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Manipulating how yeast cells work could lead to new medical treatments  external link

When a stimulus descends upon a cell, it sets off a flurry of activity. Sensors on the surface take in information and relay it inside to other proteins, which perform computations and transmit their findings. The cell makes a decision and responds to the stimulus.

Megan McClean wants to figure out how it all works and then manipulate the process — fundamental research with implications for identifying drug targets and designing medical treatments.

“How can I predict what a cell’s going to do, and how can I make it do exactly what I want it to do? I find that really interesting. It’s the secret control freak in me,” she jokes.

McClean, an assistant professor of biomedical engineering at the University of Wisconsin–Madison, studies cellular signaling pathways, the biological networks that transform external signals into internal decisions such as whether to grow or die.

Photo: Portrait of Megan McClean

Megan McClean

Now her work to better understand and engineer those signaling processes will get a boost, thanks to a Maximizing Investigators’ Research Award from the National Institutes of Health that provides her with $1.8 million over five years. In addition to supporting the range of research projects in her lab, it affords her the flexibility to pursue new questions as they emerge.

“We can grow and pivot and change direction as new things come up, which is really great, because a lot of science happens unexpectedly,” she says.

Since joining the College of Engineering faculty in 2015, McClean has devoted most of her attention to studying Saccharomyces cerevisiae (budding yeast) as a model. It’s a quick-growing, single-celled microorganism that’s easy to genetically manipulate and has key similarities to the cells of mammals. In particular, the signaling pathways she’s focused on — mitogen-activated protein kinase, or MAPK, which control some stress responses — also exist in humans.

“The reason I like the MAP kinase pathways is that they’re pretty well understood, and so if I want to model something and then ask an experimental question, that’s a really good place to ask it,” she says. “And they are also very clearly important in cancer in human cells, so understanding misregulation there should help, hopefully, understand some of the same things that can go wrong in higher organisms.”

By probing yeast cells, McClean hopes to glean lessons on topics such as how pathways filter environmental stimuli, what affects their response time, how signaling cuts across pathways, and how a robust structure can insulate pathways and make them difficult to target with drugs.

“How can I predict what a cell’s going to do, and how can I make it do exactly what I want it to do? I find that really interesting. It’s the secret control freak in me.”

She and her lab members do this by using microfluidic models to create precise environments in which to observe cellular behavior and by engineering light-sensitive proteins to optically control responses, a method known as optogenetics.

“One of the nice things about being in an engineering department and having access to engineering students is that we can iterate pretty flexibly between the biological experiment that we want to do and the device we need to build,” says McClean, who developed her interest in biology while studying applied mathematics at the University of California, Berkeley and Harvard University. “We’re not constrained to what device we can buy off the shelf.”

McClean has also begun expanding her research agenda to include pathogenic fungi. She hopes to build upon her knowledge of cellular response in budding yeast and uncover why and how pathogenic yeast cells decide to disperse from a localized infection site and spread to other parts of the body.

“That’s totally new and uncharted waters for us,” she says, “and UW–Madison turns out to be a really great place for it, because there’s a very strong pathogenic fungi group here.”

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Competition attracts future grants, jump starts research and student careers  external link

Photo: Students around molten glass project

Fall Research Competition funding has allowed an art professor to buy materials for her studio, ship her work to exhibitions, and have a graduate student project assistant with the necessary experience to assist her in the hot shop. Photo: Bryce Richter

UW–Madison faculty and staff recipients of Fall Research Competition awards say they are thankful for the funding to help them acquire the resources they need to engage in their research. But perhaps most important, they say, is the student support they are able to provide thanks to the funding.

Funding for this research competition, provided by the Office of the Vice Chancellor for Research and Graduate Education, is available because of impressive efforts of UW–Madison faculty and staff in filing successful patents through the Wisconsin Alumni Research Foundation (WARF).

Helen Lee, UW–Madison assistant professor of glassworking and head of glass in the Art Department, says Fall Research Competition funding has allowed her to buy materials for her studio, crate and ship her work to exhibitions, and have a graduate student project assistant with the necessary experience to assist her in the hot shop.

Her studio and the UW–Madison Glass Lab are housed in the Arts Loft near the Kohl Center. Lee’s artwork explores the morphological nature of language using a material that is constantly in flux. Her work examines how language changes — in form, over time, and across cultures.

Photo: Portrait of Helen Lee

Helen Lee

“Since I work in a highly skilled craft discipline, I prioritize having a project assistant with substantial glassblowing experience under their belt,” Lee says. “Glassblowing is a collaborative activity, where the main glassblower (or ‘gaffer’) works with an assistant to realize forms. You technically can work solo, but it is far more limiting and inefficient and safety is also a concern. I wouldn’t be able to make any of the work that I make in glass without a highly skilled assistant.”

Lee is also collaborating with Kristen Pickett, professor of kinesiology, to examine the value of glassblowing as a modality of therapy for people living with movement disorders.

Like Lee, Vaishali Bakshi, associate professor of psychiatry, says a Fall Research Competition award will help her acquire materials and hire the graduate student support she needs to gather data for her research.

Bakshi’s research is focused on how stressful situations can release chemicals in the brain that reshape the brain’s responses. The long-term goal of her Fall Research Competition-funded research is to help develop better treatments for people with post-traumatic stress disorder (PTSD).

Photo: Portrait of Vaishali Bakshi

Vaishali Bakshi

She is gathering preliminary data to establish new techniques and test new hypotheses that she will incorporate into future NIH grant proposals. She says this additional data will help her be more successful when applying for a large federal grant.

Bakshi will explore in a rodent model whether fear responses to repeated exposure to a predator causes permanent changes in the brain. Her preliminary studies have shown that this type of psychological trauma causes long-lasting hypersensitivity of a protein, the alpha1 noradrenergic receptor, in a part of the brain known to regulate fear responses: the basolateral amygdala. Her grant will allow her to extend this work.

“The fall competition is helping me a lot right now at a crucial stage in my research work and is helping me stay competitive,” she says.

Elizabeth Cox, professor of pediatrics, also has used fall competition grants to develop pilot data for larger extramural awards. Cox’s research focuses on interventions that help health care providers do the right thing for each patient, and making that “right thing” the easiest thing to do.

Cox says her idea for examining her research from the patient perspective came from a teen she employed in her lab.

Photo: Portrait of Elizabeth Cox

Elizabeth Cox

“One day, he said, ‘I have type 1 diabetes and I don’t take care of my disease. I go to my clinic visits and they tell me the same things every time and none of it helps me’,” she recalls. “That’s when a lightbulb went on for me: We are having kids come for visits, but what are we doing in those visits?

“His comment to me was the genesis of all of the work I have done since, in looking at treatment for type 1 diabetes from the patient perspective.”

In 2010, Cox received her first fall competition support for a project with then graduate student Katie Fritz, who pilot tested an intervention to address barriers to self-management for youth and teens with type 1 diabetes.

“We used the pilot data on the effectiveness and feasibility of the intervention to secure a three-year extramural award to evaluate the impact of this intervention in a multi-site randomized, controlled trial,” Cox says. In that trial, youth with type 1 diabetes and their parents were involved from the start. They created the study logo, helped write consent forms, and crafted language to the control participants about why they were important.

In 2013, Cox received support for a collaboration with Betty Chewning and Beth Martin, professors in the School of Pharmacy, and then graduate student Michael Dunphy. They developed a tablet-based tool to identify the topics that teens most want to discuss during routine type 1 diabetes visits. The next step is to further test this tool for use in clinical practice.

In 2015, she received support for a collaboration with Mari Palta, professor of Population Health Sciences. Preliminary data from this award were used to secure a three-year, $600,000 Innovative Clinical or Translational Science Award from the American Diabetes Association.

“The fall competition is helping me a lot right now at a crucial stage in my research work and is helping me stay competitive.”

Vaishali Bakshi

“The Fall Research Competition is a great way to jump start a new collaboration,” Cox says. “Mentoring a graduate student with the funding support also can be a very rewarding experience.”

Information about the 2018 Fall Research Competition can be found on the OVCRGE’s website. The online application is open and the deadline for submitting an application is 4:30 p.m. Sept. 21.

Faculty members and investigators with permanent PI status may submit one application to this year’s competition. This may be an individual submission or a collaboration with another faculty member or permanent PI. Applicants will be notified of the outcome in December.

Those interested in applying are invited to read the FAQs relevant to each division — biological sciencesphysical sciencessocial sciences and the arts and humanities — and to reach out to the divisional associate vice chancellor for research with additional questions.

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Students prepare for healthcare careers in UW summer physiology course  external link

In Physiology 335, students capture and analyze data from their own bodies using computer software and electrode wires. Sinclair Richards

For those aspiring to be health care professionals, understanding the fundamentals of the human body is essential. A Summer Term course is helping UW–Madison students form that foundation.

John Kink, a rising senior studying microbiology, sees Physiology 335 as a gateway to his career as a physician’s assistant. The course is also a prerequisite for a wide variety of basic science and pre-clinical majors, making it very popular with nearly 100 students enrolled in the class.

The course’s three formats — lab, discussion and lecture — allow students to dive into all of the major systems of the human body from the cellular level to the organ-system level.

“This is one of the most fundamental human physiology courses that you can take compared to other undergraduate courses,” says Dr. Grace Lee, the course’s lab instructor. “It’s a breadth of almost every single system in the human body.”

Students apply material they learn in lecture to the lab and discussion, she says, which is helpful in preparing them for careers in the health sciences. According to Kink, the labs are especially “hands-on, engaging and interactive.”

By attaching electrode wires onto themselves, students are able to study the electrical activity happening inside of their own bodies. Lee says this not only helps students learn the underlying properties of the human body, but also prompts them to develop professional skills that are transferable to future careers.

“Because they’re working in teams of three or four people, they’re held accountable to come to lab, develop teamwork skills, communicate with one another and treat each other in a respectful way,” she says. “Those lessons are going to carry over into health care.”

The Physiology 335 lab is facilitated by a group of teaching assistants who lead and instruct students during the activities. Sinclair Richards

Lee says the class also prompts students to apply what they learn in class to their own health. By gaining a better knowledge of the body’s systems, students can “start making educational decisions about how they’re going to take care of themselves.”

Kink, in particular, is a testament to the impact that the course material has on its students.

“I definitely now have a better understanding of how my body works,” he says. “I’m able to make better health decisions on my own and this will later help me in my career as a physician’s assistant.”

While taking away conceptual information about the body is important to the course, Lee says there is ultimately a life philosophy to be learned as well. In a field where there is high pressure to be perfect, she hopes students can learn from their mistakes.

“In this class, it’s not about perfection,” Lee says. “It’s about progression.”

Though the class is challenging, she says students can arrive with the mentality that they’re going to learn something no matter what. And according to Kink, that is certainly true.

“There are lessons to be learned here that can apply to any realm,” he says. “That’s what makes this so important.”

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Is fire the new normal in the American West?  external link

The summer of 1988 was unusually hot, dry and windy in the American West, and 30 years ago this year, those conditions combined at Yellowstone National Park in Wyoming to create what were among the largest and most severe fires the park had ever seen.

The Yellowstone Fires of 1988 ultimately burned more than 1 million acres of forestland in and around the park. But ever-resilient and even reliant on fire, the forests recovered.

However, those unusually hot, dry conditions are now a normal feature of the climate of the West and fires burn with more frequency and severity than ever before. The 1988 fires were a 100- to 300-year event, but several large, hot fires have burned there since. A scan of today’s headlines shows just how common, destructive and sometimes tragic these fires have become.

Monica Turner, a University of Wisconsin–Madison professor of integrative biology, was at Yellowstone in the immediate aftermath of the 1988 fires to study and closely document the forests’ recovery. She has spent the last three decades of her career there, and in places like Grand Teton National Park, to better understand the nature of forests and fire. She and her research team and colleagues are examining how the patterns of fire and recovery are changing, particularly as the climate warms and drought becomes more common. They want to know: What does this mean for the forests we treasure?

 

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A video game can change the brain, may improve empathy in middle schoolers  external link

A space-exploring robot crashes on a distant planet. In order to gather the pieces of its damaged spaceship, it needs to build emotional rapport with the local alien inhabitants. The aliens speak a different language but their facial expressions are remarkably humanlike.

This fantastical scenario is the premise of a video game developed for middle schoolers by University of Wisconsin–Madison researchers to study whether video games can boost kids’ empathy, and to understand how learning such skills can change neural connections in the brain.

In the experimental video game “Crystals of Kaydor,” a robot crash lands on an alien planet. In order to rebuild the spaceship, players must, as the robot, build rapport with the aliens by deciphering the emotions on their humanlike faces.

Results published this week in npj Science of Learning (a Nature journal) reveal for the first time that, in as few as two weeks, kids who played a video game designed to train empathy showed greater connectivity in brain networks related to empathy and perspective taking. Some also showed altered neural networks commonly linked to emotion regulation, a crucial skill that this age group is beginning to develop, the study authors say.

“The realization that these skills are actually trainable with video games is important because they are predictors of emotional well-being and health throughout life, and can be practiced anytime — with or without video games,” says Tammi Kral, a UW–Madison graduate student in psychology who led the research at the Center for Healthy Minds.

Photo: Portrait of Tammi Kral

Tammi Kral

Photo: Portrait of Richard Davison

Richard Davison

Richard Davidson, director of the center and a professor of psychology and psychiatry at UW–Madison, explains that empathy is the first step in a sequence that can lead to prosocial behavior, such as helping others in need.

“If we can’t empathize with another’s difficulty or problem, the motivation for helping will not arise,” says Davidson, who headed the research team. “Our long-term aspiration for this work is that video games may be harnessed for good and if the gaming industry and consumers took this message to heart, they could potentially create video games that change the brain in ways that support virtuous qualities rather than destructive qualities.”

On average, youth between the ages of 8 and 18 rack up more than 70 minutes of video gameplay daily, according to data from the Kaiser Family Foundation. This spike in gameplay during adolescence coincides with an explosion in brain growth as well as a time when kids are susceptible to first encounters with depression, anxiety and bullying. The team wanted to learn whether there were ways to use video games as a vehicle for positive emotional development during this critical period.

Researchers randomly assigned 150 middle schoolers to two groups. One played the experimental game, called “Crystals of Kaydor,” which was created for research purposes and intended to teach empathy. The second group played a commercially available and entertaining control game called “Bastion” that does not target empathy.

GIF of alien making happy faces

In Crystals of Kaydor, kids interacted with aliens on a distant planet and learned to identify the intensity of their emotions.

GIF: Alien making sad faces

The aliens’ humanlike faces conveyed emotions such as anger, fear, happiness, surprise, disgust and sadness.

In Crystals of Kaydor, kids interacted with the aliens on the distant planet and learned to identify the intensity of emotions they witnessed on their humanlike faces, such as anger, fear, happiness, surprise, disgust and sadness. The researchers measured how accurate the players were in identifying the emotions of the characters in the game. The activity was also intended to help the kids practice and learn empathy.

Those who played Bastion partook in a storyline where they collected materials needed to build a machine to save their village, but tasks were not designed to teach or measure empathy. Researchers used the game because of its immersive graphics and third-person perspective.

The team obtained functional magnetic resonance imaging scans in the laboratory from both groups before and after two weeks of gameplay, looking at connections among areas of the brain, including those associated with empathy and emotion regulation. Participants in the study also completed tests during the brain scans that measured how accurately they empathized with others.

Screen imager: Action in video game

The game — developed in partnership with Gear Learning at UW–Madison and researchers from the University of California, Irvine — is only being used for research purposes and is not available to the public but has helped inform other games being submitted to the FDA for clinical applications.

The researchers found stronger connectivity in empathy-related brain networks after the middle schoolers played Crystals of Kaydor compared to Bastion. Moreover, Crystals players who showed strengthened neural connectivity in key brain networks for emotion regulation also improved their score on the empathy test. Kids who did not show increased neural connectivity in the brain did not improve on the test of empathic accuracy.

“The fact that not all children showed changes in the brain and corresponding improvements in empathic accuracy underscores the well-known adage that one size does not fit all,” says Davidson. “One of the key challenges for future research is to determine which children benefit most from this type of training and why.”

Teaching empathy skills in such an accessible way may benefit populations who find these skills challenging, including individuals on the autism spectrum, Davidson adds.

The game — developed in partnership with Gear Learning at UW–Madison and researchers Constance Steinkuehler and Kurt Squire, who are now professors of informatics at the University of California, Irvine — is only being used for research purposes and is not available to the public but has helped inform other games being submitted to the FDA for clinical applications.

Learn more from the Center for Healthy Minds about simple and tech-free ways to teach empathy in youth.

This research was funded by a grant from the Bill & Melinda Gates Foundation.

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Corn that acquires its own nitrogen identified, reducing need for fertilizer  external link

Photo: Dripping gel on corn plant

The dripping gel from this corn plant harbors bacteria that convert atmospheric nitrogen into a form usable by the plant. Photo: Howard-Yana Shapiro

A public-private collaboration of researchers at the University of Wisconsin–Madison, the University of California, Davis, and Mars Inc., have identified varieties of tropical corn from Oaxaca, Mexico, that can acquire a significant amount of the nitrogen they need from the air by cooperating with bacteria.

To do so, the corn secretes copious globs of mucus-like gel out of arrays of aerial roots along its stalk. This gel harbors bacteria that convert atmospheric nitrogen into a form usable by the plant, a process called nitrogen fixation. The corn can acquire 30 to 80 percent of its nitrogen in this way, but the effectiveness depends on environmental factors like humidity and rain.

Scientists have long sought corn that could fix nitrogen, with the goal of reducing the crop’s high demand for artificial fertilizers, which are energy intensive, expensive and polluting. Further research is required to determine if the trait can be bred into commercial cultivars of corn, the world’s most productive cereal crop.

The findings are reported Aug. 7 in the journal PLOS Biology.

Nature provides the solution

“It has been a long-term dream to transfer the ability to associate with nitrogen-fixing bacteria from legumes to cereals,” says Jean-Michel Ané, a professor of bacteriology and agronomy at UW–Madison and a co-author of the new study.

Legumes, such as beans, are the only group of crop plants previously known to acquire a significant amount of nitrogen through fixation, which they perform in specialized tissues called root nodules.

Howard-Yana Shapiro, the chief agricultural officer at Mars, a senior fellow in the Department of Plant Sciences at UC Davis and a co-author of the report, identified the indigenous varieties of corn in a search for cultivars that might be able to host nitrogen-fixing bacteria.

The corn is grown in the Sierra Mixe region of Oaxaca in southern Mexico, part of the region where corn was first domesticated by Native Americans thousands of years ago. Farmers in the area grow the corn in nitrogen-depleted soils using traditional practices with little or no fertilizer, conditions that have selected for a novel ability to acquire nitrogen. The biological materials for this investigation were accessed and utilized under an Access and Benefit Sharing Agreement with the Sierra Mixe community and with the permission of the Mexican government.

Photo: Closeup of Jean-Michel Ané in front of a tree trunk

Jean-Michel Ané

The corn is striking. Most corn varieties grow to about 12 feet and have just one or two groups of aerial roots that support the plant near its base. But the nitrogen-fixing varieties stand over 16 feet tall and develop up to eight or 10 sets of thick aerial roots that never reach the ground. Under the right conditions, these roots secrete large amounts of sugar-rich gel, providing the energy and oxygen-free conditions needed for nitrogen-fixing bacteria to thrive.

Establishing that plants are incorporating nitrogen from the air is technically challenging.

“It took us eight years of work to convince ourselves that this was not an artifact,” says Ané, whose lab specializes in studying and quantifying nitrogen fixation. “Technique after technique, they’re all giving the same result showing high levels of nitrogen fixation in this corn.”

The group used five different techniques across experiments in Mexico and Madison to confirm that the Sierra Mixe corn’s gel was indeed fixing nitrogen from the air and that the plant could incorporate this nitrogen into its tissues.

“What I think is cool about this project is it completely turns upside down the way we think about engineering nitrogen fixation,” says Ané.

The gel secreted by the corn’s aerial roots appears to work primarily by excluding oxygen and providing sugars to the right bacteria, sidestepping complex biological interactions. The research team was even able to simulate the natural gel’s effects with a similar gel created in the lab and seeded with bacteria. The simplicity of the system provides inspiration to researchers looking to identify or create more crop plants with this trait.

“This corn showed us that nature can find solutions to some problems far beyond what scientists could ever imagine.”

Jean-Michel Ané

Breeding the trait into commercial cultivars of corn could reduce the need for artificial nitrogen fertilizers, which have a host of disadvantages. More than 1 percent of the world’s total energy production goes toward producing nitrogen fertilizer. Developed countries contend with waterways polluted by leaching nitrogen, while adequate fertilizer is often inaccessible or too expensive for farmers in developing countries. Corn that fixes some of its own nitrogen could mitigate these issues, but more research will be required.

“Engineering corn to fix nitrogen and form root nodules like legumes has been a dream and struggle of scientists for decades,” says Ané. “It turns out that this corn developed a totally different way to solve this nitrogen fixation problem. The scientific community probably underestimated nitrogen fixation in other crops because of its obsession with root nodules.”

“This corn showed us that nature can find solutions to some problems far beyond what scientists could ever imagine,” Ané says.

Researchers from UW–Madison, UC Davis and Mars Inc. have made a remarkable discovery: an indigenous variety of Mexican corn that can also fix nitrogen from the atmosphere, instead of requiring synthetic fertilizers.

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A stent-free future for common cardiovascular ailments  external link

Researchers from the University of Wisconsin–Madison and the Ohio State University College of Medicine believe they’ve found a better strategy than stents for maintaining open blood vessels in the wake of surgeries such as angioplasties or bypasses.

When a patient is suffering from a clogged artery, the go-to procedure has been opening up the vessel with a balloon (called angioplasty) and placing a tube, called a stent, inside the vessel to keep it open. Modern stents are even built to release drugs to prevent future clogs.

But there are downsides to these drug-eluting stents. The medication stops the overgrowth of smooth muscle cells that cause re-narrowing — a process called neointimal hyperplasia — but it also poisons the endothelial cells that form the inner wall of the blood vessel. And the presence of the stent, a foreign object in the body, increases the risk of blood clots.

Illustration: Cross-section of plaque in an artery

A team of researchers from UW–Madison and Ohio State is developing a new approach for maintaining open blood vessels in the wake of surgeries such as angioplasties or bypasses. Illustration: IStock/HYWARDS

Shaoqin “Sarah” Gong, a UW–Madison Vilas Distinguished Professor of biomedical engineering and investigator at the Wisconsin Institute for Discovery, and her collaborators, K. Craig Kent and Lian-Wang Guo of Ohio State, recently received a $2.4 million grant from the National Institutes of Health to develop a new, stent-free approach using nanoparticles to deliver a drug.

The four-year grant builds upon promising preliminary studies in which the Ohio State researchers identified potential drug targets and Gong, an expert in nanomedicine, devised a delivery method by engineering biomimetic nanoclusters to carry a drug to the appropriate location. The group details that preliminary work in a paper published in the September 2018 issue of the journal Biomaterials.

Photo: Portrait of Sarah Gong

Shaoqin “Sarah” Gong

By inhibiting the targeted pathways, the researchers believe they can suppress the growth of smooth muscle cells while also protecting the endothelial cells and allowing them to re-grow after surgery.

To safely deliver a drug to do that, they’ll rely on Gong’s drug-loaded nanoclusters, which are coated with a “biomembrane,” such as a platelet.

After doctors inject the nanoparticle through an IV, its biomembrane coating would act as a guide to take the particle to the targeted location, says Gong.

“You want to deliver your drug more specifically to the injured vasculature,” says Gong, explaining the advantage of mimicking a biological mechanism.

The interdisciplinary team of investigators believes once the new approach is fully developed, it could benefit millions of patients with various cardiovascular diseases.

At UW–Madison, Gong is also a member of the UW Carbone Cancer Center, the McPherson Eye Research Institute and the UW Institute for Clinical and Translational Research, and an affiliate of the Department of Chemistry and the Department of Materials Science and Engineering.

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Combining on and off switches, one protein can control flowering in plants  external link

As plants stretch toward the summer sun, they are marching toward one of the most important decisions of their lives — when to flower. Too early, and they might miss out on key pollinators. Too late, and an early frost could damage their developing seeds.

Farmers who rely on their crops to flower at just the right time can only sit and worry. It’s up to the plants.

That decision of when to flower is ultimately made by cells that must stop sending out leaves in order to start producing flowers. Scientists typically think of these critical decisions about cell fate as being controlled by the balance between one group of regulating proteins that accelerate cells toward one fate and other proteins that keep the brakes on. When the brake is released at the right cue, the cell marches toward its destiny as leaf, or flower.

Photo: Closeup of Arabidopsis with white flowers

Working in the model plant Arabidopsis, UW–Madison biologists have discovered a previously unknown mechanism for controlling cellular decisions, one which combines an on-and-off switch in a single protein. Photo: Dawid Skalec

But new research published Aug. 6 in the journal Nature Genetics by University of Wisconsin–Madison biologists has discovered a previously unknown mechanism for controlling cellular decisions, one which combines an on-and-off switch in a single protein. Professor of Genetics and Wisconsin Institute for Discovery researcher Xuehua Zhong and her lab found that the protein EBS can bind to two different chemical modifications on histones, proteins that DNA wraps around, either promoting or preventing the transition to flowering in plants.

Because the basic building blocks of EBS are found across plants and animals, this style of regulating crucial decisions about development and tissue generation is likely to be widespread. The researchers say that this linking of a developmental on-and-off switch in one protein provides opportunities for improving crops and could also help scientists study diseases like cancer.

Every organism starts out as a single cell, which means that a cell must be able to express both flower and leaf genes, although not at the same time. These young cells are undecided about their fate.

This linking of a developmental on-and-off switch in one protein provides opportunities for improving crops and could also help scientists study diseases like cancer.

“It’s like a first-year freshman. They have not declared a major yet,” says Zhong. “So how do you maintain this undecided state? One way is what we call epigenetics.”

Epigenetic regulation uses chemical decorations on DNA to help control which genes are active and which are shut off. Regulatory proteins can bind to activating or repressing chemical marks to promote or restrict which genes are turned on, which in turn controls what type of tissue a cell may become, or how an organism will change its growth.

Typically, gene activation is controlled by one protein, while another protein will inhibit the gene’s expression. But Zhong’s lab found that EBS is different.

“This one protein has domains that can read both activating and repressing marks, and then make the switch to turn on or turn off,” says Shuiming Qian, a scientist in Zhong’s lab who led the work.

Photo: Portrait of Xuehua Zhong

Xuehua Zhong

Photo: Portrait of Shuiming Qian

Shuiming Qian

Photo: Portrait of Ray Scheid

Ray Scheid

“There have been proteins that can bind multiple modifications at once, but we’ve never seen one that can bind both repressive and active marks at the same time,” adds Ray Scheid, a graduate student in the Zhong lab who contributed to the study. The UW–Madison researchers also collaborated with scientists at the Chinese Academy of Sciences to study the structure of EBS.

Plant scientists have long known that if EBS is absent, plants flower early. Working in the model plant Arabidopsis, the research team found that if they disrupt the ability of EBS to bind to epigenetic modifications — either repressive or activating marks — flowering still occurs early, showing that the balance between on and off is crucial for EBS to work at all.

Zhong’s lab also showed that when it is time to flower, EBS changes its shape, which makes it more strongly attach to the activating modifications. That change from “off” to “on” lets EBS turn on a set of genes that put the flowering program into action.

“If we can reduce a plant’s life cycle and complete the season earlier, that could be very important for many crops.”

Xuehua Zhong

The joining of an on-and-off switch in a single protein provides flexibility in making key decisions about cell fate and development, says Zhong. The research team also sees opportunities for research and, one day, applications based on influencing how cells decide what to become through the control of just one protein.

One application that comes to mind for Zhong is based on what EBS is already good at — controlling flowering.

“In Wisconsin, we have very short growing seasons,” says Zhong. “If we can reduce a plant’s life cycle and complete the season earlier, that could be very important for many crops.”

This work was supported by the National Science Foundation Career Program (grant MCB-1552455), the National Institutes of Health-MIRA (grant R35GM124806), National Institutes of Health (grant GM059785-15/P250VA), the National Institutes of Health National Cancer Institute (grant R01CA193481), the Chinese National Key R&D Program (grant 2016YFA0503200), National Natural Science Foundation of China (grants 31622032 and 31770782), the Chinese Academy of Sciences and the Alexander von Humboldt Foundation.

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Eating crickets can be good for your gut, according to new clinical trial  external link

Photo: Deep-fried insects displayed at an open-air market

Deep-fried insects at a food stall in Bangkok, Thailand. More than 2 billion people around the world regularly consume insects. Photo: Takoradee/CC by S-A 3.0

Valerie Stull was 12 when she ate her first insect.

“I was on a trip with my parents in Central America and we were served fried ants,” she says. “I remember being so grossed out initially, but when I put the ant in my mouth, I was really surprised because it tasted like food — and it was good!”

Today, Stull, a recent doctoral graduate of the University of Wisconsin–Madison Nelson Institute for Environmental Studies, is the lead author of a new pilot clinical trial published in the journal Scientific Reports that looks at what eating crickets does to the human microbiome.

It shows that consuming crickets can help support the growth of beneficial gut bacteria and that eating crickets is not only safe at high doses but may also reduce inflammation in the body.

“There is a lot of interest right now in edible insects,” Stull says. “It’s gaining traction in Europe and in the U.S. as a sustainable, environmentally friendly protein source compared to traditional livestock.”

More than 2 billion people around the world regularly consume insects, which are also a good source of protein, vitamins, minerals and healthy fats. The research team was interested in documenting for the first time via clinical trial the health effects of eating them.

Photo: Portrait of Jonathan Patz

Jonathan Patz

Photo: Portrait of Valerie Stull

Valerie Stull

“This study is important because insects represent a novel component in Western diets and their health effects in human populations haven’t really been studied,” says co-corresponding author Tiffany Weir, a professor of food science and human nutrition at Colorado State University. “With what we now know about the gut microbiota and its relationship to human health, it’s important to establish how a novel food might affect gut microbial populations. We found that cricket consumption may actually offer benefits beyond nutrition.”

Raising insects for protein not only helps protect the environment, but also offers a more healthful option than meat in many wealthy countries with high-meat diets, says co-author Jonathan Patz, director of the UW–Madison Global Health Institute, where Stull will begin a postdoctoral research position in the fall.

Crickets, like other insects, contain fibers, such as chitin, that are different from the dietary fiber found in foods like fruits and vegetables. Fiber serves as a microbial food source and some fiber types promote the growth of beneficial bacteria, also known as probiotics. The small trial probed whether insect fibers might influence the bacteria found in the gastrointestinal tract.

For two weeks, 20 healthy men and women between the ages of 18 and 48 ate either a control breakfast or a breakfast containing 25 grams of powdered cricket meal made into muffins and shakes. Each participant then ate a normal diet for a two-week “washout period.” For the following two weeks, those who started on the cricket diet consumed a control breakfast and those who started on the control diet consumed a cricket breakfast.

Photo: Bergmans and Stull in a kitchen putting mealworms into a blender

Graduate students Rachel Bergmans, left, and Valerie Stull make a nutritious shake using roasted and ground insects in 2015. Photo: Jeff Miller

Every participant served as their own control for the study and the researchers were blinded with respect to which diet each participant was on at any given time.

The researchers collected blood samples, stool samples and answers to gastrointestinal questionnaires immediately before the study began, immediately following the first two-week diet period and immediately after the second two-week diet period.

Participants’ blood samples were tested for a host of health measures, like blood glucose and enzymes associated with liver function, and also for levels of a protein associated with inflammation. The fecal samples were tested for the byproducts of microbial metabolism in the human gut, inflammatory chemicals associated with the gastrointestinal tract, and the overall makeup of the microbial communities present in the stools.

Participants reported no significant gastrointestinal changes or side effects and the researchers found no evidence of changes to overall microbial composition or changes to gut inflammation. They did see an increase in a metabolic enzyme associated with gut health, and a decrease in an inflammatory protein in the blood called TNF-alpha, which has been linked to other measures of well-being, like depression and cancer.

“There is a lot of interest right now in edible insects,” Stull says. “It’s gaining traction in Europe and in the U.S. as a sustainable, environmentally friendly protein source compared to traditional livestock.”

Additionally, the team saw an increase in the abundance of beneficial gut bacteria like Bifidobacterium animalis, a strain that has been linked to improved gastrointestinal function and other measures of health in studies of a commercially available strain called BB-12.

But, the researchers say, more and larger studies are needed to replicate these findings and determine what components of crickets may contribute to improved gut health.

“This very small study shows that this is something worth looking at in the future when promoting insects as a sustainable food source,” says Stull.

Related: Could squirmy livestock dent Africa’s protein deficit?

Stull is co-founder of an award-winning startup and research collaboration called MIGHTi, the Mission to Improve Global Health Through Insects. In the future, MIGHTi hopes to provide home-use insect-farming kits to communities that already consume insects, including many in southern Africa. Insects require far less water to farm than traditional livestock and can help improve food security in impoverished communities while providing economic opportunities to women.

“Most of the insects consumed around the world are wild-harvested where they are and when they are available,” says Stull, who has eaten insects — including caterpillars, cicadas, grasshoppers and beetle larvae — all over the world. “People love flying termites in Zambia, which come out only once or twice a year and are really good; they taste like popcorn and are a crunchy, oily snack.”

She hopes to promote insects as a more mainstream food in the United States, and though the industry is currently small, the rise of edible insect producers and companies using insects in their food products may make this possible.

“Food is very tied to culture, and 20 or 30 years ago, no one in the U.S. was eating sushi because we thought it was disgusting, but now you can get it at a gas station in Nebraska,” she says.

Related: UW’s bug-eating advocate had global impact

The study was funded by a multistate Hatch project (W3122: Beneficial and Adverse Effects of Natural Chemicals on Human Heath and Food Safety), the Karen Morris-Fine New Investigator Success Fund, the Climate Quest competition, and the Clinical and Translational Science Award program of the NIH National Center for Advancing Translational Sciences (UL1TR000427). Entomo Farms donated a portion of the cricket powder used in the study.

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Cellular communication system in mice helps control female fertility  external link

When Joan Jorgensen was an undergraduate at the University of Wisconsin–Madison, her roommate confided that she had just one period before going through menopause in high school. Doctors told Jorgensen’s roommate that she would never have biological children.

“This is devastating news at any age, let alone a high school girl,” says Jorgensen, who is now a professor in the Department of Comparative Biosciences at the UW–Madison School of Veterinary Medicine.

Joan Jorgensen

That experience stuck with Jorgensen, whose research focuses on fertility problems like premature ovarian failure, which leads to an early loss of viable eggs and which her roommate experienced. Using animal models, Jorgensen tries to understand how female fertility is affected by development of the ovary, which includes how cells organize to support eggs for the entire lifetime of that individual.

In new research published Aug. 2 in the journal PLOS Genetics, Jorgensen, graduate researcher Anqi Fu and others discovered that two genes work together to construct a cellular communication system in the ovaries of mice to maintain healthy eggs. The researchers describe this system as a series of junctions between the eggs and the cells that surround and support the eggs, known as granulosa cells. Both cells reach out to form multiple junctions that exchange information and ensure the proper development and survival of the egg leading up to ovulation.

This research provides a piece of the puzzle of female infertility, and Jorgensen looks to build off these findings to uncover more information on premature ovarian failure and other fertility problems. Jorgensen and Fu collaborated with researchers at the University of Melbourne, Monash University, and the University of Toronto to complete this work.

Premature ovarian failure, in which the ovaries stop producing estrogen, is often caused by premature loss of the egg supply and affects as many as 3 percent of all women, according to the National Institutes of Health. In most cases the cause is unknown. Problems with the development of follicles — the combination of an egg and its surrounding granulosa cells — are likely behind many cases of premature ovarian failure.

Jorgensen’s lab had previously found that mice missing two genes, IRX3 and IRX5, had defective follicles. In the current study, they looked for how these genes work together to keep follicles healthy.

The researchers showed that mice with either IRX3 or IRX5 deleted had fewer pups, which led the researchers to suspect that communication within the follicle was breaking down. Looking within the ovary, they tracked the expression of each gene.

Early on, the researchers saw that IRX3 and IRX5 were expressed throughout the follicle. But as the follicle began to mature, IRX3 became isolated to the egg, while IRX5 was only expressed in the granulosa cells.

From their separate vantage points, these two genes synchronize the two cell types to help them establish communication networks. Jorgensen’s team saw that the granulosa cells and the eggs extend parts of their membranes to form junctions with each other. These junctions allow signals to be transported in both directions. With IRX3 or IRX5 deleted, these junctions fell apart, interrupting communication within the follicle and destabilizing it.

“We think of IRX3 and IRX5 as the supervisors in connecting these two cells,” says Jorgensen.

Despite this discovery of a role for these genes in follicle development in mice, researchers still aren’t sure if these same genes have a similar effect in humans.

“That’s another thing we would like to learn — we want to be able to link it to human causes,” says Jorgensen.

Jorgensen and Fu say the next step will be to evaluate exactly how these genes direct these key cell-to-cell interactions.

“If we can figure out how those networks are placed, we think that will be a major step in understanding the basic foundations of how follicles are built,” says Jorgensen. “That will go a long way towards helping women that have infertility, especially those that undergo premature ovarian failure.”

This work was supported by National Institutes of Health (R01HD075079), National Cancer Institute (P30 CA014520), and a University of Wisconsin Carbone Cancer Center Support Grant.

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