to further increase the levels of field resistance to S. hermonthica through breeding.

Such Striga resistant maize hybrids may encourage farmers that abandoned farms due to severe Striga infestation to go back into maize production. This would contribute to food security and provide income-generating opportunities to farmers that depend on maize as an important food crop in Striga infested areas.

Source: Crop Science Society of America
Time Stamp: 3/15/2010 at 6:12:08 PM UTC

Observation of Confinement Phenomenon in Condensed Matter

Sunday, November 29, 2009

Force of interaction between magnetic particles grows stronger with increasing distance

An experiment has confirmed that spinons, particle-like magnetic excitations, can be confined in a magnetic insulator similar to the way elementary quarks are confined within individual protons and neutrons. The finding, in a well-described magnetic system, may offer new ways to explore Quantum Chromodynamics, the theory that describes the fundamental interactions of quarks.

The observations of spinon confinement were made at the Science and Technology Facilities Council’s Rutherford Appleton Laboratory in the United Kingdom by an international team of physicists. The team realized serendipitously that a theory developed 12 years earlier by theoretical physicist Alexei Tsevelik, now at the U.S. Department of Energy’s Brookhaven National Laboratory, and collaborators accurately predicted the current findings. Together, the scientists describe the theory and their new observations in the November 29th issue of Nature Physics.

The concept of confinement is one of the central ideas in modern physics, being at the core of the theory of nuclear forces,” Tsvelik said. “In certain systems, when constituent particles are bound together by an interaction whose strength increases with increasing particle separation, individual particles cannot exist in a free state and therefore can be observed only indirectly.”

The most famous example of confinement is of quarks which are held together in protons and neutrons, for example, by the strong force, a force that grows stronger with increasing distance.

It has been interesting for us that a similar situation of confinement can be modeled in condensed matter systems,” Tsvelik said. “Instead of quarks being confined in protons and neutrons, we have other quantum entities that act just like particles — elementary excitations of magnetic systems called spinons.”

In the case of the current experiment, the spinons exist on parallel chains of copper-oxide separated by inert calcium. Spinons on individual chains are not confined, but as soon as two chains are brought together to form ladder-like arrangements, the inter-ladder interactions confine the spinons.

That is, the spinons can appear now only in pairs and cannot fly away from each other too far,” Tsvelik said. “The result of this confinement is a particle we call a ‘magnon.’ It is like two quarks pairing up to form a meson.”

The original theory paper published by Tsvelik and collaborators 12 years ago described the magnetic excitation spectrum of such a system in detail. The team performing the experiments at Rutherford observed a signature that fit that description.

Now that we have an example of confinement in a condensed matter system, our next step is to check further predictions of the theory to make sure there are no unpleasant surprises,” Tsvelik said. The scientists will also measure the responses in other compounds to see if they observe similar effects.

Tsvelik’s research is funded by the DOE Office of Science.

Additional news release on this research from Helmholtz-Zentrum Berlin:
Image Caption: Alexei Tsevelik
Image Credit: Brookhaven National Laboratory
Source: Brookhaven National Laboratory
Time Stamp: 11/29/2009 at 6:47:17 PM UTC

New Hydrogen-Storage Method Discovered

Monday, November 23, 2009

Scientists at the Carnegie Institution have found for the first time that high pressure can be used to make a unique hydrogen-storage material. The discovery paves the way for an entirely new way to approach the hydrogen-storage problem. The researchers found that the normally unreactive, noble gas xenon combines with molecular hydrogen (H2) under pressure to form a previously unknown solid with unusual bonding chemistry. The experiments are the first time these elements have been combined to form a stable compound. The discovery debuts a new family of materials, which could boost new hydrogen technologies. The paper is published in the November 22, 2009, advanced online publication of Nature Chemistry.

Xenon has some intriguing properties, including its use as an anesthesia, its ability to preserve biological tissues, and its employment in lighting. Xenon is a noble gas, which means that it does not typically react with other elements.

As lead author Maddury Somayazulu, research scientist at Carnegie’s Geophysical Laboratory, explained: “Elements change their configuration when placed under pressure, sort of like passengers readjusting themselves as the elevator becomes full. We subjected a series of gas mixtures of xenon in combination with hydrogen to high pressures in a diamond anvil cell. At about 41,000 times the pressure at sea level (1 atmosphere), the atoms became arranged in a lattice structure dominated by hydrogen, but interspersed with layers of loosely bonded xenon pairs. When we increased pressure, like tuning a radio, the distances between the xenon pairs changed–the distances contracted to those observed in dense metallic xenon.”

The researchers imaged the compound at varying pressures using X-ray diffraction, infrared and Raman spectroscopy. When they looked at the xenon part of the structure, they realized that the interaction of xenon with the surrounding hydrogen was responsible for the unusual stability and the continuous change in xenon-xenon distances as pressure was adjusted from 41,000 to 255,000 atmospheres.

Why was the compound so stable? “We were taken off guard by both the structure and stability of this material,” said Przemek Dera, the lead crystallographer who looked at the changes in electron density at different pressures using single-crystal diffraction. As electron density from the xenon atoms spreads towards the surrounding hydrogen molecules, it seems to stabilize the compound and the xenon pairs.

Xenon is too heavy and expensive to be practical for use in hydrogen-storage applications,” remarked Somayazulu. “But by understanding how it works in this situation, researchers can come up with lighter substitutes.”

It’s very exciting to come up with new hydrogen-rich compounds, not just for our interest in simple molecular systems, but because such discoveries can be the foundation for important new technologies,” commented Russell Hemley, director of the Geophysical Laboratory and a co-author. “This hydrogen-rich solid represents a new pathway to forming novel hydrogen storage compounds and the new pressure-induced chemistry opens the possibility of synthesizing new energetic materials.”

This research was funded by the Department of Energy, Basic Energy Sciences hydrogen storage, and the National Science Foundation, Division of Materials Research.

Source: Carnegie Institution of Washington
Time Stamp: 11/23/2009 at 4:03:21 PM UTC

Scientists Challenged to Create Better Tools for Image Analysis

Thursday, April 9, 2009

The Allen Institute for Brain Science, the Howard Hughes Medical Institute (HHMI), and the Krasnow Institute for Advanced Study at George Mason University are launching an international scientific challenge to speed development of new computational tools that accurately and automatically reconstruct the “shape” of brain cells from available light microscopy data.

The organizers hope the DIADEM Challenge—short for Digital Reconstruction of Axonal and Dendritic Morphology—will lead to innovative solutions to a frustrating problem that has slowed efforts to create a functional atlas of the brain. Neuroscientists agree that a systematic characterization of neurons with their dendrites and axons is essential, since these tree-like structures are highly correlated with the electric activity of, and precise connections between, neurons and are thus linked to the functions of specific brain circuits. But scientists currently spend weeks—and, in some cases, months—tracing the intricate neuronal processes by hand, using data supplied by imaging studies.

Manual tracing of neurons has created an intolerable bottleneck and is currently limiting the pace of discovery in neural circuit analysis.”
Giorgio A. Ascoli

Manual tracing of neurons has created an intolerable bottleneck and is currently limiting the pace of discovery in neural circuit analysis,” said Giorgio A. Ascoli of the Krasnow Institute for Advanced Study. “Automating this process will open the exciting path to the comprehensive characterization of neuronal structure and connectivity.”

The DIADEM Challenge is open to individuals and teams from the private sector and academic laboratories. The organizers will award a $75,000 cash prize to the winning individual or team whose algorithm is judged to perform the best in tests using real data. Funding for the prize is provided by HHMI and the Allen Institute.

Solving this computational bottleneck will be key for larger scale studies of brain wiring and to generate an atlas of connections in the brain,” said Allan Jones of the Allen Institute. “Sponsoring the DIADEM Challenge fits in well with the Allen Institute’s mission of providing broad enabling tools and data to the scientific community.”

Competitors will have a year to implement an algorithm for digital reconstruction of neuronal morphology and to test it against manual reconstruction, which is the current “gold standard.” Up to five finalists will compete in a final round at HHMI’s Janelia Farm Research Campus in Ashburn, Virginia, in August 2010.

The National Institutes of Health is providing partial support to a scientific conference that is independent of—but held in conjunction with—the final round of the DIADEM Challenge. Yuan Liu, program director for Computational Neuroscience and Neuroinformatics at the National Institute of Neurological Disorders and Stroke, is co-organizing the scientific conference with Ascoli and Karel Svoboda of Janelia Farm.

The idea for the DIADEM Challenge was originally discussed in 2007 at a scientific workshop at Janelia Farm. Scientists at the meeting noted that progress in understanding neural circuits was being slowed by the tedious task of tracing the structure of individual nerve cells by hand.

Even with the advent of computer technology that enables mapping in three dimensions, the full reconstruction of single neurons may take months. The vast majority of axons (the long neuronal projections that transmit information to neighboring cells) and dendrites (the branches on nerve cells that receive information from neighboring cells) must be traced manually. Researchers trace axons and dendrites that have been labeled with markers, such as green fluorescent protein, and imaged using a variety of microscopy techniques.

Participants in the DIADEM Challenge will have the opportunity to test their algorithms on the latest data supplied by neuroscientists. Thus, they will have a chance to assess their solutions in a real-world environment.

Ascoli, Liu, and Svoboda believe the DIADEM Challenge and associated conference could lead to significant scientific and technical advancements.

It will certainly result in a critical assessment of the remaining obstacles to a complete solution,” said Svoboda. “This will be an exciting opportunity to bring computational and experimental scientists together to see if they can solve this problem.”

Full details about the DIADEM Challenge—including detailed rules and information for competitors—can be found at
Source: HHMI
Time Stamp: 4/9/2009 at 3:21:15 PM UTC

How the Retina Works

Tuesday, April 7, 2009

Like a Multi-layered Jigsaw Puzzle of Receptive Fields

About 1.25 million neurons in the retina -- each of which views the world only through a small jagged window called a receptive field -- collectively form the seamless picture we rely on to navigate our environment. Receptive fields fit together like pieces of a puzzle, preventing “blind spots” and excessive overlap that could blur our perception of the world, according to researchers at the Salk Institute for Biological Studies.

In the April 7 issue of the journal Public Library of Science, Biology, the scientists say their findings suggest that the nervous system operates with higher precision than previously appreciated and that apparent irregularities in individual cells may actually be coordinated and finely tuned to make the most of the world around us.

Previously, the observed irregularities of individual receptive fields suggested that the collective visual coverage might be uneven and irregular, potentially posing a problem for high-resolution vision. “The striking coordination we found when we examined a whole population indicated that neuronal circuits in the retina may sample the visual scene with high precision, perhaps in a manner that approaches the optimum for high-resolution vision,” says senior author E.J. Chichilnisky, Ph.D., an associate professor in the Systems Neurobiology Laboratories.

All visual information reaching the brain is transmitted by retinal ganglion cells. Each of the 20 or so distinct ganglion cell types is thought to transmit a complete visual image to the brain, because the receptive fields of each type form a regular lattice covering visual space. However, within each regular lattice, the individual cells’ receptive fields have irregular and inconsistent shapes, which could potentially result in patchy coverage of the visual field.

To understand how the visual system overcomes this problem, postdoctoral researcher and first author Jeffrey L. Gauthier, Ph.D., used a microscopic electrode array to record the activity of ganglion cells in isolated patches of retina, the tissue lining the back of the eye.

After monitoring hundreds of ganglion cells over several hours, he distinguished between different cell types based on their light response properties. “Often people record from many cells simultaneously but they don’t know which cell belongs to which type,” says Gauthier. Without this information, he says, he wouldn’t have been able to observe that the receptive fields of neighboring cells of a specific type interlock, complementing each others’ irregular shapes.

The receptive fields of all four cell types we examined were precisely coordinated,” he says, “but we saw no coordination between cells of different types, emphasizing the importance of clearly distinguishing one cell type from another when studying sensory encoding by a population of neurons.”

Researchers who also contributed to the work include postdoctoral fellows Greg D. Field, Ph.D., Martin Greschner, Ph.D., and Jonathon Shlens, Ph.D., all in the Chichilnisky Laboratory, as well as postdoctoral researcher Alexander Sher, Ph.D., and professor Alan M. Litke, Ph.D., both at the Santa Cruz Institute for Particle Physics, University of California, Santa Cruz.

This work was supported by the National Institutes of Health, the National Science Foundation, the Chapman Foundation, the Helen Hay Whitney Foundation, the Burroughs Wellcome Fund, the Deutscher Akademischer Austauschdienst and the McKnight Foundation.

The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.

Image Caption: Each neuron in the retina views the world through a small, irregularly shaped window. These regions fit together like pieces of a puzzle, preventing "blind spot" and excessive overlap that could blur our perception of the world.
Image Credit: Dr. Jeffrey Gauthier / Salk Institute for Biological Studies
Source: Salk Institute
Time Stamp: 4/7/2009 at 4:08:16 AM UTC

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