Using computer simulations, a team of University of Wisconsin-Madison researchers has identified some of the pathways through which single complementary strands of DNA interact and combine to form the double helix. Present in the cells of all living organisms, DNA is composed of two intertwined strands and contains the genetic "blueprint" through which all living organisms develop and function. Individual strands consist of nucleotides, which include a base, a sugar and a phosphate moiety. Understanding hybridization, the process through which single DNA strands combine to form a double helix is fundamental to biology and central to technologies such as DNA microchips or DNA-based nanoscale assembly. The research by the Wisconsin group begins to unravel how DNA strands come together and bind to each other, says <a href="http://www.engr.wisc.edu/che/faculty/depablo_juan.html">Juan J. de Pablo</a>, UW-Madison Howard Curler Distinguished Professor of Chemical and Biological Engineering. The team published its findings today (Oct. 5) in the Proceedings of the National Academy of Sciences. In addition to senior author de Pablo, the group included <a href="http://www.genetics.wisc.edu/faculty/profile.php?id=143">David C. Schwartz</a>, a UW-Madison professor of chemistry and genetics, and former postdoctoral research fellow Edward J. Sambriski, now an assistant professor of chemistry at Delaware Valley College in Pennsylvania. The three drew on detailed molecular DNA models developed by de Pablo's research group to study the reaction pathways through which double-stranded DNA undergo denaturation, where the molecule uncoils and separates into single strands, and hybridization, through which complementary DNA strands bind, or "hybridize." In Watson-Crick base pairing, A (adenine) pairs with T (thymine), while G (guanine) pairs with C (cytosine). Reaction pathways are the trajectories single DNA strands follow to find each other and connect via such complementary pairs. The researchers studied both random and repetitive base sequences. Random sequences of the four bases — A, T, G and C — contained little or no regular repetition. To the researchers' surprise, a couple of bases located toward the center of the strand associate early in the hybridization process. The moment they find each other, they bind and the entire molecule hybridizes rapidly and in a highly organized manner. Conversely, in repetitive sequences, the bases alternated regularly, and the group found that these sequences bind through a so-called diffusive process. "The two strands of DNA somehow find each other, they connect to each other in no particular order, and then they slide past each other for a long time until the exact complements find one another in the right order, and then they hybridize," says de Pablo. Results of the team's study show that DNA hybridization is very sensitive to DNA composition, or sequence. "Contrary to what was thought previously, we found that the actual process by which complementary DNA strands hybridize is very sensitive to the sequence of the molecules," he says. Knowledge of how the process occurs could enable researchers to more strategically design technologies such as gene chips. For example, says de Pablo, if a researcher wanted to design sequences that bind very rapidly or with high efficiency, he or she could place certain bases in specific locations, so that the hybridization reaction could occur faster or more reliably. Ultimately, the research could help biologists understand why some hybridization reactions are faster or more robust than others. "One of the really exciting things about this work is that the hybridization reaction between two strands of DNA is really fundamental to life itself," says de Pablo. "It is the basis for much of biology. And it is amazing to me that, until now, we knew little of how this reaction actually proceeds." The National Science Foundation-funded Nanoscale Science and Engineering Center on Templated Synthesis and Assembly at the Nanoscale at UW-Madison sponsored the research. Using computer simulations, a team of University of Wisconsin-Madison researchers has identified some of the pathways through which single complementary strands of DNA interact and combine to form the double helix. Models begin to unravel how single DNA strands combine 17171 2009-10-05T14:09:00-05:00

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<a href="http://www.vetmed.wisc.edu/people/dopferd">Dörte Döpfer</a>'s research has very real consequences for public health. "It's a question of life and death," says the University of Wisconsin-Madison veterinary epidemiologist and specialist in the food-borne bugaboo Escherichia coli O157:H7. "Ten of those bacteria can kill a person, especially young children and the elderly." But the National Science Foundation's $1 million grant to Döpfer and UW-Madison bacteriology professor <a href="http://fri.wisc.edu/kaspar.htm">Charles Kaspar</a> is not just a novel dissection of a murderous pathogen. It's a shot at righting an economy. Döpfer's grant is one piece of UW-Madison's growing collection of research projects funded by the American Recovery and Reinvestment Act, the federal government's economic stimulus package. By mid-August, the university had drawn better than $39 million in funding for more than 130 research projects and programs. The work is spread across the range of academic disciplines — including public health, computer science, psychology, economics and engineering — and comes from agencies such as the National Science Foundation (NSF), the National Institutes of Health (NIH), the Department of Energy and the National Endowment of the Arts. The research planned by Döpfer and Kaspar was funded as part of a $1.4 million project including Texas A&M University epidemiologist and computer modeler Renata Ivanek-Miojevic. The collaborators will study the ecology of E. coli bacteria inside and outside hosts (such as cattle) and how the bacterium may evolve methods to survive in one environment that put it at a disadvantage in the other. The proposal scored points for being innovative, pulling together a team of scientists and steering business to off-campus companies to purchase the high-speed DNA replicating equipment planned for Döpfer's lab. "The reviewers recognized that we were young investigators," Döpfer says. "They liked the idea of interdisciplinary study. And they were also interested, I believe, in the equipment included, that we're stimulating the economy in that regard as well." It certainly couldn't have hurt that Döpfer is now hiring. "We are adding a grad student and a technician, depending on who we can get," she says. "It's two positions for three years, full-time. There's another person with Chuck Kaspar and two more at Texas A&M." The E. coli study hit stimulus pay dirt on its first submission, but it's not uncommon among UW-Madison researchers to see a once- or twice-rejected proposal resurrected by the influx of money. "The way I look at it is, with the NSF, if you have a good idea you write a proposal and then you get in line," says <a href="http://limnology.wisc.edu/personnel/carpenter/">Stephen Carpenter</a>, UW-Madison zoology professor. "It's possible, but fairly unusual, to get them on the first try." Carpenter's NSF grant — $519,443 for work intended to expand our understanding of how much biomass from dry land makes its way into the lake food chain and eventually into fish — had narrowly missed approval on its first submission. "What the stimulus package did is clear the queue," Carpenter says. "It's like you were at the grocery store in a long line to check out, and then they opened half a dozen more check out stations." His work will begin in earnest in the summer of 2010, bringing with it jobs for students and staff who may otherwise have been idle or working outside their area of expertise. "It's actually pretty inefficient to have half the country's scientists looking for resources instead of doing science." Carpenter says. Though she was far from sitting idle, a stimulus-funded grant of $843,887 from the NIH came at just the right time for <a href="http://www.engr.wisc.edu/che/faculty/murphy_regina.html">Regina Murphy</a>, professor of chemical and biological engineering. "I have work going right now, but I would have had to shut down without this funding," says Murphy, who has been working with pharmacy professor Jeff Johnson to identify how a brain protein called transthyretin limits the deposit of harmful plaque in the brains of Alzheimer's disease sufferers. While the money kept Murphy's research going, it bought her lab another two years — not the five years requested in her grant application. In fact, many of the stimulus grants come with a caveat — indicative of the oversight requirements and ephemeral nature of the money — like the one posted online with an abstract describing Murphy's work: "This project is being supported with funds from the American Recovery and Reinvestment Act, which may involve a reduction in the research aims and scope." That leaves Murphy's lab in a familiar fix in two years, hunting for financial backing to keep working on a project that does not lend itself well to temporary shutdown. "You have people working in the lab who know the project. You have animals going," Murphy says. "It's not something you can stop after two years." Not that Murphy, who also has an NSF grant to study malformed and diseased-causing proteins, would complain about another two years and the ability to add a researcher to the team. There's little or nothing to complain about from a researcher's perspective, Carpenter says. "I'm delighted. I have no idea what the economic impact will be, but it's making a lot of good things happen, and it makes room for many more good ideas," Carpenter says. "It would be a great time to send in a good idea." Visit <a href="http://www.stimulus.wisc.edu">this site</a> to learn more about how stimulus funds are being used at UW-Madison. The university has drawn more than $38 million in funding for more than 120 research projects and programs from the American Recovery and Reinvestment Act. The work is spread across the range of academic disciplines, including public health, computer science, psychology, economics and engineering. Funding comes from agencies such as NSF, the National Institutes of Health (NIH), the Department of Energy and the National Endowment for the Arts. http://stimulus.wisc.edu/ UW-Madison's 'good ideas' get lift from stimulus funds 16996 2009-08-26T09:36:00-05:00

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In a presentation today (Aug. 19) to the American Chemical Society meeting, Ankit Agarwal, a postdoctoral researcher at the University of Wisconsin-Madison, described an experimental approach to wound healing that could take advantage of silver's antibacterial properties, while sidestepping the damage silver can cause to cells needed for healing. Silver is widely used to prevent bacterial contamination in wound dressings, says Agarwal, "but these dressings deliver a very large load of silver, and that can kill a lot of cells in the wound." Wound healing is a particular problem in diabetes, where poor blood supply that inhibits healing can require amputations, and also in burn wards. Agarwal says some burn surgeons avoid silver dressings despite their constant concern with infection. Using a new approach, Agarwal has crafted an ultra-thin material carrying a precise dose of silver. One square inch contains just 0.4 percent of the silver that is found in the silver-treated antibacterial bandages now used in medicine. In tests in lab dishes, the low concentration of silver killed 99.9999 percent of the bacteria but did not damage cells called fibroblasts that are needed to repair a wound. Agarwal builds the experimental material from polyelectrolyte multilayers — a sandwich of ultra-thin polymers that adhere through electrical attraction. To make the sandwich, Agarwal alternately dips a glass plate in two solutions of oppositely charged polymers and finally adds a precise dose of silver. "This architecture is very easily tuned to different applications," Agarwal says, because it allows exact control of such factors as thickness, porosity and silver content. The final sandwich may range from a few nanometers to several hundred nanometers in thickness. (One nanometer is one-billionth of a meter; a human hair is about 60,000 nanometers in diameter.) <a href="http://www.engr.wisc.edu/che/faculty/abbott_nicholas.html">Nicholas Abbott</a>, a professor of chemical and biological engineering who advises Agarwal, says during the past decade, "about a bazillion papers have been published on polyelectrolyte multilayers. It's been a tremendous investment by material scientists, and that investment is now ripe to be exploited." The project was supported by seed funding from the <a href="http://www.warf.org">Wisconsin Alumni Research Foundation</a> (WARF) and benefited from contributions by Christopher Murphy, Jonathan McAnulty and Charles Czuprynski of UW-Madison's School of Veterinary Medicine; Ronald Raines of the Department of Biochemistry; and Michael Schurr, a burn surgeon at the School of Medicine and Public Health. The work was conducted under the auspices of the <a href="http://discovery.wisc.edu/discovery">Wisconsin Institutes for Discovery</a>, the public-private interdisciplinary research facility now under construction on the UW-Madison campus. Although both mammalian cells and bacteria are sensitive to silver, bacteria are much more sensitive, leaving a sweet spot — a concentration of silver that can kill bacteria without harming cells needed for healing. In tests using mouse cells and sample bacteria, Agarwal has tuned the dose to find the sweet spot where the silver bullet destroys 99.9999 percent of the bacteria, but does not harm fibroblasts. Indeed, the system is so sensitive that increasing the silver dose from 0.4 percent to 1 percent of the level used in a commercial dressing severely damaged the fibroblasts. To kill bacteria, silver must take the form of charged particles, or ions, and the tiny silver nanoparticles that Agarwal embeds in the sandwich can be designed to release ions for days or weeks as needed. In contrast, Agarwal says, commercial wound dressings contain a large dose of silver ions, which are released faster and with less control. The required dose of silver can also be reduced because the new material would be designed to stay in close contact with the wound, Abbott says. "In a commercial dressing, the silver is part of the bandage that is placed on the wound surface. We envision this material becoming incorporated into the wound; the cells will grow over it and it will eventually decay and be absorbed into the body, much like an absorbable suture." Tests on animals will be needed to before the new material can be tested on humans, says Abbott. "A commercial dressing needs to have a large quantity of silver so it can diffuse to the wound bed, and that quantity turns out to be toxic to mammalian cells in lab dishes. We are putting the silver where we need it, so we can use a small loading of silver, which does not exhibit toxicity to mammalian cells because the silver is precisely targeted." In a presentation today (Aug. 19) to the American Chemical Society meeting, Ankit Agarwal, a postdoctoral researcher at the University of Wisconsin-Madison, described an experimental approach to wound healing that could take advantage of silver's anti-bacterial properties, while sidestepping the damage silver can cause to cells needed for healing. New approach to wound healing may be easy on skin, but hard on bacteria 16974 2009-08-19T08:52:00-05:00

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Capping an intensely competitive process, five proposals from University of Wisconsin-Madison faculty have been selected to form the intellectual heart of the <a href="http://discovery.wisc.edu/discovery">Wisconsin Institute for Discovery</a> (<acronym title="Wisconsin Institute for Discovery">WID</acronym>). WID is the public half of the <a href="http://discovery.wisc.edu/discovery">Wisconsin Institutes for Discovery</a>, complemented by the private <a href="http://discovery.wisc.edu/morgridge">Morgridge Institute for Research</a>. Both entities will occupy the new interdisciplinary research facility now under construction in the 1300 block of University Avenue. Chosen from a final pool of 12 proposals, the five research themes and their faculty leaders selected for inclusion in the new institute are: <ul> <li>Epigenetics or how genes are activated or inactivated, led by <a href="http://www.bmolchem.wisc.edu/faculty/denu.html">John M. Denu</a>, a professor of biomolecular chemistry in the UW-Madison School of Medicine and Public Health.</li> <li>Tissue engineering scaffold research, led by <a href="http://www.engr.wisc.edu/me/faculty/turng_lih-sheng.html">Lih-Sheng Turng</a>, UW-Madison professor of mechanical engineering.</li> <li>Health Technology Design in the Living Environments Laboratory aimed at accelerating the development of personal care diagnostic and therapeutic technology, led by <a href="http://www.engr.wisc.edu/ie/faculty/brennan_patricia.html">Patricia Flatley Brennan</a>, professor of industrial and systems engineering and nursing.</li> <li>Optimization in Biology and Medicine, a mathematical approach to minimize or maximize the variables of a given subject, led by <a href="http://pages.cs.wisc.edu/~ferris/">Michael C. Ferris</a>, professor of computer science.</li> <li>Systems Biology, an integrated, "system level" understanding of living organisms, spearheaded by <a href="http://www.engr.wisc.edu/che/faculty/yin_john.html">John Yin</a>, professor of chemical and biological engineering. </li> </ul> <div id="sideBar"> <h2>Related:</h2> Read more about the five <a href="http://www.news.wisc.edu/16869">Wisconsin Institute for Discovery research themes</a> </div> Interim WID Director John D. Wiley, who led the selection process with the WID Program Committee, says the selection of the five research themes to occupy the new institute is a key step in charting the long-term future of a novel interdisciplinary center. "It was a difficult selection process," Wiley notes. "We had 12 excellent proposals, and narrowing the list to a select few was hard. But we feel we have identified five areas of research that fit neatly into the mission of WID and will mesh with and enhance the goals and activities of the Morgridge Institute for research." The selection of the five WID research themes concludes a process that began nearly three years ago with a call for proposals for the Discovery Seed Grant Initiative, which jump-started WID programming by funding eight projects from a campuswide competition. The full WID research theme competition, according to Wiley, represented a rare chance for faculty to construct novel programs of research. A key goal of the new institute is to intermingle faculty, staff and students from across campus in interdisciplinary research that can be translated beyond academia and help underpin the future economy of the state. The selection process for the WID research themes, beginning with a call that elicited 26 pre-proposals, was intense and rigorous, Wiley explains. The WID Program Committee selected 12 pre-proposals for submission as full proposals. Submitted full proposals were peer-reviewed by internal and external expert reviewers, with each proposal receiving at least one external and two internal reviews. Final selection was then made by the WID Program Committee. "All 26 of the pre-proposals were excellent, so selecting 12 finalists was already a difficult process. Naming only five themes from among the 12 outstanding finalists was even more difficult," says Wiley, noting that the committee was convinced that many of the good ideas and proposed projects from the pre-proposals and final proposals will be engaged with WID and the Morgridge Institute, regardless of location on campus. The WID Program Committee included Chancellor Biddy Martin; Provosts or Interim Provosts Patrick Farrell, Julie Underwood and Paul DeLuca; Graduate School Dean Martin Cadwallader; WID Interim Directors Marsha Mailick Seltzer and Wiley; Morgridge Institute Director Sangtae Kim; College of Engineering Dean Paul Peercy; professor and chair of bacteriology Jo Handelsman; professor and chair of physiology Rick Moss; and professor of computer sciences Miron Livny. The successful faculty proposers will occupy space in the new WID facility, which is being constructed with support from the state of Wisconsin, UW-Madison alumni John and Tashia Morgridge and the Wisconsin Alumni Research Foundation. Wiley says the selection of the WID research themes caps a process set in motion by the visions of alumni donors John and Tashia Morgridge, Gov. Jim Doyle, the WARF and Morgridge Institute boards of directors, and WARF managing director Carl Gulbrandsen. "I would like to thank all of these people and the organizations that have helped to make this possible," Wiley says. "We are well on our way to establishing exciting new programs of research that will significantly enhance our research portfolio as well as the reputation of our university and state." Capping an intensely competitive process, five proposals from University of Wisconsin-Madison faculty have been selected to form the intellectual heart of the Wisconsin Institute for Discovery (WID). Five big ideas to fill out Wisconsin Institute for Discovery portfolio 16868 2009-06-30T09:16:00-05:00

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Molecular and cellular biologists have made tremendous scientific advances by dissecting apart the functions of individual genes, proteins, and pathways. Researchers at the University of Wisconsin-Madison College of Engineering are looking to expand that understanding by putting the pieces back together, mathematically. <a href="http://www.engr.wisc.edu/che/faculty/yin_john.html">John Yin</a>, a professor of <a href="http://www.engr.wisc.edu/che/">chemical and biological engineering</a>, developed computer models of a relatively simple virus to show that genes alone do not make an organism. With mathematical representations of the virus's known biology, he and former graduate student Kwang-il Lim demonstrate how genomic organization and regulation can have a large impact on biological outcomes. As shown in a new paper, simply shuffling the order of the five genes in the virus's genome has a huge impact on how well the virus grows and how it interacts with its simulated host cell. Their new results are reported today (Feb. 6) in the journal <a href="http://www.ploscompbiol.org/">PLoS Computational Biology</a>. The eventual goal is to understand the full picture of how an organism's genome guides its growth and development, Yin says. "How does the biology of individual genes come together in genetic interactions to ultimately give rise to behavior?" He and Lim, now a postdoctoral fellow at the University of California-Berkeley, computationally modeled the lifecycle of the vesicular stomatitis virus (VSV), a well-studied virus with only five genes and years of background research on its growth and function. Virologists have previously created strains with 11 of the possible gene arrangements, but with their computational models, the Wisconsin researchers were able to simulate all 120 possible gene-order variants. Comparisons of the simulated strains revealed that the positions of the first and last genes are key to viral success. The work has many potential applications. Understanding how to control the virus's growth and infectivity will help guide efforts to develop VSV as a cancer-targeting agent and create vaccines against more problematic viruses such as HIV-1 and influenza. The models can also be used to investigate the genetic basis of other viral characteristics. For example, Yin is currently working to simulate drug effects on a virus to look for ways the virus can evolve drug resistance. Ultimately he hopes his approach will scale up to more complex organisms with more complex genomes. For example, the completion of the Human Genome Project has inspired hopes of understanding how a person's genome determines their biology. The era of such "predictive biology" is a long way off yet, Yin says, but the ability to identify key elements of genetic organization and regulation are a critical early step. "This establishes a foundation for linking a genome to developmental processes and ultimately to phenotypes or behavior of biological systems," he says. Molecular and cellular biologists have made tremendous scientific advances by dissecting apart the functions of individual genes, proteins, and pathways. Researchers at the University of Wisconsin-Madison College of Engineering are looking to expand that understanding by putting the pieces back together, mathematically. Mathematical models reveal how organisms transcend the sum of their genes 16241 2009-02-06T09:08:00-06:00

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