Culture

The brain is not a passive recipient of injury or disease. Research has shown that when neurons die and disrupt the natural flow of information they maintain with other neurons, the brain compensates by redirecting communications through other neuronal networks. This adjustment or rewiring continues until the damage goes beyond compensation.

This process of adjustment, a result of the brain's plasticity, or its ability to change or reorganize neural networks, occurs in neurodegenerative conditions such as Alzheimer's, Parkinson's and Huntington's disease (HD). As the conditions progress, many genes change the way they are normally expressed, turning some genes up and others down. The challenge for researchers like Dr. Juan Botas who studies HD, has been to determine which of the gene expression changes are involved in causing the disease and which ones help mitigate the damage, as this may be critical for designing effective therapeutic interventions.

In his lab at Baylor College of Medicine, Botas and his colleagues look to understand what causes the loss of communication or synapses between neurons in HD. Up until now, research has focused on neurons because the normal huntingtin gene, whose mutation causes the condition, contributes to maintaining healthy neuronal communication. In the current work, the researchers looked into synapses loss in HD from a different perspective.

Focusing on glia to understand Huntington's disease

The mutated huntingtin gene is not only present in neurons, but in all the cells in the body, opening the possibility that other cell types also could be involved in the condition.

"In this study we focused on glia cells, which are a type of brain cell that is just as important as neurons to neuronal communication," said Botas, professor of molecular and human genetics and of molecular and cellular biology at Baylor and a member of the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.

We thought that glia might be playing a role in either contributing or compensating for the damage observed in Huntington's disease."

Initially thought to be little more than housekeeping cells, glia turned out to have more direct roles in promoting normal neuronal and synaptic function.

In a previous work, Botas and his colleagues studied a fruit fly model of HD that expresses the human mutant huntingtin (mHTT) gene in neurons, to understand which of the many gene expression changes that occur in HD are causing disease and which ones are compensatory.

"One class of compensatory changes affected genes involved in synaptic function. Could glia be involved?" Botas said. "To answer this question, we created fruit flies that express mHTT only in glia, only in neurons or in both cell types."

Comparing changes in gene expression

The researchers began their investigation by comparing the changes in gene expression present in the brains of healthy humans with those in human HD subjects and in HD mouse and fruit fly models. They identified many genes whose expression changed in the same direction across all three species but were particularly intrigued when they discovered that having HD reduces the expression of glial cell genes that contribute to maintaining neuronal connections.

"To investigate whether the reduction of expression of these genes in glia either helped with disease progression or with mitigation, we manipulated each gene either in neurons, glial cells or both cell types in the HD fruit fly model. Then we determined the effect of the gene expression change on the function of the flies' nervous system," Botas said.

They evaluated the flies' nervous system health with a high-throughput automated system that assessed locomotor behavior quantitatively. The system filmed the flies as they naturally climbed up a tube. Healthy flies readily climb, but when their ability to move is compromised, the flies have a hard time climbing. The researchers looked at how the flies move because one of the characteristics of HD is progressive disruption of normal body movements.

Turning down the genes worked

The results revealed that in HD, turning down glial genes involved in synaptic assembly and maintenance is protective.

Fruit flies with the mutant huntingtin gene in their glial cells in which the researchers had deliberately turned down synaptic genes climbed up the tube better than flies in which the synaptic genes were not dialed down.

"Our study reveals that glia affected by HD respond by tuning down synapse genes, which has a protective effect," Botas said. "Some gene expression changes in HD promote disease progression, but other changes in gene expression are protective. Our findings suggest that antagonizing all disease-associated alterations, for example using drugs to modify gene expression profiles, may oppose the brain's efforts to protect itself from this devastating disease. We propose that researchers studying neurological disorders could deepen their analyses by including glia in their investigations."

A new research paper published in the American Journal of Clinical Nutrition last week showed that a low Omega-3 Index is just as powerful in predicting early death as smoking. This landmark finding is rooted in data pulled and analyzed from the Framingham study, one of the longest running studies in the world.

The Framingham Heart Study provided unique insights into cardiovascular disease (CVD) risk factors and led to the development of the Framingham Risk Score based on eight baseline standard risk factors--age, sex, smoking, hypertension treatment, diabetes status, systolic blood pressure, total cholesterol (TC), and HDL cholesterol.

CVD is still the leading cause of death globally, and risk can be reduced by changing behavioral factors such as unhealthy diet, physical inactivity, and use of tobacco and alcohol. Therefore, researchers in this study say biomarkers integrating lifestyle choices might help identify individuals at risk and be useful to assess treatment approaches, prevent morbidity, and delay death.

Among the diet-based biomarkers are fatty acids (FAs), whether measured in plasma or red blood cell (RBC) membranes. The FAs most clearly associated with reduced risk for CVD and for total mortality (i.e., death from any cause) are the omega-3 FAs, EPA and DHA, which are typically found in fish like salmon and herring, as well as omega-3 supplements like fish and algal oil.

In a 2018 report that included 2500 participants in the Framingham Offspring Cohort followed for a median of 7.3 years (i.e., between ages ?66 and 73), the baseline RBC EPA + DHA content [the omega-3 index (O3I)] was significantly and inversely associated with risk for death from all causes.

In fact, individuals with the highest Omega-3 Index were 33% less likely to succumb during the follow-up years compared with those with the lowest Omega-3 Index. Similar associations have been seen in the Women's Health Initiative Memory Study, the Heart and Soul Study, and the Ludwigshafen Risk and Cardiovascular Health Study.

The Omega-3 Index measures the amount of EPA and DHA in red blood cell membranes and is a marker of omega-3 status. An optimal Omega-3 Index is 8% or higher, an intermediate Omega-3 Index is between 4% and 8%, and a low Omega-3 Index is 4% and below. Most Americans have an Omega-3 Index below 4%, which puts them a significantly higher risk of early death.

According to researchers in this study, the finding that any FA-based metric would have predictive power similar to that of the well-established standard risk factors was unexpected, and it suggests that RBC FAs--via imperfectly understood mechanisms--somehow reflects an in vivo milieu that consolidates into one measure the impact on the body of all these standard risk factors.

"It is interesting to note that in Japan, where the mean Omega-3 Index is greater than 8%, the expected life span is around five years longer than it is in the United States, where the mean Omega-3 Index is about 5%. Hence, in practice, dietary choices that change the Omega-3 Index may prolong life," said Michael McBurney, PhD, FCNS-SCN, lead researcher in this study. "In the final combined model, smoking and the Omega-3 Index seem to be the most easily modified risk factors. Being a current smoker (at age 65) is predicted to subtract more than four years of life (compared with not smoking), a life shortening equivalent to having a low vs. a high Omega-3 Index."

"The information carried in the concentrations of four red blood cell fatty acids was as useful as that carried in lipid levels, blood pressure, smoking, and diabetic status with regard to predicting total mortality," said Dr. Bill Harris, who was also an author on this study. "This speaks to the power of the Omega-3 Index as a risk factor and should be considered just as important as the other established risk factors, and maybe even more so."

DURHAM, N.C. - The brain's neurons tend to get most of the scientific attention, but a set of cells around them called astrocytes - literally, star-shaped cells - are increasingly being viewed as crucial players in guiding a brain to become properly organized.

Specifically, astrocytes, which form about half the mass of a human brain, seem to guide the formation of synapses, the connections between neurons that are formed and remodeled as we learn and remember.

A new study from Duke and UNC scientists has discovered a crucial protein involved in the communication and coordination between astrocytes as they build synapses. Lacking this molecule, called hepaCAM, astrocytes aren't as sticky as they should be, and tend to stick to themselves rather than forming connections with their fellow astrocytes.

This finding, in studies on mice with the gene for hepaCAM knocked out of their astrocytes, is an important clue in efforts to understand several brain disorders, including cognitive decline, epilepsy and autism spectrum disorders. The work appears June 24 in the journal Neuron.

A rare disorder called megalencephalic leukoencephalopathy (MLC) is also known to be caused by a mutation in the hepaCAM gene, and this work might provide answers about what exactly has gone wrong. MLC is a developmental disorder that grows progressively worse, causing macrocephaly (a large head), swelling of the brain's white matter, intellectual disability and epilepsy.

By removing hepaCAM selectively from astrocytes to see what it does, "we sort of made the cells into introverts," said senior author Cagla Eroglu, an associate professor of cell biology at the Duke University School of Medicine. "They're normally wanting to reach out, but without hepaCAM, they started to hug themselves instead."

"If the astrocyte makes junctions to its neighbors, then you start to have a network," Eroglu said. "To make a functional brain, you need a functional astrocytic network."

The researchers zeroed in on hepaCAM by looking for genes that are highly active in astrocytes and which have been implicated in brain dysfunction. They partnered with another group working on hepaCAM at the University of Barcelona, but that group has been looking at the molecule for its role in regulating chloride signaling channels in astrocytes.

The Duke group found that removing hepaCAM from astrocytes led to a synaptic network that was too easily excited and not as well dampened. "The effect on the inhibitory synapses was the strongest," said first author Katie Baldwin, who recently became an assistant professor of cell biology and physiology at the University of North Carolina at Chapel Hill. "You're putting the inhibition down and the excitation up, so that really could point to a mechanism for epilepsy."

Baldwin, who did this work as a postdoctoral researcher in Eroglu's lab, is planning to further pursue these questions in her new lab at UNC, testing whether hepaCAM-deficient mice behave differently or have changes in learning and memory, or whether they exhibit the stress and social anxiety that are markers of autism spectrum disorders. She said they might also reintroduce the disease-mutation versions of the protein to mice that were born without it to see what effects it has.

"We know hepaCAM is interacting with itself between two astrocytes, but we don't know what it's interacting with at the synapse," Baldwin said. "We don't know if it could be interacting with hepaCAM which is also found in the neurons, or if it could be some other protein that we don't know about yet."

When most Americans think of seaweed, they probably conjure images of a slimy plant they encounter at the beach. But seaweed can be a nutritious food too. A pair of UConn researchers recently discovered Connecticut-grown sugar kelp may help prevent weight gain and the onset of conditions associated with obesity.

In a paper published in the Journal of Nutritional Biochemistry by College of Agriculture, Health, and Natural Resources faculty Young-Ki Park, assistant research professor in the Department of Nutritional Sciences, and Ji-Young Lee, professor and head of the Department of Nutritional Sciences, the researchers reported significant findings supporting the nutritional benefits of Connecticut-grown sugar kelp. They found brown sugar kelp (Saccharina latissima) inhibits hepatic inflammation and fibrosis in a mouse model of diet-induced non-alcoholic steatohepatitis, a fatty liver disease.

They studied the differences between three groups of mouse models. They placed two on high-fat diets but incorporated sugar kelp, a kind of seaweed, into the diet of one. The third group was on a low-fat diet as a healthy control. The group that ate sugar kelp had lower body weight and less adipose tissue inflammation - a key factor in a host of obesity-related diseases - than the other high-fat group.

Consuming sugar kelp also helped prevent the development of steatosis, the accumulation of fat in the liver. Nonalcoholic steatohepatitis (NASH) is a condition often associated with obesity that can cause inflammation and reduced functionality in the liver.

The mice on the sugar kelp diet also had healthier gut microbiomes. The microbiome is a collection of bacteria and other microorganisms in and on our bodies. The diversity and composition of the microbiome are key to maintaining a host of health functions.

"I wasn't surprised to see the data, as we know seaweeds are healthy," Lee says. "But it's still pretty amazing data as this is the first scientific evidence for health benefits of the Connecticut-grown sugar kelp."

This study is the first time researchers have looked at the link between the US-grown sugar kelp and obesity.

"There hadn't been a study about this kind of aspect before," Park says.

Park and Lee saw an opportunity to conduct research on the nutritional science of seaweed, a growing agricultural industry in the United States. They hoped that, by gathering concrete data on the health benefits of sugar kelp, it could encourage people to consume seaweed.

"Consumers these days are getting smarter and smarter," Lee says. "The nutritional aspect is really important for the growth of the seaweed industry in Connecticut."

The researchers specifically used Connecticut-grown sugar kelp, as Connecticut regulates the safety of seaweeds. This is important for monitoring heavy metals that seaweed may absorb from the water.

Most of the seaweed consumed in the US is imported. Park and Lee hope more research on the benefits of locally grown seaweed will prompt consumers to support the industry stateside.

"It's really an ever-growing industry in the world," Lee says.

After completing this pre-clinical study, the researchers now hope to move into clinical studies to investigate the benefits sugar kelp may have for other health concerns. They also want to work on reaching out to people to teach them how to incorporate sugar kelp into their diet.

This work represents a fruitful collaboration between researchers, farmers, and the state.

"Farmers need to know what we're doing is a good thing to help boost their sales," Park says. "We can be a partner."

In collaboration with Anoushka Concepcion, an extension educator with the Connecticut Sea Grant and UConn Extension Program, Park and Lee hope to build stronger partnerships with seaweed growers in Connecticut.

New research from the University of California, Santa Cruz shows how regional shelter-in-place orders during the coronavirus pandemic emboldened local pumas to use habitats they would normally avoid out of fear of humans. This study, published in the journal Current Biology, is part of a growing wave of research working to formally document the types of unusual changes to wildlife movements and behaviors that people around the world reported during pandemic lockdowns.

Golden jackals, for example, were spotted foraging in broad daylight in urban Tel Aviv, Israel, and mountain lions were seen strolling through downtown Santiago, Chile. Urban environments had suddenly become quiet and empty as shelter-in-place orders brought human movement to a grinding halt--an effect some researchers have called the "anthropause." Wildlife seemed to be taking advantage. The new study shows this was certainly true for pumas in the Santa Cruz Mountains. Researchers were able to clearly connect changes in the cats' habitat use with reduced human mobility during shelter-in-place orders.

Chris Wilmers, an environmental studies professor at UC Santa Cruz, led this research. Wilmers is the principal investigator for the Santa Cruz Puma Project, and he has been studying local mountain lion populations for over a decade. In particular, his research uses data from GPS tracking collars placed on wild pumas to show how fear of humans affects mountain lion behavior and ecology. When the pandemic hit, his team was already tracking data from several collared cats, and he recognized a unique research opportunity.

"When the shelter-in-place orders started, it was immediately clear that things were very different," Wilmers said. "You'd go outside and there were very few cars. Entire neighborhoods were completely quiet. So we wondered how this might affect the mountain lion population. Would they respond this quickly to reduced human presence?"

To answer that question, the team analyzed about two years worth of mountain lion tracking data for a set of six collared cats to see where the pumas roamed and what types of habitats they used. Researchers compared these tracks with the distribution of housing density and the geographic boundaries of the "urban edge," which indicates where vehicle and pedestrian traffic is heightened. During regional shelter-in-place orders, they found that cats were significantly more likely to move into or closer to the urban edge. And these changes happened rapidly: within days or weeks of the beginning of COVID-19 lockdowns.

In an effort to hone in on the cause of this change, the team ruled out any influence of natural factors--like topography, vegetation cover, or distance to the nearest water source--that might affect the cats' choice of habitats. They also compared year-over-year tracking data to show that seasonal variability wasn't affecting the results. Pumas do have a strong preference for habitats with lower housing density, but this factor did not change significantly during the study period. The key difference that appeared to be driving the trend of mountain lions moving into urban areas was reduced human mobility during the pandemic.

After regional shelter-in-place orders went into effect on March 17, 2020, local human mobility declined more than 50 percent, according to Apple mobility data, which show the number of navigation requests for driving and walking trips received through Apple Maps. During this time period, when people confined themselves in their homes, the data showed a strong relationship between declining levels of human mobility and pumas' increased willingness to venture closer to or into urban areas.

"We found that they totally relaxed their fear of the urban edge," Wilmers said. "It's not that they weren't scared of cities; they were still scared, but only of high housing density, not the extra impact of human mobility. If you take all the car trips and pedestrian trips and human mobility out of it, then, all of a sudden, mountain lions don't fear the city as much."

Wilmers says this finding helps to build understanding of the unique impacts of human mobility on wildlife. Conservation efforts often focus on the ways that humans are destroying habitats--through development and pollution, for example--but the mere presence of people moving across a landscape also takes a toll on animals that fear humans. And this too is a conservation challenge.

"It's important because our mobility just keeps increasing," Wilmers explained. "In the early part of the 20th century, we got cars, and that really increased our mobility. Now we have things like ride-sharing apps, mountain bikes, and electric bikes, and these are all ways that we're becoming more and more mobile across more types of landscapes. It's an important thing to think about as we try to conserve and manage ecosystems."

Another key point this research illustrates is that fear, or the removal of a source of fear, can bring about rapid changes in animal behavior that ripple out through ecosystems. Ecologists call this concept the "landscape of fear." And the pandemic showed just how integrated into this landscape humans really are. People are usually the ones exerting the influence of fear upon other animals, but there are some things that even we fear.

"Humans have always been the top dog in landscapes of fear, but this study shows that those influences of humans can be reversed relatively quickly by a pathogen, particularly a pandemic-causing pathogen," Wilmers said. "It's interesting from a theoretical perspective, and it's also important in a practical sense because it shows that, not only are pandemics going to have major health consequences for people, but there are also going to be important ecological impacts."

For the past several years, chemical engineer Michelle O'Malley has focused her research on the anaerobic fungi found in the guts of herbivores, which make it possible for those animals to fuel themselves with sugars and starches extracted from fibrous plants. O'Malley's work, reflected in multiple research awards and journal articles, has centered on how these powerful fungi might be used to extract value-added products from the nonedible parts of plants -- roots, stems and leaves -- that are generally considered waste products.

Now, her lab has discovered that those same fungi likely produce novel "natural products," which could function as antibiotics or other compounds of use for biotechnology. The research is described in a paper titled "Anaerobic gut fungi are an untapped reservoir of natural products," published in the Proceedings of the National Academy of Sciences (PNAS).

All living things are equipped with natural defenses to ensure their survival. Microbes often depend on synthesized natural products that act as defenses against environmental threats and allow them to compete with other microbes. Many such natural products have served as the source of antibiotics used to fight disease in humans.

Anaerobic fungi, by definition, do not use oxygen to fuel their production of natural products. Thus, said O'Malley, "It costs them a lot more metabolically to make something than it does an aerobe." Further, anything an anaerobic microbe produces has to be carefully "designed" and extremely efficient, since energy is scarce in the oxygen-free microbes.

O'Malley's lab in 2017 provided the U.S. Department of Energy with several anaerobic gut fungi, which were then sequenced as part of a larger collaboration.

"We started seeing something we didn't expect to find: the building blocks -- biosynthetic gene clusters, or BGCs -- that antibiotics are typically built from," O'Malley said of that work. "BGCs sit near each other on the genome and participate in stepwise chemical reactions. In this case, they are loading a molecule onto an enzyme -- chemically decorating it, if you will -- and then passing it to another enzymatic module and, in this way, making it into an increasingly complex molecule."

That molecular assembly-line process is important, she says, because it emulates how antibiotics are often made. "BGCs could also be of useful for making value-added chemicals, because they have lot of complex chemistry built in," she added. "So, they might be able to be used as drop-in biofuels, as coatings, and as monomers to make novel materials."

But the most important implications, she said, are the antibiotic possibilities. In the paper, lead author Candice Swift, who earned her Ph.D. in O'Malley's lab and is now a postdoctoral researcher at the University of South Carolina's School of Public Health, demonstrates not only that the BGCs are present where they were not expected to be -- anaerobic fungi have never been thought to have antibiotic properties -- they are, even more surprisingly, active and actually making something. "They are transcribed," O'Malley noted.

Swift's analysis suggests that the compounds they found have not been identified previously. "We discovered them, and, based on what is known about these biosynthetic gene clusters, they could be making novel antibiotics," O'Malley said. "We haven't shown that definitively here, but it's one possibility that would make sense, because the fungi exist as kind of minority players in their community, so they probably have some edge or ability that allows them to stick around in the face of overwhelming competition. That's what we think they might be doing. We haven't proven it, but it's an attractive way to look at it."

So, if the anaerobic fungi are producing natural antibiotics, how difficult would it be to translate them into use in humans? "If you identify a novel antibiotic, the key to making that at scale is knowing how it's built," O'Malley explained. "That's a big question. We'll try to address that in a follow-up paper, but if you can figure out the genetic recipe for how they're made, it's straightforward to apply it in another system."

O'Malley said that the scientific community "has become pretty good at making antibiotics, recombinantly or through genetic engineering," and that all, or nearly all antibiotics, are derived from natural products -- either made in nature or inspired by the compounds that nature builds.

The next stage in this research will involve using genetic tools to boost production and isolate the compounds to figure out exactly what compounds are being made. For that work, O'Malley is partnering with other researchers in the BioPolymers, Automated Cellular Infrastructure, Flow, and Integrated Chemistry Materials Innovation Platform (BioPACIFIC MIP), which the National Science Foundation funded last year as a collaboration between UCSB and UCLA.

By Benjamin Boettner

(Boston) - Muscular dystrophies are a group of genetic diseases that lead to the progressive loss of muscle mass and function in patients, with the incurable Duchenne Muscular Dystrophy (DMD), which affects all the body's muscles primarily in boys, being particularly severe. DMD can be caused by more than 7,000 unique mutations in the largest gene of the human genome, which encodes a central protein in muscle fibers. While this astounding number of mutations all variably block muscle function, the affected muscles share another common feature - chronic inflammation.

As chronic inflammation significantly contributes to the speed and severity of muscle degeneration, researchers are pursuing different anti-inflammatory approaches that could be applied to the weakening muscles of DMD patients. Thus far, it has become clear that broad, systemically applied anti-inflammatory therapies cannot reach sufficient efficacies in individual muscles and that, in addition, they can be toxic to patients and increase their risk of infections. To overcome these barriers, locally acting therapies that could be applied on-site at affected muscles would have significant advantages.

Now, a research team at Harvard's Wyss Institute for Biologically Inspired Engineering and John A. Paulson School of Engineering and Applied Sciences (SEAS) led by Wyss Institute Founding Core Faculty member David Mooney, Ph.D., has developed a new approach in which specifically designed anti-inflammatory nanoparticles (NPs) that could be applied locally and selectively to chronically inflamed muscles severely affected or at more immediate risk of deterioration, and maybe difficult to reach with oral therapeutics. In an advanced mouse model of DMD, this strategy increased the volume of muscles covered by myofibers and improved muscle functions by boosting the numbers of infiltrating anti-inflammatory regulatory T cells (Tregs). The findings are published in Science Advances.

A biomaterial-based solution: design and validation

"Using NP-based cytokine delivery, we can create a therapeutic immune status in muscles affected by DMD that targets inflammation as a universal driver of the disease," said Mooney, who leads the Wyss Institute's Immuno-Materials Platform and is also the Robert P. Pinkas Family Professor of Bioengineering at SEAS. "Given the localized delivery of the highly effective cytokine interleukin-4 (IL-4), this approach could be developed as a stand-alone therapy, or in the future be used in combination with genetic approaches designed to repair specific DMD mutations in patients."

Pro-inflammatory and anti-inflammatory immune cells recruited to wasting muscles and further differentiating in them are thought to play an active game of tug-of-war. Both can temporarily get the upper hand with muscles going through continuous cycles of myofiber injury and regeneration while, in the longer-term, injury always wins. Importantly, the identities and activities of immune cells are controlled by pro- and anti-inflammatory cytokines, immune-modulating molecules that are released by immune or other cells in muscle tissue.

In 2018, Mooney's team had shown that gold nanoparticles (NPs) presenting the anti-inflammatory cytokine interleukin-4 (IL-4) when locally injected into acutely injured muscles of mice, could improve the muscles' strength by 40% compared to control NPs. The NPs were designed such that a core NP of gold was partially coated with a layer of the biocompatible polymer polyethylene glycol (PEG). To the parts of the NP surface revealed by gaps in the coating, IL-4 cytokine molecules were then bound (chemically conjugated), allowing them to be protected by the surrounding PEG, and to remain bioactive for extended times following their injection into muscle tissue and up-take by muscle immune cells.

To study the effects of NPs carrying IL-4 NPs as well as NPs carrying IL-10 (a differently acting anti-inflammatory cytokine) on DMD-affected muscles, the researchers used an existing mouse model, known as Mdx, that carries a specific DMD mutation found in human patients. As muscle degeneration occurs much slower in Mdx mice than in human patients, they developed a microinjury approach in which hind limb muscles of aged Mdx mice were repeatedly injured to accelerate murine disease progression and more closely mimic human disease. In Mdx mice, the microinjury caused chronic DMD-like inflammation and damage that persisted for several weeks.

Invigorating muscles with T cell action

One week after terminating the microinjury procedure, they injected IL-4 NPs (and IL-10 NPs) directly into the chronically injured muscle and after another two weeks analyzed the effects. "Cytokine therapy with IL-4 but not IL-10 conjugated to NPs significantly increased the area in cross-sections covered by muscle fibers and, in living animals, the treated muscles showed a four-fold increase in contraction force and speed (velocity) compared to mice in control groups," said first-author Theresa Raimondo, Ph.D., who performed the work as a graduate student in Mooney's group and now is a Postdoctoral Fellow at MIT.

DMD becomes most life threatening when the diaphragm and cardiac muscles become affected. The team hopes that their strategy one day could help improve breathing and heart function in patients, although future studies will have to assess this possibility.

"Interestingly, we could chalk up the regenerative effects to a specific increase in Tregs, an immunosuppressive T cell type that was known to counteract inflammatory processes in muscles weakened by DMD."

The team observed a 50% increase in the number of Tregs in chronically injured muscles of aged Mdx mice while the numbers of other types of immune cells, including neutrophils, dendritic cells, natural killer cells, monocytes, and macrophages remained unchanged with their NP-based cytokine therapy.

Especially macrophages in their anti-inflammatory state called M2 had also been suggested to contribute the restoring muscle strength and function in mouse models of DMD, and were found previously by Mooney's team to be key to repairing acutely injured muscles in normal mice. However, in the chronically inflamed muscles of the advanced Mdx model that were targeted with NP-based IL-4 therapy in the new study, M2 macrophages did not significantly contribute to the therapeutic effect. "Our combined findings highlight that the same cytokine therapy can achieve very different immunological outcomes with therapeutic effects on muscles dependent on the type of inflammation that is present," said Mooney.

"This approach developed by Dave Mooney's group at the Wyss' Immuno-Material Initiative could be developed as an alternative, strategically applied solution for treating patients with Duchenne Muscular Dystrophy whose loss of muscle mass and function cannot be effectively stopped by any other means. The same basic principle of NP-based cytokine therapy could also have potential for a variety of other muscle disorders where inflammation is a major force," said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children's Hospital, and Professor of Bioengineering at SEAS.

PRESS CONTACT

Wyss Institute for Biologically Inspired Engineering at Harvard University
Benjamin Boettner, benjamin.boettner@wyss.harvard.edu, +1 617-432-8232

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ITHACA, N.Y. - Tossing worn-out solar panels into landfills may soon become electronics waste history.

Designing a recycling strategy for a new, forthcoming generation of photovoltaic solar cells - made from metal halide perovskites, a family of crystalline materials with structures like the natural mineral calcium titanate - will add a stronger dose of environmental friendliness to a green industry, according to Cornell University-led research published June 24 in Nature Sustainability.

The paper shows substantial benefits to recycling perovskite solar panels, though they are still in the commercial development stage, said Fengqi You, the Roxanne E. and Michael J. Zak Professor in Energy Systems Engineering in the College of Engineering.

"When perovskite solar panels reach the end of their useful life, how do we deal with this kind of electronic waste?" said You, also a faculty fellow at the Cornell Atkinson Center for Sustainability. "It is a new class of materials. By properly recycling it, we could potentially reduce its already low carbon footprint.

"As scientists design solar cells, they look at performance," You said. "They seek to know energy conversion efficiency and stability, and often neglect designing for recycling."

Last year, You and his laboratory found that photovoltaic wafers in solar panels containing all-perovskite structures outperform photovoltaic cells made from state-of-the-art crystalline silicon, and the perovskite-silicon tandem - with cells stacked like pancakes to better absorb light - perform exceptionally well.

Perovskite photovoltaic wafers offer a faster return on the initial energy investment than silicon-based solar panels because all-perovskite solar cells consume less energy in the manufacturing process.

Recycling them enhances their sustainability, as the recycled perovskite solar cells could bring 72.6% lower primary energy consumption and a 71.2% reduction in carbon footprint, according to the paper, "Life Cycle Assessment of Recycling Strategies for Perovskite Photovoltaic Modules," co-authored by Xueyu Tian, a doctoral student at Cornell Systems Engineering, and Samuel D. Stranks of the University of Cambridge.

"Lowering the energy needed to produce the cells indicates a significant reduction of energy payback and greenhouse gas emissions," said Tian.

The best recycled perovskite cell architecture could see an energy payback time of about one month, with a carbon footprint as low as 13.4 grams of carbon dioxide equivalent output per kilowatt hour of electricity produced. Without recycling, the energy payback time and carbon footprint of new perovskite solar cells show a range of 70 days to 13 months, and 27.5 to 158.0 grams of carbon dioxide equivalent throughout their life cycles.

Today's market-leading silicon photovoltaic cells can expect an energy payback period of 1.3 to 2.4 years, with an initial carbon footprint between 22.1 and 38.1 grams of carbon dioxide equivalent emissions per kilowatt hour output.

"Recycling makes perovskites outcompete all other rivals," Tian said.

Informed state and federal policies, along with recycling infrastructure development strategies, can further mitigate the environmental impacts in making photovoltaic solar cells.

Said You: "The real value of an effective green perovskite solar panel industry may rely on a recycling program."

ITHACA, N.Y. - As mosquito-borne diseases pose risks for half the world's population, scientists have been releasing sterile or genetically modified male mosquitos in attempts to suppress populations or alter their traits to control human disease.

But these technologies have failed to spread very rapidly because they require successful mating of modified mosquitoes with mosquitoes in nature and not enough research exists to fully explain which male traits females seek when they choose a mate.

Now, a new Cornell study of Aedes aegypti mosquitoes investigates how a mating cue called "harmonic convergence" might affect immunity against parasites, bacteria and dengue virus in offspring, which has important implications for trade-offs male mosquitoes make between investing energy towards immunity or investing it on traits that impact mating and fitness.

Previous research has shown that when choosing a mate, a female will use a male's ability to beat his wings at the same frequency as her own as a cue for a male's fitness and desirability. Other studies have also shown that the male offspring from pairs that harmonically converge are better able to achieve harmonic convergence themselves.

"We decided to look to see if the cues that a female responds to might correlate with the downstream genes that a male passes on to offspring that could protect them against parasites and pathogens," said Courtney Murdock, associate professor in the Department of Entomology in the College of Agriculture and Life Sciences, and senior author of the paper, "Sex, age, and parental harmonic convergence behavior affect the immune performance of Aedes aegypti offspring," published June 11 in Nature Communications Biology.

Christine Reitmeyer, a former postdoctoral researcher in Murdock's lab who is currently working at the Pirbright Institute in the United Kingdom, is the paper's first author.

In their study, the researchers separated harmonically converging pairs and non-converging pairs of Aedes aegypti, which transmit dengue, yellow fever, chikungunya and Zika viruses. Males and females of each group were housed together for up to four days. Though females avoid mating with non-converging males in the wild, the males will harass the female into mating under these conditions.

The researchers examined a subset of male and female offspring from the convergent pairs and the non-convergent pairs. They then investigated the effects of pairings that resulted from harmonic convergence on three types of offspring immunity, as well as how these effects were altered by offspring sex, age and life-history stage.

They tested humoral melanization, a defense response where insects will coat a pathogen or parasite with melanin in its gut in order to wall it off and prevent infection. They did this by injecting a tiny bead into the mosquitoes' midsection, and then removing the bead and assessing whether the bead was uncoated, partially coated or fully coated.

They also injected mosquitoes with fluorescently labelled Escherichia coli bacteria and tested how well they grew after 24 hours. And they exposed the females (as males don't feed on blood) to dengue virus and looked for its presence in tissues, especially saliva glands, from where the virus is transmitted during a blood meal.

Overall, males were less capable of melanizing beads and resisting bacterial infections than females.

Additionally, male offspring from converging parents were significantly less able to melanize compared with nonconverging male offspring.

"I think this is because males from converging pairs tend to invest more energy in mating effort and the ability to harmonically converge than on immunity, at least when it comes to melanization," Murdock said.

At the same time, these males fended off bacterial infection better than their nonconverging peers at rates similar to females when they were young, but their defenses dropped rapidly as they aged.

With regard to dengue, females from converging parents showed higher immunity early in life, which waned and matched offspring from nonconverging parents as they aged. But overall, the presence of virus found in saliva was so low that the researchers concluded more study is needed.

"The bottom line is that if convergence is going to have an effect, it's going to affect male ability when it comes to immune response," Murdock said, "and then, the direction of the effect is probably going to be dependent upon the physiological costs associated with that immune response."

The findings also have implications for mosquito control, Murdock said. If modified males have introduced traits that make them undesirable to female mosquitoes in nature, these approaches to suppress or replace mosquito populations will not be sustainable in the field over time, she added.

Early in the COVID-19 pandemic, scientists identified how SARS-CoV-2, the virus that causes COVID-19, gets inside cells to cause infection. All current COVID-19 vaccines and antibody-based therapeutics were designed to disrupt this route into cells, which requires a receptor called ACE2.

Now, researchers at Washington University School of Medicine in St. Louis have found that a single mutation gives SARS-CoV-2 the ability to enter cells through another route - one that does not require ACE2. The ability to use an alternative entry pathway opens up the possibility of evading COVID-19 antibodies or vaccines, but the researchers did not find evidence of such evasion. However, the discovery does show that the virus can change in unexpected ways and find new ways to cause infection. The study is published June 23 in Cell Reports.

"This mutation occurred at one of the spots that changes a lot as the virus circulates in the human population," said co-senior author Sebla Kutluay, PhD, an assistant professor of molecular microbiology. "Most of the time, alternative receptors and attachment factors simply enhance ACE2-dependent entry. But in this case, we have discovered an alternative way to infect a key cell type -- a human lung cell -- and that the virus acquired this ability via a mutation that we know arises in the population. This is something we definitely need to know more about."

The finding was serendipitous. Last year, Kutluay and co-senior author M. Ben Major, PhD, the Alan A. and Edith L. Wolff Distinguished Professor of Cell Biology & Physiology, planned to study the molecular changes that occur inside cells infected with SARS-CoV-2. Most researchers study SARS-CoV-2 in primate kidney cells because the virus grows well in them, but Kutluay and Major felt it was important to do the study in lung or other cells similar to the ones that are naturally infected. To find more relevant cells capable of growing SARS-CoV-2, Kutluay and Major screened a panel of 10 lung and head-and-neck cell lines.

"The only one that was able to be infected was the one I had included as a negative control," Major said. "It was a human lung cancer cell line with no detectable ACE2. So that was a crazy surprise."

Kutluay, Major and colleagues -- including co-first authors and postdoctoral researchers Maritza Puray-Chavez, PhD, and Kyle LaPak, PhD, as well as co-authors Dennis Goldfarb, PhD, an assistant professor of cell biology & physiology and of medicine, and Steven L. Brody, MD, the Dorothy R. and Hubert C. Moog Professor of Pulmonary Diseases in Medicine, and a professor of radiology -- discovered that the virus they were using for experiments had picked up a mutation. The virus had originally been obtained from a person in Washington state with COVID-19, but as it was grown over time in the laboratory, it had acquired a mutation that led to a change of a single amino acid at position 484 in the virus's spike protein. SARS-CoV-2 uses spike to attach to ACE2, and position 484 is a hot spot for mutations. A variety of mutations at the same position have been found in viral variants from people and mice, and in virus grown in the lab. Some of the mutations found in virus samples taken from people are identical to the one Kutluay and Major found in their variant. The Alpha and Beta variants of concern have mutations at position 484, although those mutations are different.

"This position is evolving over time within the human population and in the lab," Major said. "Given our data and those of others, it is possible that the virus is under selective pressure to get into cells without using ACE2. In so many ways, it is scary to think of the world's population fighting a virus that is diversifying the mechanisms by which it can infect cells."

To determine whether the ability to use an alternative entry pathway allowed the virus to escape COVID-19 antibodies or vaccines, the researchers screened panels of antibodies and blood serum with antibodies from people who have been vaccinated for COVID-19 or recovered from COVID-19 infection. There was some variation, but in general, the antibodies and blood sera were effective against the virus with the mutation.

It is not yet clear whether the alternative pathway comes into play under real-world conditions when people are infected with SARS-CoV-2. Before the researchers can begin to address that question, they must find the alternative receptor that the virus is using to get into cells.

"It is possible that the virus uses ACE2 until it runs out of cells with ACE2, and then it switches over to using this alternative pathway," Kutluay said. "This might have relevance in the body, but without knowing the receptor, we cannot say what the relevance is going to be."

Major added, "That's where we're going right now. What is the receptor? If it's not ACE2, what is it?"

Over the last decade, severe outbreaks of bacterial canker have caused huge economic losses for kiwi growers, especially in Italy, New Zealand, and China, which are among the largest producers. Bacterial canker is caused by the bacterial pathogen Pseudomonas syringae pv. actinidiae (Psa) and more recent outbreaks have been particularly devastating due to the emergence of a new, extremely aggressive biovar called Psa3.

Due to its recent introduction, the molecular basis of Psa3's virulence is unknown, making it difficult to develop mitigation strategies. In light of this dilemma, a group of scientists at the University of Verona and University of Rome collaborated on a study comparing the behavior of Psa3 with less-virulent biovars to determine the basis of pathogenicity.

They found that genes involved in bacterial signaling (the transmission of external stimuli within cells) were especially important, especially the genes required for the synthesis and degradation of a small chemical signal called c-di-GMP, that suppresses the expression of virulence factors. Compared to other biovars, Psa3 produces very low levels of c-di-GMP, contributing to an immediate and aggressive phenotype at the onset of infection before the plant can corral a defense response.

"It was exciting to discover this diversified arsenal of pathogenicity strategies among closely related bacterial strains that infect the same hosts but display different behaviors," said Elodie Vandelle, one of the scientists involved with this study. "Although their 'small' genomes mainly contain the same information, our research shows that bacterial populations within a pathovar are more complex than expected and their pathogenicity may have evolved throughout different strategies to attack the same host."

Their research highlights the importance of working on a multitude of real-life pathogenic bacterial strains to shed light on the diversity of virulence strategies. This approach can contribute to the creation of wider pathogenicity working models. In terms of kiwi production, Vandelle hopes their findings can help scientists develop new mitigation methods. In the long-term, their research could lead to the identification of key molecular switches responsible for the transition between high and low bacterial virulence phenotypes.

"This identification would allow, at industrial level, to develop new targeted strategies to control phytopathogenic bacteria, weakening their aggressiveness through switch control, instead of killing them," Vandelle explained. "This would avoid the occurrence of new resistances among bacterial communities, thus guaranteeing a sustainable plant protection."

New research has discovered that common artificial sweeteners can cause previously healthy gut bacteria to become diseased and invade the gut wall, potentially leading to serious health issues.

The study, published in the International Journal of Molecular Sciences, is the first to show the pathogenic effects of some of the most widely used artificial sweeteners - saccharin, sucralose, and aspartame - on two types of gut bacteria, E. coli (Escherichia coli) and E. faecalis (Enterococcus faecalis).

Previous studies have shown that artificial sweeteners can change the number and type of bacteria in the gut, but this new molecular research, led by academics from Anglia Ruskin University (ARU), has demonstrated that sweeteners can also make the bacteria pathogenic. It found that these pathogenic bacteria can attach themselves to, invade, and kill Caco-2 cells, which are epithelial cells that line the wall of the intestine.

It is known that bacteria such as E. faecalis which cross the intestinal wall can enter the blood stream and congregate in the lymph nodes, liver, and spleen, causing a number of infections including septicaemia.

This new study discovered that at a concentration equivalent to two cans of diet soft drink, all three artificial sweeteners significantly increased the adhesion of both E. coli and E. faecalis to intestinal Caco-2 cells, and differentially increased the formation of biofilms.

Bacteria growing in biofilms are less sensitive to antimicrobial resistance treatment and are more likely to secrete toxins and express virulence factors, which are molecules that can cause disease.

Additionally, all three sweeteners caused the pathogenic gut bacteria to invade Caco-2 cells found in the wall of the intestine, with the exception of saccharin which had no significant effect on E. coli invasion.

Senior author of the paper Dr Havovi Chichger, Senior Lecturer in Biomedical Science at Anglia Ruskin University (ARU), said: "There is a lot of concern about the consumption of artificial sweeteners, with some studies showing that sweeteners can affect the layer of bacteria which support the gut, known as the gut microbiota.

"Our study is the first to show that some of the sweeteners most commonly found in food and drink - saccharin, sucralose and aspartame - can make normal and 'healthy' gut bacteria become pathogenic. These pathogenic changes include greater formation of biofilms and increased adhesion and invasion of bacteria into human gut cells.

"These changes could lead to our own gut bacteria invading and causing damage to our intestine, which can be linked to infection, sepsis and multiple-organ failure.

"We know that overconsumption of sugar is a major factor in the development of conditions such as obesity and diabetes. Therefore, it is important that we increase our knowledge of sweeteners versus sugars in the diet to better understand the impact on our health."

Researchers at Harvard University and the Broad Institute of MIT and Harvard have created a first detailed atlas of a critical region of the developing mouse brain, applying multiple advanced genomic technologies to the part of the cerebral cortex that is responsible for processing sensation from the body. By measuring how gene activity and regulation change over time, researchers now have a better understanding of how the cerebral cortex is built, as well as a brand new set of tools to explore how the cortex is affected in neurodevelopmental disease. The study is published in the journal Nature.

"We have had a long-standing interest in understanding the development of the mammalian cerebral cortex, as it is the seat of higher-order cognition and the part of the brain that has expanded and diversified the most during human evolution," said Paola Arlotta, the co-senior author of the study and the Golub Family Professor of Stem Cell and Regenerative Biology at Harvard University. "In this study, we looked at the cortex with a very fine lens, practically profiling all of its cells, one by one, every day of development. We catalogued changes in gene expression and regulation at an unprecedented level of temporal resolution to build a first single-cell-resolution molecular map of this amazing tissue. The map allowed us to extract first mechanistic principles governing how the cortex is built, and begin to decode how genetic abnormalities affect such highy controlled process in the embryo."

"In the developing brain, we have to consider three things: the types of cells that are present, where those cells are located, and at what stage they are in development. In addition, by identifying the drivers that direct this process in normal development, we can better understand what may go wrong in disease," said co-senior author Aviv Regev, who was a core institute member at the Broad Institute when the study began and is currently Head of Genentech Research and Early Development.

The researchers focused on the somatosensory cortex, which may serve as a model for other regions of the cerebral cortex because it contains cells representing all of its major classes. For every day of cortex development, the researchers analyzed the brain using multiple technologies at the single-cell level. They used RNA-seq to measure which genes are expressed, as well as spatial transcriptomics to measure where genes are expressed in the tissue. They also used ATAC-seq to measure which parts of the genome were accessible for regulation.

"These technologies allowed us to look at different modes of gene expression and how genes are regulating each other. By combining these three modalities, we have a stronger sense of which are the important genes for directing neuronal development, for example" said Daniela Di Bella, a postdoctoral fellow in the Arlotta lab and co-first author of the study.

For instance, it has been unclear exactly when the cortex's diversity of different neuron populations is established. "We found that the different flavors of neurons are decided during the neuron maturation process, rather than pre-established in their stem cells," Di Bella said.

The researchers also used their data to predict the underlying mechanism of how genetic mutation leads to defects in cortical development, finding which specific developmental steps are failing and which cells are being affected.

"We have created a uniquely comprehensive molecular atlas of the developing somatosensory cortex, and we are continuing to mine the data for more insights," said co-first author Ehsan Habibi. "Our goal is for our data to serve as a resource for the wider neuroscience community and inform how the field looks at brain development, both during normal and disease processes."

"These combined, extensive measurements provided us with a first dynamic view of the symphony of molecular events that unfold as this critical region of the brain is built in the embryo," said Arlotta, who is also an institute member in the Stanley Center for Psychiatric Research at the Broad Institute. "Researchers have been studying the process of development of the cerebral cortex for over a century, but the mechanistic events that govern how cells are made and how they interact to ultimately form functional circuit have remained elusive. As a field, we have historically looked at this complex developing tissue one cell type at a time, and investigated small numbers of genes for their roles in putting together pieces of this amazing puzzle. But the brain does not develop one cell type at the time -- it is truly a symphony in the sense that hundreds of cell types undergo development together, using ever-changing lanscapes of genes to form the adult tissue. Now imagine having for the first time the full 'recipe' of genes that any given cell class uses as its development unfolds. Imagine also gaining detailed knowledge of the 'codes of genes' that turn on or off as distinct lineages of cells separate from each other and get built. This type of overarching mechanistic knowledge offers an opportunity to study cortical development in a brand new way, looking at all cells and all genes. We never had information this complete before and I must admit that I stared at the data in awe, thinking about the type of discovery that it enables."

"Ten years ago, this study would not have been possible because the technologies either did not exist or were not mature enough yet," Regev said. "But with advances in single-cell and spatial transcriptomics, and new machine learning algorithms for large data analysis, we were able to map where cells develop, put those maps together, and watch development unfold like a movie over time. We could not only reconstruct the movie, but could also link that picture to a greater biological understanding of brain development. We hope this approach could one day help us better understand and treat diseases of the brain."

Arlotta added: "It is a pretty interesting movie -- one that I have looked forward to filming for most of my scientific career."

Researchers at UCSF have found that extreme caloric restriction diets alter the microbiome in ways that could help with weight loss but might also result in an increased population of Clostridiodes difficile, a pathogenic bacterium that can lead to severe diarrhea and colitis.

Such diets, which allow people only 800 calories per day in liquid form, are an effective approach to weight loss in people with obesity. The unexpected results of this study raise the question of how much the microbiome influences weight loss and which bacteria are significant in that process. The study appears in the June 23, 2021, issue of Nature.

"Our results underscore that the role of calories in weight management is much more complex than simply how much energy a person is taking in," said Peter Turnbaugh, PhD, an associate professor of microbiology and immunology and a senior author on the study. "We found that this very-low-calorie diet profoundly altered the gut microbiome, including an overall decrease in gut bacteria."

Turnbaugh and his research team leveraged a clinical trial looking at a very-low-calorie liquid diet. That trial, which resulted in successful weight loss for many of the participants, was led by Joachim Spranger, MD, a professor of endocrinology and metabolic diseases at Charité Universitätsmedizin in Berlin, and co-senior author on the Nature study.

To investigate the microbial connection between this very-low-calorie diet and shedding pounds, Spranger's team collected and sequenced fecal samples from 80 participants - all of whom were post-menopausal women - before and after the trial, which lasted 16 weeks. The team then worked with members of the Turnbaugh lab to analyze the data and to transplant the samples into mice that had been raised in sterile environments.

The researchers allowed these mice to continue eating the same amount of food and found, to their surprise, that the rodents that had received a transplant of the post-diet microbiome lost weight.

"We drove weight loss just by colonizing these mice with a different microbial community," Turnbaugh said.

The next step was to identify bacteria that could be responsible for the weight loss. To do that, Jordan Bisanz, PhD, a former postdoctoral fellow in the Turnbaugh lab and a first author on the study, sequenced the gut microbiomes of the test mice and compared them to those of control mice.

Bisanz discovered a bacterial factor behind changes in weight the team had observed: higher levels of C. difficile.

In the gut, C. difficile is associated with the process of fat metabolism. Initially, fats are digested with the help of bile salts. These bile salts are then broken down by bacteria other than C. difficile, producing what are called secondary bile salts. These bacterial metabolites keep the growth of C. difficile under control. In other words, people who are eating less, particularly less fat, can produce less bile, which in turn leads to fewer secondary bile acids and less of a check on the population of C. difficile.

"Ordinarily we would predict increased inflammation or even colitis following an increase in C. difficile," said Turnbaugh, who is also an investigator at the Chan Zuckerberg Biohub, Curiously, when he and his team examined the mice, they found only mild inflammation. That lack of inflammation suggests that C. diff could have important effects on metabolism that are distinguishable from the bacterium's ability to drive severe intestinal disease.

At the same time, Turnbaugh notes, it's not at all certain what would happen if someone stayed on the diet for a longer period of time and whether that could result in a full-blown C. difficile infection, which can be life threatening if it gets out of control.

"Let's be clear; we are definitely not promoting C. difficile as a new weight loss strategy," said Turnbaugh. "We've got a lot of biology left to unpack here." The data raise a lot of interesting and unexplored questions about what role C. difficile is playing beyond the severe inflammatory conditions associated with it, he said.

It's important to understand whether diet-induced changes to C. difficile level are harmful in humans, and how the balance between different microbial species in the gut is affected by different dietary choices, Turnbaugh said. Ultimately, that knowledge could allow clinicians to add or remove specific microbes in a patient's gut to help maintain a healthy body weight.

"Multiple lines of research shows that the gut microbiome can either hinder or enhance weight loss," said Turnbaugh. "We want to better understand how common weight loss diets might impact the microbiome and what the downstream consequences are for health and disease."

AMES, Iowa -- A new study of small Iowa towns found that vulnerable populations within those communities face significantly more public health risks than statewide averages.

The study, published this week in PLOS ONE, a peer-reviewed open access journal, was led by Benjamin Shirtcliff, associate professor of landscape architecture at Iowa State University.

He focused on three Iowa towns - Marshalltown, Ottumwa and Perry - as a proxy for studying shifting populations in rural small towns, in particular how vulnerable populations in these towns are affected by their built environment (where people live and work) and environmental risks. Shirtcliff wants to understand how small towns can prioritize investment into their built environment for vulnerable populations on the heels of declining economic resources due to population change.

The study found the three towns have significantly higher environmental exposures than state averages, including more exposure to diesel, air toxins, lead paint in older homes and proximity to potential chemical accidents.

These risks are exacerbated for and increase physical and mental stress on populations with social vulnerability (minority status, low-income, linguistic isolation, below high school education, and populations under age 5 and over 64), which are also significantly higher in the three small towns than state averages.

With the growth of industrialized agriculture over the past few decades, small towns' populations have shifted: "...what environmental justice advocates describe as a 'double jeopardy' of injustice where people with the fewest resources reside in low-income communities with high level of environmental risk and unable defend against social threats like racism," according to the study.

Urban areas benefit from more green space, which would make it seem as if small towns surrounded by green landscapes would have greater benefits. That's not always the case, Shirtcliff says, due to the routine application of pesticides, fertilizers and other organic and inorganic toxins.

"There is a rural health paradox: These small towns may appear on the outside that they're healthier and safer, but the reality is that the metrics cities use are not really compatible," he said.

This exposes a knowledge gap in current research: Measures of environmental risk and design on vulnerable populations in urban areas are not comparable to those in small towns.

'Parallel communities'

Shirtcliff describes these small towns as having "parallel communities," or populations that rarely interact due to their opposing work and personal schedules, geography and language barriers.

This research began following one of Shirtcliff's design studios in Perry four years ago. During an interview with Jon Wolseth, assistant director of community and economic development with ISU Extension and Outreach, he and fellow researchers learned about the parallel communities in the town.

"When we think about public health these days, we think about viruses and epidemics," he said. "What's increasingly being supported through research is that the neighborhoods we live in have huge impacts on our mental and physical health."

As some Iowans move to more urban areas from small towns, the built environment they leave behind is sometimes neglected.

Now, there are new barriers that people in these towns face to report and seek care for poor health effects from their built environment. There is also sometimes an information barrier; for example, rural populations may not correlate higher rates of asthma with the landscape.

"Although the influx of foreign-born workers and their families to small towns has enabled economic growth in the hands of a local few, the stability of small towns is fragile," according to the study. "A decline in local investment coupled with aging infrastructure is likely to impact the built environments in small towns, potentially compounding deleterious effects as vulnerable populations bring families and become established."

Shirtcliff puts a call out to the landscape architecture profession, which can sometimes focus on broad-reaching issues such as major parks and environmental remediation, to also focus their efforts on "the banal, everyday 'human environment' where a sidewalk, street tree, and crosswalk make a fundamental difference." Low-cost interventions such as these can counteract "a mounting public health crisis in small towns," he says.