Wisconsin Institute for Discovery

Lake Wisconsin, WI, United States

Wisconsin Institute for Discovery

Lake Wisconsin, WI, United States

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News Article | April 18, 2017
Site: phys.org

Now, a University of Wisconsin-Madison professor of bacteriology has shown the first proof that a certain group of amoeba called dictyostelids can penetrate biofilms and eat the bacteria within. "This is the first demonstration that dicty are able to feed on biofilm-enmeshed bacteria," Marcin Filutowicz says. In an article now online in the journal Protist, Filutowicz, first author Dean Sanders of the Wisconsin Institute for Discovery, and colleagues show time-lapse, microscopic movies proving the amoeba's voracious appetite for five species of bacteria. In the study, the researchers pitted four types of amoeba called dictyostelium (dictys) against biofilm-forming bacteria that harm plants or humans. The target bacteria included: As expected, the results depended on the strain of dicty and species of bacteria; in several cases, the dictys completely obliterated a thriving biofilm containing millions of bacteria within a day or two. The study, Filutowicz says, "contains the first movies ever to show dicty cells moving into a biofilm and devouring the bacteria." Because they form a multi-cellular phase sometimes called a "slug," dictys are sometimes called "social amoeba." Beyond the visual evidence, spore germination and the subsequent union of single-celled dictys into a multi-cellular "slug" both showed successful attacks against all four species of bacteria. Filutowicz became interested in dictys after discovering a neglected archive of about 1,800 strains amassed by Kenneth Raper, a bacteriology colleague who started collecting the soil-borne microbes around the world in the 1930s. "Raper was the first to isolate dictys, but after he died, his life work was scattered around the department and neglected," Filutowicz says. Filutowicz was intrigued, but he knew very little about dictys. Then, the answer to his most fundamental question—"How do I grow them?" triggered a mental chain reaction. He found that Raper and his followers were feeding and growing dictys in the lab using bacterial prey, but nobody had apparently pursued their real-world potential as microbe hunters. "If you grow them on E coli [a common resident of the human intestine], I quickly realized, because dictys are not pathogenic, we might use them as a biological weapon against bacteria." Having previously started Conjugon, a company devoted to developing benign bacteria to defeat pathogenic microbes, Filutowicz says he was "attuned to biological approaches, which were unheard then, and so this idea fell on a very fertile mind." With bacteria becoming resistant to a growing number of antibiotics, that's welcome news, although using a living organism may add complexity to the task of getting regulatory approval. Since 2010, Filutowicz has learned a good deal about how dicty "graze" upon bacteria, and which ones they prefer. "We looked at how these cells dismantle biofilms, trying to understand what physical, chemical and mechanical forces deconstruct the biofilms, and how the dictys move in 3-D space. These are phagocytes, and they behave much like our own immune cells," says Filutowicz. His collaborator, Curtis Brandt, a professor of ophthalmology and visual science at UW-Madison, has produced promising results suggesting that the organisms are harmless to rodents, and is preparing to use dictys to fight bacterial keratitis, an eye infection, first in rodents and then in humans, in research supported by the National Institutes of Health. "This medical application may not reach the clinic in my lifetime, but it has a lot of promise, and eventually we may be able to advance it in many other medical uses," Filutowicz says. In 2010, Filutowicz formed Amoebagone, to advance research into use of dictys, starting by trying to fight fire blight and other bacterial infections of fruit trees and vegetables; supported by the National Science Foundation. Between the far-off human medical potential, and the near-term use in agriculture, Filutowicz is delightedly pulling on the thread left by Ken Raper's beneficial microbes; licensed by the Wisconsin Alumni Research Foundation to AmoebaGone. "To make a discovery, it needs some level of naiveté," he says. "If you know too much, you immediately appreciate why things will not work, cannot work. Otherwise, if it was a good idea, people would have done it already. Colleagues said dictys behaved like human phagocytes, but they never mentioned harnessing them as biological controls. Every day I walk through the departmental hallway and read the inscription: "Discovery consists of seeing of what everybody has seen and thinking what nobody has thought. I was lucky enough to enter this as the foolish innocent." Explore further: Researchers develop novel method to find new antibiotics


News Article | April 18, 2017
Site: www.eurekalert.org

MADISON -Bacteria have developed an uncountable number of chemistries, lifestyles, attacks and defenses through 2.5 billion years of evolution. One of the most impressive defenses is biofilm -- a community of bacteria enmeshed in a matrix that protects against single-celled predators and antibiotics -- chemicals evolved by competitors through the course of evolution, including other bacteria and fungi. Now, a University of Wisconsin-Madison professor of bacteriology has shown the first proof that a certain group of amoeba called dictyostelids can penetrate biofilms and eat the bacteria within. "This is the first demonstration that dicty are able to feed on biofilm-enmeshed bacteria," Marcin Filutowicz says. In an article now online in the journal Protist, Filutowicz, first author Dean Sanders of the Wisconsin Institute for Discovery, and colleagues show time-lapse, microscopic movies proving the amoeba's voracious appetite for five species of bacteria. In the study, the researchers pitted four types of amoeba called dictyostelium (dictys) against biofilm-forming bacteria that harm plants or humans. The target bacteria included: As expected, the results depended on the strain of dicty and species of bacteria; in several cases, the dictys completely obliterated a thriving biofilm containing millions of bacteria within a day or two. The study, Filutowicz says, "contains the first movies ever to show dicty cells moving into a biofilm and devouring the bacteria." Because they form a multi-cellular phase sometimes called a "slug," dictys are sometimes called "social amoeba." Beyond the visual evidence, spore germination and the subsequent union of single-celled dictys into a multi-cellular "slug" both showed successful attacks against all four species of bacteria. Filutowicz became interested in dictys after discovering a neglected archive of about 1,800 strains amassed by Kenneth Raper, a bacteriology colleague who started collecting the soil-borne microbes around the world in the 1930s. "Raper was the first to isolate dictys, but after he died, his life work was scattered around the department and neglected," Filutowicz says. Filutowicz was intrigued, but he knew very little about dictys. Then, the answer to his most fundamental question -- "How do I grow them?" triggered a mental chain reaction. He found that Raper and his followers were feeding and growing dictys in the lab using bacterial prey, but nobody had apparently pursued their real-world potential as microbe hunters. "If you grow them on E coli [a common resident of the human intestine], I quickly realized, because dictys are not pathogenic, we might use them as a biological weapon against bacteria." Having previously started Conjugon, a company devoted to developing benign bacteria to defeat pathogenic microbes, Filutowicz says he was "attuned to biological approaches, which were unheard then, and so this idea fell on a very fertile mind." With bacteria becoming resistant to a growing number of antibiotics, that's welcome news, although using a living organism may add complexity to the task of getting regulatory approval. Since 2010, Filutowicz has learned a good deal about how dicty "graze" upon bacteria, and which ones they prefer. "We looked at how these cells dismantle biofilms, trying to understand what physical, chemical and mechanical forces deconstruct the biofilms, and how the dictys move in 3-D space. These are phagocytes, and they behave much like our own immune cells," says Filutowicz. His collaborator, Curtis Brandt, a professor of ophthalmology and visual science at UW-Madison, has produced promising results suggesting that the organisms are harmless to rodents, and is preparing to use dictys to fight bacterial keratitis, an eye infection, first in rodents and then in humans, in research supported by the National Institutes of Health. "This medical application may not reach the clinic in my lifetime, but it has a lot of promise, and eventually we may be able to advance it in many other medical uses," Filutowicz says. In 2010, Filutowicz formed Amoebagone, to advance research into use of dictys, starting by trying to fight fire blight and other bacterial infections of fruit trees and vegetables; supported by the National Science Foundation. Between the far-off human medical potential, and the near-term use in agriculture, Filutowicz is delightedly pulling on the thread left by Ken Raper's beneficial microbes; licensed by the Wisconsin Alumni Research Foundation to AmoebaGone. "To make a discovery, it needs some level of naiveté," he says. "If you know too much, you immediately appreciate why things will not work, cannot work. Otherwise, if it was a good idea, people would have done it already. Colleagues said dictys behaved like human phagocytes, but they never mentioned harnessing them as biological controls. Every day I walk through the departmental hallway and read the inscription: "Discovery consists of seeing of what everybody has seen and thinking what nobody has thought. I was lucky enough to enter this as the foolish innocent."


Cut to 2016, and HTCondor is on to a new collision: helping scientists detect gravitational waves caused 1.3 billion years ago by a collision between two black holes 30 times as massive as our sun. From revealing the Higgs boson, among the smallest particles known to science, to detecting the impossibly massive astrophysics of black holes, the HTCondor High Throughput Computing (HTC) software has proven indispensable to processing the vast and complex data produced by big international science. Computer scientists at the University of Wisconsin—Madison pioneered these distributed high throughput computing technologies over the last three decades. The announcement in February that scientists from the Laser Interferometer Gravitational-Wave Observatory (LIGO) unlocked the final door to Albert Einstein's Theory of Relativity—proof that gravitational waves produce ripples through space and time—has a rich back story involving HTCondor. Since 2004, HTCondor has been a core part of the data analysis effort of the project that includes more than 1,000 scientists from 80 institutions across 15 countries. By the numbers, more than 700 LIGO scientists have used HTCondor over the past 12 years to run complex data analysis workflows on computing resources scattered throughout the U.S. and Europe. About 50 million core-hours managed by HTCondor in the past six months alone supported the data analysis that led to the detection reported in the February 2016 papers. The path of HTCondor to LIGO was paved by a collaboration that started more than a decade ago between two University of Wisconsin teams—the 29-member LIGO team at UW-Milwaukee and the HTCondor team at UW–Madison. This interdisciplinary collaboration helped transform the computational model of LIGO and advance the state of the art of HTC. The HTCondor team is led by Miron Livny, UW–Madison professor of computer sciences and chief technology officer for the Morgridge Institute for Research and the Wisconsin Institute for Discovery. The HTCondor software implements innovative high-throughput computing technologies that harness the power of tens of thousands of networked computers to run large ensembles of computational tasks. "What we have is the expertise of two UW System schools coming together to tackle a complex data analysis problem," says Thomas Downes, a UW-Milwaukee senior scientist of physics and LIGO investigator. "The problem was, how do you manage thousands upon thousands of interrelated data analysis jobs in a way that scientists can effectively use? And it was much more easily solved because Milwaukee and Madison are right down the street from each other." The UW-Milwaukee team began using HTCondor in the early 2000s as part of an NSF Information Technology Research (ITR) project. Its then-lead scientist, Bruce Allen, landed a job as director of the Albert Einstein Institute for Gravitational Physics in Hannover, Germany, one of the leading hubs in the LIGO project. Duncan Brown, then a UW-Milwaukee physics Ph.D. candidate, became a professor of physics at Syracuse University, leading that university's LIGO efforts. Allen, Brown and others worked hard at Milwaukee to demonstrate the value of the HTCondor approach to the mission of LIGO, eventually leading to its adoption at other LIGO sites. HTCondor soon became the go-to technology for the core LIGO data groups at UW-Milwaukee, Syracuse University, the Albert Einstein Institute, the California Institute of Technology (Caltech), and Cardiff University in the UK. Peter Couvares has a 360-degree view of HTCondor's relationship to LIGO. He worked on the HTCondor team for 10 years at UW–Madison, and managed the relationship between LIGO and HTCondor for about five years after joining the LIGO team led by Brown at Syracuse. Today he is a senior scientist at Caltech managing the LIGO data analysis computing team. Why is the HTCondor software such a boon to big science endeavors like LIGO? "We know it will work—that's the killer feature of HTCondor," says Couvares. It works, he adds, because HTCondor takes seriously the core challenge of distributed computing: It's impossible to assume that a network of thousands of individual computers will not have local failures. HTCondor bakes that assumption into its core software. "The HTCondor team always asks people to think ahead to the issues that are going to come up in real production environments, and they're good about not letting HTCondor users take shortcuts or make bad assumptions," Couvares adds. In a project like LIGO, that approach is especially important. The steady stream of data from LIGO detectors is a mix of gravitational information and noise such as seismic activity, wind, temperature and light—all of which helps define and differentiate both good and bad data. "In the absence of noise, this would have been a very easy search," Couvares says. "But the trick is in picking a needle out of a haystack of noise. The biggest trick of all the data analysis in LIGO is to come up with a better signal-to-noise ratio." Stuart Anderson, LIGO senior staff scientist at Caltech, has been supporting the use of HTCondor within LIGO for more than a decade. The reason HTCondor succeeds is less about technology than it is about the human element, he says. "The HTCondor team provides a level of long-term collaboration and support in cyber-infrastructure that I have not seen anywhere else," he says. "The team has provided the highest quality of technical expertise, communication skills and collaborative problem-solving that I have had the privilege or working with." Adds Todd Tannenbaum, the current HTCondor technical lead who works closely with Anderson and Couvares: "Our relationship with LIGO is mutually profitable. The improvements made on behalf of our relationship with LIGO have greatly benefited HTCondor and the wider high throughput computing community." Ewa Deelman, research associate professor and research director at the University of Southern California Information Sciences Institute (ISI), became involved with HTCondor in 2001 as she launched Pegasus, a system that automates the workflow for scientists using systems like HTCondor. Together, Pegasus and HTCondor help lower the technological barriers for scientists. "I think the automation and the reliability provided by Pegasus and HTCondor are key to enabling scientists to focus on their science, rather than the details of the underlying cyber-infrastructure and its inevitable failures," she says. The future of LIGO is tremendously exciting, and the underpinning high-throughput computing technologies of HTCondor will change with the science and the computing technologies. Most agree that with the initial observation of gravitational waves, a potential tsunami of data awaits from the universe. "The field of gravitational wave astronomy has just begun," says Couvares. "This was a physics and engineering experiment. Now it's astronomy, where we're seeing things. For 20 years, LIGO was trying to find a needle in a haystack. Now we're going to build a needle detection factory." Adds Livny: "What started 15 years ago as a local Madison-Milwaukee collaboration turned into a computational framework for a new field of astronomy. We are ready and eager to address the evolving HTC needs of this new field. By collaborating with scientists from other international efforts that use technologies ranging from a neutrino detector in the South Pole (IceCube) to a telescope floating in space (Hubble) to collect data about our universe, HTC will continue to support scientific discovery." Explore further: Science powerhouses unite to help search for gravitational waves


News Article | November 23, 2016
Site: www.eurekalert.org

MADISON, Wis. -- In our guts, and in the guts of all animals, resides a robust ecosystem of microbes known as the microbiome. Consisting of trillions of organisms -- bacteria, fungi and viruses -- the microbiome is essential for host health, providing important services ranging from nutrient processing to immune system development and maintenance. Now, in a study comparing mice raised in a "germ free" environment and mice raised under more typical lab conditions, scientists have identified yet another key role of the microbes that live within us: mediator of host gene expression through the epigenome, the chemical information that regulates which genes in cells are active. Writing online this week (Nov. 23, 2016) in the journal Molecular Cell, a team of researchers from the University of Wisconsin-Madison describes new research helping tease out the mechanics of how the gut microbiome communicates with the cells of its host to switch genes on and off. The upshot of the study, another indictment of the so-called Western diet (high in saturated fats, sugar and red meat), reveals how the metabolites produced by the bacteria in the stomach chemically communicate with cells, including cells far beyond the colon, to dictate gene expression and health in its host. "The bugs are somehow driving gene expression in the host through alteration of the epigenome," explains John Denu, a UW-Madison professor of biomolecular chemistry and a senior researcher at the Wisconsin Institute for Discovery, and a co-author of the new study. "We're starting to understand the mechanism of how and why diet and the microbiome matter." The study, which was led by Kimberly Krautkramer, an MD/Ph.D. student in the UW School of Medicine and Public Health, revealed key differences in gene regulation in conventionally raised mice and mice raised in a germ-free environment. The mice were provided with two distinct diets: one rich in plant carbohydrates similar to fruits and vegetables humans consume; the other mimicking a Western diet, high in simple sugars and fat. A plant-based diet, according to Federico Rey, a UW-Madison professor of bacteriology and also a co-corresponding author of the new report, yields a richer microbiome: "A good diet translates to a beautifully complex microbiome," Rey says. "And we see that the gut microbiome affects the host epigenome in a diet-dependent manner. A plant-based diet seems to favor host-microbe communication." The new Wisconsin study shows that a small set of short-chain fatty acids produced as the gut bacteria consume, metabolize and ferment nutrients from plants are important chemical messengers, communicating with the cells of the host through the epigenome. "One of the findings here is that microbial metabolism or fermentation of plant fiber results in the production of short-chain fatty acids. These molecules, and potentially many others, are partially responsible for the communication" with the epigenome, says Denu. In the study, the gut microbiota of the animals that were fed a diet rich in sugar and fat have a diminished capacity to communicate with host cells. According to the Wisconsin team, that may be a hint that the template for a healthy human microbiome was set in the distant past, when food from plants made up a larger portion of diet and sugar and fat were less available than in contemporary diets with more meat and processed foods. "As we move away from plant-based diets, we may be losing some of that communication between microbes and host," notes Rey. "With a Western-type diet, it seems like the communication between microbes and host gets lost." Foods rich in fat and sugar, especially processed foods, are more easily digested by the host, but are not necessarily a good source of food for the flora inhabiting the gut. The result is a less diverse microbiome and less communication to the host, according to the researchers. A surprising finding in the study is that the chemical communication between the microbiome and host cells is far reaching. In addition to talking to cells in the colon, the microbiome also seems to be communicating with cells in the liver and in fatty tissue far removed from the gut. That, says Denu, is more evidence of the importance of the microbiome to the well-being of its host. The kicker experiment in the study, says Denu, was providing mice raised in a germ-free environment with three different short-chain fatty acids that the study showed to be important messengers to the epigenome. The supplement was enough to promote the kind of healthy interplay between microbiota and host cells seen in mice given a diet high in plant fiber. "It helps show that the collection of three short-chain fatty acids produced in the plant-based diet are likely major communicators," adds Denu. "We see that it is not just the microbe. It's microbial metabolism." This research was funded by the National Institutes of Health under grants F30 DK108494 and GM059789-15/P250VA. Additional support was provided by the Clinical and Translational Science Award program through the NIH National Center for Advancing Translational Sciences grants UL1TR000427, KL2TR000428, DK108259, and DK101573.


News Article | November 25, 2016
Site: www.medicalnewstoday.com

The study - by a team at the University of Wisconsin-Madison (UW-Madison) - is published in the journal Molecular Cell. Genes - strips of DNA contained in chromosomes - are the blueprint for making organisms and sustaining life. However, while their DNA makeup is relatively fixed, genes respond to changes in environment. Interactions with the environment do not change the genes, but they alter their expression by switching them on and off through chemical tags on the DNA. The complete set of genetic material contained in our genes is called the genome, and the multitude of molecules that tell the genome what to do is called the epigenome. Our gut is home to trillions of microbes - altogether, they can weigh up to 2 kilograms. They not only help to digest food via fermentation, but in the process produce molecules called metabolites that influence health and disease - for instance, to improve immune function and defend against infection. In their paper, the UW-Madison researchers explain that while we have discovered that the colonies of microbes in our gut - collectively termed the gut microbiota - produce a myriad of metabolites that affect health and disease, the underlying molecular mechanisms are poorly understood. For their study, the researchers used mice raised on two different diets: one rich in plant carbohydrates (mimicking a human diet rich in fruits and vegetables) and the other high in simple sugars and fats (mimicking a Western diet). The researchers found that a small group of short-chain fatty acids - metabolites produced when gut bacteria ferment nutrients from plants - were communicating with the cells of the host animals through the epigenome. One of the investigators, John M. Denu, a UW-Madison professor of biomolecular chemistry and a senior researcher at the Wisconsin Institute for Discovery, says the short-chain fatty acids, and potentially many others, are partially responsible for the communication with epigenome. When Prof. Denu and colleagues compared the mice fed on a Western-style diet with the ones on a diet rich in plant carbohydrates, they found the Western-style diet prevents many of the epigenetic changes that occur in the plant-rich diet. In a further set of experiments, the researchers then supplemented the diet of mice raised in a germ-free environment (so they have no gut microbiota to speak of) with the short-chain fatty acids - metabolites of gut bacteria fermentation. They found that the short-chain fatty acid supplements restored the types of epigenetic changes seen in normal mice raised on the plant-rich diet. Prof. Denu suggests their findings help show "the collection of three short-chain fatty acids produced in the plant-based diet are likely major communicators. We see that it is not just the microbe. It's microbial metabolism." He and his colleagues also note that while foods rich in fat and sugar - hallmarks of the Western diet - are more easily digested, they are not necessarily a good source of nutrients for gut microbes. This results in a less diverse microbiome, and less communication with the epigenome, they suggest. They conclude that their findings have "profound implications for understanding the complex functional interactions between diet, gut microbiota, and host health." Another surprising result of the study is that the communication between the gut microbiome and the host reaches beyond the colon. For example, the team found evidence of communication with cells of the liver and fatty tissue of the gut. Discover how high-fat diets alter gut microbes in a way that aggravates a serious eye disease.


News Article | November 15, 2016
Site: globenewswire.com

MADISON, Wis., Nov. 15, 2016 (GLOBE NEWSWIRE) -- The prospect of creating artery "banks" available for cardiovascular surgery, bypassing the need to harvest vessels from the patient, could transform treatment of many common heart and vascular ailments. But it's a big leap from concept to reality. The Morgridge Institute for Research and the University of Wisconsin-Madison will address both the engineering and biomedical hurdles in this process through a five-year, $8 million project funded by the National Heart, Lung and Blood Institute (NHLBI). Patients needing bypass surgeries would benefit from a better source for arteries, says project leader James Thomson, a stem cell research pioneer and Director of Regenerative Biology at Morgridge. Replacement tissue currently comes from another part of the patient's body, and suitable tissue can't be found for many patients. Current synthetic alternatives also fail at a high rate. Diseases of blood vessels — including coronary artery disease — kill more people worldwide than any other single cause. "Tissue engineering for blood vessels is a pretty mature field," says Thomson. "But there are still two major problems: One is the time it takes to make the vessels, and the other is the source of the cells to grow them." For example, taking induced pluripotent (iPS) stem cells from an individual patient, growing the relevant cells and assembling them into an artery would overcome the problem of transplant rejection, Thomson says. However, it would be cost-prohibitive and take months to complete — too long to be clinically useful to a patient. The promising alternative is to create tissue with cells banked from a unique population of people who are genetically compatible donors, based on rare alleles that circumvent rejection. Alleles are gene pairings that control certain characteristics, such as blood type. It has been estimated that about 100 different cell lines from this rare population would be enough to cover a majority of the U.S. population. The Morgridge and UW-Madison effort covers four phases and addresses key questions about the feasibility of this approach. The model for the project is designed around treating critical limb ischemia, a debilitating condition that restricts blood flow to limbs and often leads to amputation or death. The Thomson group is working to create the optimal cellular building blocks of the artery — endothelial and smooth muscle cells — that will be most suitable for transplantation and continue to grow and remodel in the patient. In tandem, a team led by UW-Madison engineer Tom Turng will develop scaffolds from natural and synthetic materials to provide structure and shape for the artery. UW-Madison engineer Naomi Chesler will build a bioreactor that provides an environment in which the arterial cells can grow around the scaffolding. The transplant surgery and resulting immune response will then be tested using a monkey limb ischemia model at the Wisconsin Regional Primate Research Center. Having a primate model is important to produce results more relevant to human health than those from mice or other short-lived animals. Pathology and laboratory medicine Professor Igor Slukvin is leading the Primate Center effort. Finally, the UW-Madison Waisman Center Biomanufacturing facility will lead the production of arterial cells that meet FDA standards for human clinical trials, paving the way for potential treatments for limb ischemia in humans. If the entire process works, Thomson estimates that potential human therapies remain about 10 years away. "This is a collaboration that really highlights what the Morgridge Institute does well because we are able to bring together multiple investigators from different departments and centers around campus," Thomson says. "We have an unusual combination of resources in Madison to be able to pull this off." The heart of the partnership to date has been between Thomson's team and the BIONATES program in the Wisconsin Institute for Discovery, led by Turng. Both labs operate on the same floor of the Discovery building, and the three-year collaboration is a prime example of how the public and private institutes work together to foster innovation. As Turng works to determine the optimal choice of materials and methods for construction of the blood vessel scaffolds – biopolymers versus synthetic polymers or a combination of both – the partnership inside the Discovery Building is vital to progress. "We have direct feedback with Thomson and the other researchers, and the iterative process can be facilitated," says Turng. "We can speak the same language." Providing proof of concept on the blood vessel work should benefit other forms of stem cell therapy, Thomson says. "This has implications beyond making vessels for transplantation; it's sort of the stepping stone to more advanced tissue engineering," he says. "Any form of cellular transplant therapy is going to need a blood supply, and we need to learn how to engineer that blood supply to work with more complex tissues."


News Article | November 15, 2016
Site: www.eurekalert.org

MADISON -- The prospect of creating artery "banks" available for cardiovascular surgery, bypassing the need to harvest vessels from the patient, could transform treatment of many common heart and vascular ailments. But it's a big leap from concept to reality. The Morgridge Institute for Research and the University of Wisconsin-Madison will address both the engineering and biomedical hurdles in this process through a five-year, $8 million project funded by the National Heart, Lung and Blood Institute (NHLBI). Patients needing bypass surgeries would benefit from a better source for arteries, says project leader James Thomson, a stem cell research pioneer and Director of Regenerative Biology at Morgridge. Replacement tissue currently comes from another part of the patient's body, and suitable tissue can't be found for many patients. Current synthetic alternatives also fail at a high rate. Diseases of blood vessels -- including coronary artery disease -- kill more people worldwide than any other single cause. "Tissue engineering for blood vessels is a pretty mature field," says Thomson. "But there are still two major problems: One is the time it takes to make the vessels, and the other is the source of the cells to grow them." For example, taking induced pluripotent (iPS) stem cells from an individual patient, growing the relevant cells and assembling them into an artery would overcome the problem of transplant rejection, Thomson says. However, it would be cost-prohibitive and take months to complete -- too long to be clinically useful to a patient. The promising alternative is to create tissue with cells banked from a unique population of people who are genetically compatible donors, based on rare alleles that circumvent rejection. Alleles are gene pairings that control certain characteristics, such as blood type. It has been estimated that about 100 different cell lines from this rare population would be enough to cover a majority of the U.S. population. The Morgridge and UW-Madison effort covers four phases and addresses key questions about the feasibility of this approach. The model for the project is designed around treating critical limb ischemia, a debilitating condition that restricts blood flow to limbs and often leads to amputation or death. The Thomson group is working to create the optimal cellular building blocks of the artery -- endothelial and smooth muscle cells -- that will be most suitable for transplantation and continue to grow and remodel in the patient. In tandem, a team led by UW-Madison engineer Tom Turng will develop scaffolds from natural and synthetic materials to provide structure and shape for the artery. UW-Madison engineer Naomi Chesler will build a bioreactor that provides an environment in which the arterial cells can grow around the scaffolding. The transplant surgery and resulting immune response will then be tested using a monkey limb ischemia model at the Wisconsin Regional Primate Research Center. Having a primate model is important to produce results more relevant to human health than those from mice or other short-lived animals. Pathology and laboratory medicine Professor Igor Slukvin is leading the Primate Center effort. Finally, the UW-Madison Waisman Center Biomanufacturing facility will lead the production of arterial cells that meet FDA standards for human clinical trials, paving the way for potential treatments for limb ischemia in humans. If the entire process works, Thomson estimates that potential human therapies remain about 10 years away. "This is a collaboration that really highlights what the Morgridge Institute does well because we are able to bring together multiple investigators from different departments and centers around campus," Thomson says. "We have an unusual combination of resources in Madison to be able to pull this off." The heart of the partnership to date has been between Thomson's team and the BIONATES program in the Wisconsin Institute for Discovery, led by Turng. Both labs operate on the same floor of the Discovery building, and the three-year collaboration is a prime example of how the public and private institutes work together to foster innovation. As Turng works to determine the optimal choice of materials and methods for construction of the blood vessel scaffolds - biopolymers versus synthetic polymers or a combination of both - the partnership inside the Discovery Building is vital to progress. "We have direct feedback with Thomson and the other researchers, and the iterative process can be facilitated," says Turng. "We can speak the same language." Providing proof of concept on the blood vessel work should benefit other forms of stem cell therapy, Thomson says. "This has implications beyond making vessels for transplantation; it's sort of the stepping stone to more advanced tissue engineering," he says. "Any form of cellular transplant therapy is going to need a blood supply, and we need to learn how to engineer that blood supply to work with more complex tissues."


News Article | November 22, 2016
Site: www.eurekalert.org

MADISON, Wis. - New insights into the mechanism behind how plants age may help scientists better understand crop yields, nutrient allocation, and even the timing and duration of fall leaf color. In a new paper published today (Tues., Nov. 22) in the journal eLife, the University of Wisconsin-Madison's Xuehua Zhong and her colleagues describe how an epigenetic protein complex acts as a link between the environment and the genome to promoting the onset of aging in plants. That complex is a specific histone deacetylase (HDAC) called HDA9 and it helps translate environmental signals, like darkness, into epigenetic change. Epigenetics refers to the alterations that influence the expression of genes encoded within the DNA of living organisms, rather than changes to the DNA itself. For instance, fall colors change when shorter daylight hours influence the expression of the genes responsible for particular leaf pigments. "Epigenetics is one of the important players in the cross-talk between the environment and our bodies," says Zhong, assistant professor of genetics and a faculty member at the Wisconsin Institute for Discovery. Her research focuses on how gene expression in growth and development is regulated by epigenetic modification and how that regulation can be influenced by environmental stimuli. Aging, or senescence, is an elaborate process vital to the life cycle of a plant. The efficiency of this process has critical implications for biological success: Premature aging could result in a reduction in yield, a grave concern for the production of offspring and cultivation of crops. Belated senescence, on the other hand, reduces a plant's efficiency by delaying reallocation of nutrients and may impact the viability of the next generation. By searching the genome of the common experimental plant model Arabidopsis thaliana (commonly known as thale cress) for locations where HDA9 binds, Zhong's group found evidence that it is a key player in the senescence process. It acts on previously identified genes that code for various components of aging. "We found that this protein binds to a lot of genes that have potential functions in the aging process. That provides some other information which led us to study the potential functions in [the process]," says Xiangsong Chen, a postdoctoral researcher working with Zhong and first author on the paper. The team says that the newly-profiled HDAC jumpstarts the process of aging, which is responsible for the many-colored leaves of the fall season. This process is also of key importance commercially, Zhong says, and the mechanistic insight into the initiation of aging is a significant step forward in epigenetics research. "We believe that this information will provide a foundation for developing a new strategy to manipulate the plant aging processes to improve crop productivity, which could prove very beneficial for agricultural improvement," says Zhong.


Flack J.C.,Wisconsin Institute for Discovery | Flack J.C.,Santa Fe Institute
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2012

To build a theory of social complexity, we need to understand how aggregate social properties arise from individual interaction rules. Here, I review a body of work on the developmental dynamics of pigtailed macaque social organization and conflict management that provides insight into the mechanistic causes of multi-scale social systems. In this model system coarse-grained, statistical representations of collective dynamics are more predictive of the future state of the system than the constantly in-flux behavioural patterns at the individual level. The data suggest that individuals can perceive and use these representations for strategical decision-making. As an interaction history accumulates the coarse-grained representations consolidate. This constrains individual behaviour and provides the foundations for new levels of organization. The time-scales on which these representations change impact whether the consolidating higher-levels can be modified by individuals and collectively. The time-scales appear to be a function of the 'coarseness' of the representations and the character of the collective dynamics over which they are averages. The data suggest that an advantage of multiple timescales is that they allow social systems to balance tradeoffs between predictability and adaptability. I briefly discuss the implications of these findings for cognition, social niche construction and the evolution of new levels of organization in biological systems. © 2012 The Royal Society.


Flack J.C.,Wisconsin Institute for Discovery | Flack J.C.,Santa Fe Institute
Current Biology | Year: 2013

A hallmark of human communication is vocal turn taking. Until recently, turn taking was thought to be unique to humans but new data indicate that marmosets, a new world monkey, take turns when vocalizing too. © 2013 Elsevier Ltd.

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