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‘KinderMining’: Tackling big data sets by keeping things simple  external link

Photo: Closeup of researcher with stem cells

A research assistant uses a pipette to change media that feed trays of human embryonic stem cell cultures in a UW-Madison research lab. Many of UW stem cell pioneer James Thomson’s landmark discoveries provided the original inspiration for the KinderMiner project. Photo: Jeff Miller

With about 100 lines of code, a Morgridge Institute for Research team has unleashed a fast, simple and predictive text-mining tool that may turbocharge big biomedical pursuits such as drug repurposing and stem cell treatments.

The algorithm, named “KinderMiner” by its inventors, has been put to use exploring one of the largest single archives of research journal papers, Europe PubMed Central. Within hours, it can scan the more than 30 million papers online in Europe PMC and provide ranked associations for select target terms and key phrases.

“We started this project to try to find a text mining approach that works more effectively for scientists,” says senior author Ron Stewart, associate director of bioinformatics at Morgridge, a biomedical institute affiliated with the University of Wisconsin-Madison. “Most often, researchers are running manual Google searches and combing through millions of hits to find, for example, certain genes that are important to a biological process or disease. It’s often based on hunches and intuition. We’re trying to automate and formalize that process.”

Photo: Ron Stewart

Ron Stewart

Photo: Finn Kuusisto

Finn Kuusisto

Finn Kuusisto, a postdoctoral researcher at the Morgridge Institute and first author on the KinderMiner paper, presented results Wednesday, March 29, at the American Medical Informatics Association’s annual Joint Summits on Translational Science in San Francisco. The summit showcases new applications in bioinformatics that are improving health care.

“There are other techniques out there that require a lot more data-wrangling,” says Kuusisto. “But in our case, we write about 100 lines of Python code, and our users can be given answers that may significantly speed up their scientific process.”

The scientists emphasize that while their queries focused on biomedicine, KinderMiner can be applied to any discipline — the only constant is the need for a massive corpus to search. The next step will be to create an online search interface available for the scientific community.

To test KinderMining, the team chose two scientific projects that prove to be time consuming and often intractable. The first is identifying relevant transcription factors to reprogram stem cells, and the second is finding potential drugs with off-label benefits or adverse effects.

For cell reprogramming, there are about 2,000 known transcription factors that might be useful in changing a cell from one state to another, such as creating induced pluripotent stem (iPS) cells from skin cells. They used KinderMining on three reprogramming efforts that are well established in research literature: creating iPS cells, creating cardiomyocytes, and maturation of liver cells.

To show the predictive power of the algorithm, the team censored the literature by date, taking out all papers beginning two years before the published dates of each discovery. They queried only up to 2004 for iPS cells, 2008 for cardiomyocytes and 2009 for liver cells.

“Most often, researchers are running manual Google searches and combing through millions of hits … It’s often based on hunches and intuition. We’re trying to automate and formalize that process.”

Ron Stewart

The results in all three tests identified numerous relevant transcription factors in the top 20 hits — again, from a potential pool of more than 2,000 factors. This is a substantial benefit to the wet lab scientists, given that the factors likely need to act in combination. For instance, if one needs to test all 2,000 factors four at a time, it represents 100 billion experiments — clearly outside the realm of possibility.

Stewart notes that KinderMining ranks the factors, and it is likely that the important factors will be in the top 10 or 20. Now if scientists test 10 factors four at a time, it requires a manageable 210 experiments, Stewart says.

They compared their results against a state of the art data mining tool called Mogrify, and the KinderMining results overlap on a large proportion of accurate hits.

“This is kind of like a ‘time machine’ for biology, where we can go back before any of the big publications came out on reprogramming, and still make a good guess about what genes are most important,” says Stewart.

Stewart works in the Morgridge regenerative biology team led by stem cell pioneer James Thomson, and many of Thomson’s landmark discoveries provided the original inspiration for this project. “It would be great if we could help someone in the Thomson lab or a related lab come up with a discovery that has great clinical benefit — but instead of taking 15 years, we do it in three years.”

The second big test involved scanning Europe PMC to identify drugs that have the effect of reducing blood glucose. Of the top 50 drugs found, 43 are known diabetes treatments, but the team found seven drugs that either raise or lower blood glucose as a secondary, off-label effect. Those hits are especially important as they demonstrate possible prediction of repurposed drug targets.

“You could spend all your time … scanning the literature for this kind of secondary drug effect and only scratch the surface of what’s out there. It’s better to write an automated machine learning package to do it instead.”

David Page

Repurposed drugs make up about 30 percent of all new drugs or vaccines approved by the U.S. Food and Drug Administration. David Page, a co-author on the study and a professor of biostatistics and medical informatics at UW-Madison, says he is excited about the potential of KinderMiner to identify promising drugs to repurpose.

“You could spend all your time — and all your students’ time — scanning the literature for this kind of secondary drug effect and only scratch the surface of what’s out there,” Page says. “It’s better to write an automated machine learning package to do it instead.”

Kuusisto and Page have received approval to use approximately 10 million de-identified electronic health records from the Veterans Administration to continue the drug repurposing work, examining several drug effects such as lowering of cholesterol levels or blood pressure.

Morgridge computational biologist John Steill, another co-author of the KinderMining study, is using the tool to improve gene marker lists, which have numerous uses such as classifying cells or samples by cell type and identifying samples that may produce tumors.

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Enzyme structures illuminate mechanism behind bacteria’s bioremediation prowess  external link

Photo: Contract employees with BP America load an oil containment boom onto a work boat to assist in oil recovery efforts from the Deepwater Horizon oil spill in the Gulf of Mexico.

Contract employees with BP America load an oil containment boom onto a work boat to assist in oil recovery efforts from the Deepwater Horizon oil spill in the Gulf of Mexico. Photo: U.S. Navy

Bacteria, like humans and animals, must eat.

Sometimes, they consume a pollutant in the environment that humans want to get rid of, a process called bioremediation. Investigating the enzymes used by bacteria to carry out that process is important for scientists to understand and possibly improve on these powerful reactions. However, until now, having a snapshot of one of these important enzymes in action has eluded science.

In a publication in the journal Nature released today (March 27, 2017), scientists from the Department of Biochemistry and Department of Chemistry at the University of Wisconsin–Madison have solved the structure of an enzyme caught in the act of attacking toluene — a chemical derived from wood and oil. The work is important because it provides a glimpse of the mechanics of a process that could be harnessed to help clean up oil spills and create valuable new chemicals.

Illustration: Toluene (green molecule) in the process of reacting with oxygen atoms (red) bound between two iron atoms (grey) in a bacterial enzyme.

Toluene (green molecule) in the process of reacting with oxygen atoms (red) bound between two iron atoms (grey) in a bacterial enzyme. Illustration: Brian Fox

“In this research, we are trying to understand how nature uses iron atoms, electrons, and oxygen gas from the air to selectively oxidize chemicals,” says biochemistry Professor and Chair Brian Fox. “This reaction is the first step in a process where the carbon atoms in toluene, called an aromatic ring, are prepared for consumption by bacteria.”

This reaction plays out at the atomic level, in a game of electron and atom transfer. The active site of the large enzyme contains two iron atoms that also store up to two electrons. These react with oxygen gas to combine and “attack” the aromatic ring of toluene, with electrons being exchanged along the way. Ultimately, an oxygen atom is added to the toluene ring, opening the door for other reactions used by the bacteria to consume toluene.

The most satisfying piece of information revealed by the combination of crystal structures and quantum chemical calculations carried out in this study, Fox says, concerns the nature of the iron-oxygen intermediate that attacks the aromatic ring. Scientists generally assumed it would take an extremely reactive iron-oxygen species to carry out this reaction. But what Fox and his team found was that a less reactive form could actually be used.

“The most highly reactive intermediates, previously thought to be part of this reaction, would also be unspecific,” explains chemistry Professor Thomas Brunold. “With that intermediate, there would be a risk for the enzyme to attack whatever is nearby, including itself. If nature could avoid this by forming a less reactive, but still sufficiently potent intermediate, it could avoid many undesired side reactions. That’s what Brian thought was happening and that’s exactly what he found.”

Photo: Brian Fox

Brian Fox

Photo: Thomas Brunold

Thomas Brunold

Brunold adds that understanding the reaction of this enzyme may be helpful for many synthetic chemists. As they design new molecules and pathways, these chemists often take hints from a great teacher — nature itself. Chemists now have knowledge to better mimic the way this enzyme functions in order to make new catalysts that are more specific for different applications.

When bacteria carry out this transformation of toluene, they start a process that rapidly removes it from the environment. In this way, bacterial bioremediation is able to remove harmful substances from the environment, something scientists are already taking advantage of to help ecosystems recover from chemical catastrophes like oil spills. Other researchers are exploring how to redirect the reactivity of this enzyme to synthesize new chemicals.

“Broadly, these types of natural reactions are environmentally friendly and cheap,” Brunold says. “In industry, researchers often perform challenging reactions with complex chemicals in harsh conditions, which can result in lots of waste and energy used. Investigating how enzymes like the one we studied catalyze their reactions can help find more efficient ways to perform these challenging reactions.”

The work is important because it provides a glimpse of the mechanics of a process that could be harnessed to help clean up oil spills and create valuable new chemicals.

For the study, lead author Justin Acheson, a former student in Fox’s lab, was able to stop the reaction midway through and generate an image of precisely how the enzyme is functioning. In an admittedly odd but effective approach, the researchers took a crystal of the enzyme and dipped it into toluene. They then exposed it to air, allowing oxygen molecules to begin the reaction. Finally, they froze the crystal, slowing down the reaction at precisely the right time to capture the intermediate before it could further react.

“There’s real importance to knowing this structure,” Fox says. “Having it gives us a unique look at how this reaction takes place. We found something unanticipated, and that gives new avenues to discovery and future application.”

This study was funded by the National Science Foundation. Use of the Advanced Photon Source was supported by the U.S. Department of Energy Office of Science.

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Yellow fever killing thousands of monkeys in Brazil  external link

In the first segment of this video, a brown howler monkey displays his or her guttural call in a federally-protected reserve in southeastern Brazil called RPPN Feliciano Miguel Abdala. In the second segment, muriqui monkeys roam the forest floor. Credit, part 1: Jefferson Cordeiro, Muriqui Project of Caratinga. Credit, part 2: K.B. Strier, Muriqui Project of Caratinga. 

In a vulnerable forest in southeastern Brazil, where the air was once thick with the guttural chatter of brown howler monkeys, there now exists silence.

Yellow fever, a virus carried by mosquitoes and endemic to Africa and South America, has robbed the private, federally-protected reserve of its brown howlers in an unprecedented wave of death that has swept through the region since late 2016, killing thousands of monkeys.

Karen Strier, a University of Wisconsin–Madison professor of anthropology, has studied the monkeys of this forest since 1983. She visited the reserve – her long-term study site near the city of Caratinga – in the state of Minas Gerais, in January of 2017. “It was just silence, a sense of emptiness,” she says. “It was like the energy was sucked out of the universe.”

Using what in some cases are decades of historical data, Strier and a team of Brazilian scientists focused on studying primates in Brazil’s patchwork Atlantic Forest are poised to help understand and manage what happens next. They have never seen monkeys perish in such numbers, so quickly, from disease.

The four-square-mile as RPPN Feliciano Miguel Abdala study forest is seen.

A view of the four-square-mile federally-protected reserve and study forest in southeastern Brazil called RPPN Feliciano Miguel Abdala. Carla Possamai, Muriqui Project of Caratinga

With her Brazilian counterpart Sérgio Lucena Mendes, a professor of animal biology at the Universidade Federal de Espirito Santo, and their former postdoctoral researcher, Carla Possamai, Strier is ready to census the monkeys that remain at the reserve, comparing the new data to prior censuses performed in the forest. They also plan to study how the surviving brown howler monkeys regroup and restructure their societies, since their existing social groups have been destroyed.

Strier’s study forest, just 4 square miles in size, is a land-locked island of green surrounded by agricultural and pasture lands. How yellow fever showed up here is a mystery, and the monkeys in the forest have nowhere else to go. Less than 10 percent of Brazil’s Atlantic Forest remains intact and much of it exists only as small patches in a fragmented landscape.

“I am very surprised at the speed with which the outbreak is advancing through the landscape and by how the virus can jump from one patch of forest to another, even if they are hundreds of meters apart,” says Mendes. “It is also surprising that it is spreading across such a large geographic region.”

The way yellow fever has spread also concerns Brazilian health officials. As of mid-March 2017, they have confirmed more than 400 human cases of the disease, mostly in Minas Gerais, causing nearly 150 human deaths. The Brazilian Ministry of Health is investigating another 900 possible cases and concern is mounting that it will spread to cities, threatening many more people.

Muriqui monkeys in a federally-protected reserve in southeastern Brazil, called RPPN Feliciano Miguel Abdala. University of Wisconsin–Madison Professor of Anthropology Karen Strier, has studied the critically-endangered muriqui monkeys in this patch of Brazil's Atlantic Forest since 1983. A recent and unprecedented outbreak of the mosquito-borne virus, yellow fever, has killed thousands of monkeys in the region, including nearly all of the muriqui's main competitors, brown howler monkeys.

Muriqui monkeys in a federally-protected reserve in southeastern Brazil, called RPPN Feliciano Miguel Abdala. UW–Madison Professor Karen Strier has studied the critically-endangered muriqui monkeys in this patch of Brazil’s Atlantic Forest since 1983. A recent and unprecedented outbreak of the mosquito-borne virus, yellow fever, has killed thousands of monkeys in the region, including nearly all of the muriqui’s main competitors, brown howler monkeys. Carla Possamai, Muriqui Project of Caratinga

Brazilian authorities also want to protect the monkeys from people who fear the animals may be spreading the disease. “We need to show that they help inform when the virus arrives in a region, because being more sensitive than humans, they die first,” Mendes explains.

A dead monkey is like a canary in a coal mine, alerting public health officials that a pathogen may be present, mobilizing preventative and precautionary efforts. So, what does it mean when so many have perished?

“No one really knows the consequences for the other primates or the forest when nearly the entire population of an abundant species dies from disease in just a few months,” says Strier. “We are in a position to learn things we never knew before, with all the background information that we have collected.”

Nearly two decades ago, Strier helped expand and secure protection for the primates at her study forest, which include four monkey species: the brown howler, the black capuchin, the buffy-headed marmoset and, Strier’s animal of interest, the critically-endangered northern muriqui.

It is too soon to say whether the howler monkey population can recover but Strier remains optimistic, in large part because of a career spent studying and helping conserve the brown howler’s main competitor, the muriquis. “The muriquis have shown us that it’s possible for small populations of primates to recover if they are well-protected,” says Strier.

When she first arrived at her study forest, known as RPPN Feliciano Miguel Abdala, there were just 50 muriquis. By September 2016, there were nearly 340, representing one-third of the species’ total known population. The animals reside in just 10 forests in southeastern Brazil and nowhere else in the world. Strier’s efforts and those of her colleagues have helped restore their numbers.

She is relieved that, so far, the muriquis appear to be less susceptible to yellow fever. “It was really tense – scary – to go into the forest, knowing the howlers were gone but not knowing how bad things might also be for the muriquis,” Strier recalls.

Muriqui monkeys in a federally-protected reserve in southeastern Brazil.

Muriqui monkeys in a federally-protected reserve in southeastern Brazil. Carla Possamai, Muriqui Project of Caratinga

Her long-term studies have revealed that muriquis have a lifespan of more than 40 years and she has known some of the individual muriquis in the forest their entire lives. Strier can recognize individuals based on natural differences in their fur and facial markings.

Now, in the face of ecological tragedy, she and her colleagues have an opportunity to study how the muriquis adapt in a forest nearly devoid of their competitors.

“It’s like a controlled natural experiment, but one you would never plan to do,” Strier says. “My happy hypothesis is that the muriquis are out foraging, feasting on all the best fruits and leaves that the howlers used to eat. Will they eat more of their favorite foods, or travel less? Will their social order change? Will they form smaller groups?”

She has documented that kind of behavioral flexibility before. In the late 1980s and early 90s, the muriquis began splitting into smaller groups. In the early 2000s, as their population grew, they began spending more time on the ground, rather than in the trees, often consuming fallen fruits and even half-eaten “leftovers” under the trees.

“I feel like I am 20 years old again” she says. “I have so many questions that are important to answer, for the primates, their Atlantic forest habitat, and for the people that share their world.”

To raise awareness about and funds for her muriqui project, Strier is working with the Brazilian non-profit that administers the reserve, called Preserve Muriqui, and Global Wildlife Conservation, a Texas-based non-profit dedicated to conserving the diversity of life on earth.

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Researchers gain insight into day-to-day lives of parents raising children with autism  external link

Like all parents, couples who have a child with autism spectrum disorder (ASD) share the ups and downs of parenting.

A new study by Waisman Center researchers at the University of Wisconsin-Madison looks at the daily experiences of these parents to provide a more detailed picture of the strengths and vulnerabilities of couples raising a child with ASD.

“I think we can use these findings to develop more effective therapies and strategies to address potential challenges in couple relationships for parents of children with ASD,” says Sigan Hartley, lead author of the new study, published this month in the Journal of Autism and Developmental Disorders.

Photo: Sigan Hartley

Sigan Hartley says until now, there’s been little research on the day-to-day lives of couples raising a child with ASD. Photo: UW-Madison School of Human Ecology

Previous findings have shown that, on average, couples with a child with ASD have higher risks of divorce and lower satisfaction with their marriages when compared to couples with a typically developing child.

“What has been missing is research that really gets at the details of what is actually happening in the day-to-day lives of these couples,” says Hartley, a Waisman Center researcher and 100 Women Chair in Human Ecology at UW-Madison.

To fill in this gap in the research, Hartley and her colleagues examined the daily experiences of 174 couples who have a child with ASD and 179 couples with a typically developing child.

Each couple kept separate “daily diaries” for two weeks, and recorded information like how much time they spent with their partners, how supported they felt, how close they felt to their partners, and the positive or negative interactions they had with them.

“These measures really let us understand how couple relationships are being altered for parents of children with ASD,” says Hartley.

The researchers found a combination of vulnerabilities and strengths. Couples parenting a child with ASD reported spending an average of 21 fewer minutes per day with their partners compared to couples with a typically developing child. That may not sound like a lot of time, but “those 21 minutes add up over weeks and months to almost 128 fewer hours spent together over a year,” says Hartley.

Spending less time together could account for why parents of children with ASD reported feeling less closeness to their partners than those raising typically developing children. The ASD group of parents also reported fewer positive interactions, such as sharing jokes, having a meaningful conversation or being intimate.

“I think we can use these findings to develop more effective therapies and strategies to address potential challenges in couple relationships for parents of children with ASD.”

Sigan Hartley

“Parents of children with ASD may have more demands on their time,” says Hartley. “They may have to navigate therapy sessions or manage special education or interventions.”

On the other hand, parents of a child with ASD showed no increase in negative interactions, like critical comments or avoiding their partner, when compared to couples with a typically developing child. These couples also felt as supported by their partners as couples with typically developing children.

“These are important relationship strengths that couples who are parenting a child with ASD can build on,” says Hartley. Finding ways to strengthen their couple dynamics can help their children as well.

“Just like any child, a child with ASD affects, and is affected by, the entire family,” says Hartley. “Developing therapies or strategies that help parents thrive and keep their relationships strong is critical for the long-term success of children.”

Other authors on the study include Leann Smith DaWalt and Haley Schultz, both at UW-Madison.

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Parsley and other plants lend form to human stem cell scaffolds  external link

Photo: Microscopic image of human cells growing on parsley

Human fibroblast cells, common connective tissue cells, growing on decellularized parsley. A team of UW-Madison researchers from the lab of bioengineering Professor William Murphy is exploring the use of plants to make the three-dimensional structures that may one day be used to repair bone and tissue. Photo: Gianluca Fontana

Borrowing from nature is an age-old theme in science. Form and function go hand-in-hand in the natural world and the structures created by plants and animals are only rarely improved on by humans.

Taking that lesson to heart, scientists at the University of Wisconsin-Madison are using the decellularized husks of plants such as parsley, vanilla and orchids to form three-dimensional scaffolds that can then be primed and seeded with human stem cells to optimize their growth in the lab dish and, ultimately, create novel biomedical implants.

Writing March 20 in the journal Advanced Healthcare Materials, a team led by William Murphy, a professor of biomedical engineering and co-director of the UW-Madison Stem Cell and Regenerative Medicine Center, describes the use of a variety of plants to create an efficient, inexpensive and scalable technology for making tiny structures that could one day be used to repair muscle, organs and bone using stem cells.

Photo: William Murphy

William Murphy

Photo: Gianluca Fontana

Gianluca Fontana

“Nature provides us with a tremendous reservoir of structures in plants,” explains Gianluca Fontana, the lead author of the new study and a UW-Madison postdoctoral fellow. “You can pick the structure you want.”

The new technology capitalizes on the elegant, efficient structural qualities of plants: strength, rigidity, porosity, low mass and, importantly, surface area. It may help overcome the limitations of current methods such as 3-D printing and injection molding to create feedstock structures for biomedical applications.

“Plants are really special materials as they have a very high surface area to volume ratio, and their pore structure is uniquely well-designed for fluid transport,” says Murphy.

The UW-Madison team collaborated with Madison’s Olbrich Botanical Gardens and curator John Wirth to identify plant species that could potentially be transformed into the miniature structures useful for biomedical applications. In addition to plants like parsley and orchid, Wirth and colleagues at Olbrich identified bamboo, elephant ear plants and wasabi as plants whose structural qualities may be amenable to creating scaffolds with properties and shapes useful in bioengineering. The team also collected plants such as the wetland-loving bulrush from the UW Arboretum.

Photo: A human fibroblast cell finds a home on a lilac leaf

A human fibroblast cell finds a home on a lilac leaf. Photo: Gianluca Fontana

“The vast diversity in the plant kingdom provides virtually any size and shape of interest,” notes Murphy, who was prompted to explore the plant world after gazing from his office window onto UW-Madison’s Lakeshore Nature Preserve. “It really seemed obvious. Plants are extraordinarily good at cultivating new tissues and organs, and there are thousands of different plant species readily available. They represent a tremendous feedstock of new materials for tissue engineering applications.”

The new approach to making scaffolds for tissue engineering depends on cellulose, the primary constituent of the cell walls of green plants. The Wisconsin team found that stripping away all of the other cells that make up the plant, and treating the leftover husks of cellulose with chemicals, entices human stem cells such as fibroblasts — common connective tissue cells generated from stem cells — to attach to and grow on the miniature structures.

Stem cells seeded into the scaffolds, according to Fontana, tend to align themselves along the pattern of the scaffold’s structure. “Stem cells are sensitive to topography. It influences how cells grow and how well they grow.”

That ability to align cells according to the structure of the plant scaffold, adds Murphy, suggests it might be possible to use the materials to control structure and alignment of developing human tissues, a feature critical for nerve and muscle tissues, which require alignment and patterning for their function.

Photo: Microscopic image of a vanilla plant stem

The stem of a vanilla plant as viewed through a scanning electron microscope. Plant structures like these, stripped of their cells, are turning out to be effective three dimensional scaffolds for growing human cells that could one day be used in cell or tissue replacement strategies. Photo: Gianluca Fontana

Another critical advantage of the plant scaffolds, notes Murphy, is the apparent ease with which they can be made and manipulated. “They are quite pliable. They can be easily cut, fashioned, rolled or stacked to form a range of different sizes and shapes.”

They are also renewable, easy to mass produce and inexpensive.

The scaffolds have yet to be tested in an animal model, but plans are underway to conduct such studies in the near future.

“Toxicity is unlikely, but there is potential for immune responses if these plant scaffolds are implanted into a mammal,” says Murphy. “Significant immune responses are less likely in our approach because the plant cells are removed from the scaffolds.”

The Wisconsin study was supported by grants from the Environmental Protection Agency, the National Institutes of Health and the National Science Foundation.

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Enormous swarms of midges teach about interconnected landscapes  external link

Photo: Researcher in swarm of midges

David Hoekman, a former postdoctoral researcher at UW–Madison, now an assistant professor at Southern Nazarene University, in a midge swarm in May 2008. Photo: Claudio Gratton

Swarms of midges rise out of a lake in northern Iceland in such enormous numbers every spring and summer that they can impair breathing and darken the sky, giving the lake its name — Myvatn, or “midge lake.”

Ecologists at the University of Wisconsin–Madison are trying to understand why the midge population can fluctuate by 100,000-fold across a decade, and what impact these massive swarms have on the surrounding landscape. It’s becoming clear that the billions of midges falling on land fertilize and alter the vegetation on the lakeside, but the cause behind such large fluctuations in the insects’ population remains a mystery.

The research aims to better understand lake-dominated environments, including those of Wisconsin.

Lake Myvatn sits at the edge of the Arctic Circle, where the sun barely sets during summer field work from May to August. The ecosystem is extreme, yet simple — a relatively small number of species, like the midges, dominate. This bare-bones environment is perfect for exploring complex interactions within ecosystems.

Photo: Claudio Gratton

Resembling a blanket of fog, midges swarm near Lake Myvatn in June 2014.

In 2005, when Claudio Gratton, a UW–Madison professor of entomology, first saw the huge numbers of midges rising out of the lake and dying on land, he thought of them as a living transfer of nutrients from water to shore. Gratton calculated that the midges were the nutritional equivalent of scattering a half-million Big Macs around the edge of the lake, which is about the size of Lake Mendota in Madison. He wondered how the lakeside responded to this nutritional glut.

To test how the midges alter the landscape, Gratton’s laboratory set up experimental plots in the vegetation around the lake. In some, they added dead midges; in others, they used netting to exclude them.

Over the years, Gratton’s team saw that where they added midges, grasses flourished. Normally starved of nutrients in the poor soil and outcompeted by heartier plants, the grasses took off in response to the influx of rotting-midge fertilizer. The research explained why grass grew in some areas and withered in others.

Photo: Claudio Gratton

Claudio Gratton

Photo: Tony Ives

Tony Ives

“Only by understanding the linkage between midges and grass can you explain this pattern in nature,” says Gratton. “The lake is causing that to happen.”

Local shepherds have long called the grass in midge-infested areas “midge grass” — they harvest the grass and feed it to their flocks. Gratton’s work suggested that the shepherds’ folklore contained a kernel of truth, and that midges might indirectly nourish the sheep by encouraging more grass growth.

Gratton was originally introduced to Lake Myvatn by Tony Ives, a UW–Madison professor of zoology, who has a lifelong connection to the island.

“I’ve been going to Iceland since I was a kid,” says Ives, whose middle name, Ragnar, was given to him in honor of an Icelandic farmer and friend of his father.

Ives learned about the unpredictable and large swings in midge population through Arni Einarsson, the director of the Lake Myvatn research station, who has studied the lake since the 1970s.

In a 2008 article in the journal Nature, Ives, Einarsson and their collaborators laid out a straightforward mathematical framework that might explain how the midge population spikes and crashes so dramatically and unpredictably. They suggested that small, random environmental changes — too much wind one year, or a late spring the next — could send the population crashing. But the true causes of this hair-trigger sensitivity remain elusive.

Photo: Midges on flowers

Midges on flowers near Lake Myvatn in August 2006. Photo: Claudio Gratton

In the nine years since, the team has been searching for clues that can help them understand the population changes better. Each year, they measure water quality, nutrient concentrations, and the amount of lakebed algae among other factors that might affect the insects. Then they wait for the midges.

“Every year around this time I start holding my breath,” wondering how the dynamic midge population will respond in spring, says Ives. “It’s kind of like slow-motion suspense.”

Supported by a 10 year National Science Foundation grant for long-term research, Ives and his collaborators are waiting for the natural experiment to proceed through an entire population boom and bust. This year, the researchers might see the population crash — but they don’t know.

As the ecologists work to better understand the spare Lake Myvatn ecosystem, they are also extending their studies to the lake-filled Wisconsin landscape. Gratton and UW–Madison postdoctoral researcher Mireia Bartrons, now at the University of Vic in Spain, developed a model of how insect emergences from Wisconsin lakes affect lakeside ecosystems. With more than 15,000 lakes and 34 percent of the state lying within 200 meters of a lake or stream, the scientists expect aquatic insects to affect a large share of the state.

Gratton sees ecosystems, whether in Iceland or the American Midwest, as an interwoven tapestry of interactions rather than isolated patches of land or water.

“The character of the land would change without these lakes,” says Gratton. “Our landscapes are completely interconnected.”

Photo: Claudio Gratton in a swarm of midges

Claudio Gratton, UW–Madison professor of entomology, in a swarm of midges near Lake Myvatn in May 2008. Photo: David Hoekman

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UW-Madison statement on proposed fiscal 2018 federal budget  external link

The following institutional statement was released on March 16, 2017 in response to requests from media.

President Trump’s fiscal year 2018 proposed federal budget includes deep cuts to scientific research on agriculture, energy, health, and the environment and to the arts. Federally-supported research is central to the health of our nation’s citizens, environment and economy.

The proposed cuts threaten efforts aimed at improving the everyday lives of Americans in a competitive and changing world. The proposed cuts would harm universities such as the University of Wisconsin–Madison, where a robust scientific and educational enterprise depends on the support of the agencies whose budgets could be significantly reduced under the plan.

Researchers at UW–Madison rely heavily on federal research dollars that they compete for from these agencies to keep their labs running, their research projects and innovations moving forward, as well as to support our students. Federally-supported research at UW–Madison has generated scores of companies and thousands of jobs. Reducing the role of the federal government in funding science and technology would place our state and nation at a serious competitive disadvantage.

The budget proposal is the first step in an ongoing process. We will continue to work with members of Wisconsin’s Congressional delegation, the Association of American Universities, the Association of Public and Land Grant Universities and the American Council on Education to share our views and ensure Wisconsin’s interests are represented.

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Smartphone technology could combat workplace injuries  external link

Photo: Man holding cellphone up to conveyor belt

Rob Radwin positions a smartphone to record video of a conveyor belt — a better method, he says, for measuring the risk presented by repetitive workplace tasks and safeguard workers against injury. Stephanie Precourt

Manufacturing industries rely on the efforts of factory employees who work daily to make, package, prepare and deliver the products we find on our shelves.

That’s a lot of physical effort, and the strain can lead to various injuries, such as carpal tunnel syndrome or tendonitis in the wrists, arms and shoulders. Risk of injury is hard on workers, and can create costs to employers for workers’ compensation, lost time and reduced productivity.

“We want to solve these problems before people get hurt,” says Rob Radwin, a University of Wisconsin-Madison professor of industrial systems engineering.

Radwin has been studying this problem for more than two decades, and he may be able to harness relatively simple technological tools such as smartphones to create a solution that is easy, efficient and economically viable.

Photo: Rob Radwin

Rob Radwin

In the most popular methods for measuring injury risk, health and safety professionals make subjective judgments based on a scale of hand activity. Although these measurements often provide reasonable predictions, there is plenty of room for error in human observation. And judging and analyzing individual work roles and tasks requires valuable time, expertise and training in ergonomics and safety. The work also requires following the nuanced actions of many individuals over a long period of time.

Current technology may speed up and standardize the process.

Radwin and his students — in collaboration with Yu Hen Hu, a UW–Madison professor of electrical and computer engineering — have developed computer vision algorithms to calculate hand activity level.

Support from the National Institutes of Health and a new $1.4 million grant from the Centers for Disease Control’s National Institute for Occupational Safety and Health will allow the researchers to use videos collected from universities, NIOSH and the Washington State Department of Labor and Industries to develop an entirely new measure for assessing health outcomes.

They plan to use the video footage to track repetitive motion, training computers to recognize patterns of hand movement required to perform repetitive movements, grasping and exerting force. By combining their hand activity measurements with the computerized ability to spot movement patterns, they can create a new, more objective basis for measuring injury risk — knowledge that could help redesign jobs and make the workplace safer.

“We want to solve these problems before people get hurt.”

The goal is to not only to sharpen risk assessment, but to enable companies to produce their own assessments via computer vision. This is where smartphones come in.

“I envision an app, and I think all the technology we need exists on my smartphone today: a high-definition camera, a high-speed processor, and the ability to do cloud computing,” Radwin says.

If Radwin can apply his measures to a smartphone application, manufacturing employers could assess risk of injury of their employees with relative ease and in their own workspace by shooting some video with a handheld camera.

“We can program phones to measure motions and quantify them in a way that is not only more accurate than the current method, but also automatic and more objective and reliable,” he says. “It’s not just for big corporations using ergonomics to cut costs. It would allow medium-sized and small businesses to access this technology as well.”

“All the technology we need exists on my smartphone today: a high-definition camera, a high-speed processor, and the ability to do cloud computing.”

Radwin hopes to help companies make often simple but impactful changes to high risk jobs. For example, if a worker is struggling to keep up with a conveyor belt — and risking injury moving fast enough to risk injury or compromise safety — the new measurement system could help pinpoint hazards, and identify ways to engineer safer tasks. Sometimes problems like these require relatively minor fixes, such as limiting the distances that a worker has to move objects so they won’t be forced to move too quickly.

“Sometimes it’s not obvious until you try and break down the task into its components,” Radwin says.

However, by looking at existing videos of worker motions, Radwin can use the same concept to ensure that these problems don’t arise in the first place.

“Now we can understand how to look at various factors in a job, and try to engineer out hazards before individuals are even involved. That’s our goal, and the goal of companies today: to do it right the first time.”

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Researchers make headway toward understanding Alexander disease  external link

Researchers at the University of Wisconsin-Madison have made a surprising and potentially crucial discovery about Alexander disease, a rare and fatal neurological disorder with no known cure.

Using a mouse model for this disease, which in humans involves the destruction of white matter in the brain, a research team led by Albee Messing, director of the UW–Madison Waisman Center, found that a protein behind the symptoms of the disease, called GFAP, is broken down more rapidly in the body than researchers previously found in cell culture studies.

The results were published recently in a new study in the Journal of Biological Chemistry.

Photo: Albee Messing

Albee Messing

Photo: Laura Moody

Laura Moody

That’s a paradigm shift, because “the popular idea was that the GFAP protein would not be degraded as quickly,” says Laura Moody, a former postdoctoral researcher in Messing’s lab and first author of the new study. “But nobody had really tested this idea.”

Scientists already knew that GFAP accumulates to excess in some cells within the nervous system, called astrocytes, leading to the loss of motor and cognitive functions in people with the disease, and in some cases even death. However, they previously thought its accumulation was due to the fact that the cells created too much protein and did not break enough of it down.

The new finding could change the way researchers think about and try to solve Alexander disease.

“This study is an essential foundation for figuring out how to reduce or prevent GFAP accumulation in cells,” says Messing, a professor of neuropathology. “Previously, we thought that decreasing synthesis or increasing degradation of GFAP would be the way to go. But now it appears as if the cells have already tried to adapt to the higher levels of GFAP by increasing degradation, so we can now focus on finding ways to decrease GFAP synthesis.”

Moody and Messing worked with colleagues at the UW–Madison Biotechnology Center to calculate the rate at which GFAP protein was being made and degraded in mice with or without Alexander disease mutations.

Photo: Exterior of Waisman Center

The UW-Madison Waisman Center

They fed the mice food that contained known quantities of two different versions, or isotopes, of nitrogen, a component of all proteins. The two isotopes — one heavy and one light — are not radioactive and don’t harm the animals.

The heavy isotope of nitrogen occurs very rarely in nature, so usually it makes up only a minute fraction of proteins. But the mice were fed food containing higher-than-normal levels of the heavy isotope so that when the mice ate this food, their bodies absorbed the nitrogen isotopes and used it for several purposes, including to make GFAP molecules.

The researchers then used a technique called mass spectrometry to track the increase of heavy nitrogen in GFAP protein in the mice. Then, they used that information to calculate how quickly GFAP was being made and degraded, or turned over in cells.

“We found that in tissue culture there was no difference in how quickly GFAP was being turned over,” says Moody. “But surprisingly, in the animal models, GFAP was turning over more quickly in animals with Alexander disease mutations than in ones without those mutations.”

The new finding could change the way researchers think about and try to solve the rare, fatal disease.

While not a direct measure of protein degradation, the increased rate of GFAP turnover in mouse models of Alexander disease strongly indicates that degradation is, in fact, increasing as well, says Messing.

Moody says the finding will change the way therapeutics for Alexander disease are devised.

“Now that we know that GFAP is being synthesized and degraded more quickly in Alexander disease, it opens up new avenues for research,” she says. “It seems that if we can slow down the synthesis of GFAP, we should also be able to slow down its accumulation and develop therapies to treat Alexander disease.”

Other authors of the study include Gregory Barrett-Wilt and Michael Sussman, both at UW-Madison. The work was largely supported by donors to the Jelte Rijkaart Fund.

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Study quantifies role of ‘legacy phosphorus’ in reduced water quality  external link

Photo: Aerial view of farm fields and wind turbines

Wind turbines and farm fields near Springfield Corners, Wisconsin. Cropland in the Yahara watershed has an overabundance of soil phosphorus, and researchers say that makes clean lakes and rivers possible only with a revolution in land and water management. Courtesy of UW-Madison Water Sustainability and Climate project

For decades, phosphorous has accumulated in Wisconsin soils. Though farmers have taken steps to reduce the quantity of the agricultural nutrient applied to and running off their fields, a new study from the University of Wisconsin-Madison reveals that a “legacy” of abundant soil phosphorus in the Yahara watershed of Southern Wisconsin has a large, direct and long-lasting impact on water quality.

Published March 13 in the journal Ecosystems, the study may be the first to provide quantifiable evidence that eliminating the overabundance of phosphorus will be critical for improving the quality of Wisconsin’s lakes and rivers.

For example, the results indicate that a 50 percent reduction in soil phosphorus in the Yahara watershed’s croplands would improve water quality by reducing the summertime concentration of phosphorus in Lake Mendota, the region’s flagship lake, by 25 percent.

Photo: Melissa Motew

Melissa Motew

Photo: Christopher Kucharik

Christopher Kucharik

“If we continue to apply phosphorus at a greater rate than we remove it, then phosphorus accumulates over time and that’s what’s been happening over many decades in the Yahara watershed,” says Melissa Motew, the study’s lead author and a Ph.D. candidate in the UW-Madison Nelson Institute for Environmental Studies.

Phosphorus seeps into soils primarily by way of fertilizer and manure, and what crops and other plants don’t use to grow then leaks into waterways with rain and snowmelt runoff. Scientists have long believed that excess soil phosphorus is a culprit behind the murky waters and smelly algal blooms in some of Wisconsin’s lakes and rivers.

Conventional efforts, like no-till farming and cover crops, have tried to address nutrient runoff by slowing its movement from soils to waterways. However, the study shows that simply preventing runoff and erosion does not address the core problem of abundant soil phosphorus, and this overabundance could override conservation efforts.

“Solutions should be focused on stopping phosphorus from going onto the landscape or mining the excess amount that is already built up,” says co-author Christopher Kucharik, a professor of agronomy and environmental studies at UW-Madison.

Using newly advanced computer models, the study shows the watershed has about four times more phosphorus in its soil than is recommended by UW-Extension, which writes the state’s nutrient management recommendations based on what crops need and a landscape’s potential for nutrient runoff.

Photo: Cornfield

Crops, such as these young rows of corn, use some of the abundant soil phosphorus reserves, but not enough to draw down the surplus. Samuel Zipper/UW-Madison Water Sustainability and Climate project

Moreover, the study indicates that if soil phosphorus levels continue to increase as the climate also changes and becomes wetter, there will be more runoff and further decline in water quality. Reducing the surplus could mitigate this risk, Motew says.

Currently, the only method known to draw down soil phosphorus is harvesting crops, but Kucharik explains that plants take up only a small amount of the surplus each year.

“It is unlikely that any cropping system will quickly draw down the excess,” he says.

It will require working with farmers to practice better nutrient accounting and counter the tendency of some to apply more fertilizer, as an insurance measure, than is needed.

“Farmers have many different decisions to make and priorities that they have to juggle. If we want to address the legacy phosphorus problem, nutrient and manure management will need to become a higher priority,” says Motew, who adds that the pressures of farming and demand for products like meat and milk underlie the problem.

But food production need not be compromised by potential solutions, Kucharik says. There is enough excess phosphorus in our soils “to support plant nutrient needs for a long time.”

“While we’ve long known that too much phosphorus is bad, the models allow us to quantify just what ‘bad’ means.”

Melissa Motew

Innovation in manure disposal would also help. Throughout Wisconsin, farmers have more manure than they know what to do with, and the primary way to get rid of it is to spread it on their land, where its phosphorus just adds to the surplus.

“Support for manure digesters, the removal of phosphorus from lake and stream sediment, and other actions to recycle the phosphorus already in place would be beneficial for reducing the concentrations in our soils over the long term,” says Kucharik.

Also key to finding solutions is the use of state-of-the-art computer models, like those developed by the research team for the study, which allowed them to identify direct relationships between soil phosphorus and water quality — a feat virtually impossible using scientific observations alone.

“While we’ve long known that too much phosphorus is bad, the models allow us to quantify just what ‘bad’ means,” says Motew. While the study method doesn’t provide a blueprint for achieving clean lakes, putting numbers behind a common-sense understanding of a complex system is a step in the right direction, she says.

The research is part of UW–Madison’s Water Sustainability and Climate project and is funded by the National Science Foundation.

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