The study in mice clarified the role of specific immune cells in the brain that contribute to chronic inflammation. Using a technique called forced cell turnover, researchers eliminated these cells in the injured brains of mice for a week and then let them repopulate for two weeks.

“It’s almost like hitting the reset button,” said senior study author Jonathan Godbout, professor of neuroscience in The Ohio State University College of Medicine.

Compared to brain-injured mice recovering naturally, mice that were given the intervention showed less inflammation in the brain and fewer signs of thinking problems 30 days after the injury.

Though temporarily clearing away these cells, called microglia, in humans isn’t feasible, the findings shed light on pathways to target that could lower the brain’s overall inflammatory profile after a concussion, potentially reducing the risk for behavioral and cognitive problems long after the injury.

“In a moderate brain injury, if the CT scan doesn’t show damage, patients go home with a concussion protocol. Sometimes people come back weeks, months later with neuropsychiatric issues. It’s a huge problem affecting millions of people,” said Godbout, faculty director of Ohio State’s Chronic Brain Injury Program and assistant director of basic science in the Institute for Behavioral Medicine Research.

“How do you treat that? At least in mice, by turning over the microglia in the brain we had a very positive effect on their behavior, cognitive status and level of inflammation in the brain. Now we can focus on cellular pathways that generate chronic inflammation as a target.”

The research is published online in the Journal of Neuroscience.

About 85% of traumatic brain injuries are similar to the type of concussion examined in this study, involving dispersed impact to the head that causes brain tissue to bump against the skull. Previous research suggests that at least 75% of people who experience a moderate brain injury have long-term mental health and cognitive complications.

Godbout’s lab previously linked depressive symptoms in mice to microglia’s sustained “high alert” status after a head injury, which causes the cells to overreact to later challenges to the immune system and become excessively inflammatory. In a more recent study in mice, his team showed that forced turnover of microglia before a head injury could reduce later neuropsychiatric complications.

“That was a proof of principle to show that a lot of the inflammation, especially in the long term, is mediated by microglia,” he said. “But there is an acute phase of inflammation — you want to initiate that repair process. There’s a positive to that early inflammatory response in the brain or spinal cord. If it lasts a long time and doesn’t fully resolve, that’s when it’s dangerous.”

In this new study, researchers waited for seven days after the brain injury to force the turnover of microglia, giving the cells time to carry out their work promoting initial healing. An experimental drug that inhibits a protein that microglia in mice need for survival was added to their food for a week, resulting in depletion of over 95% of microglia in their brains.

After allowing 16 days for the microglia to repopulate, researchers compared the intervention mice to injured mice that recovered without the cell turnover treatment. The intervention mice performed better than control mice on tasks testing their memory and depressive symptoms.

Further analyses of injured brain tissue suggested the cell turnover reversed some injury-related damage to neurons, lowered overall inflammation and improved the brain’s ability to adapt to change. Researchers also injected mice with a molecule that triggers an immune response to mimic an infection, and found that sickness behavior was lower in the intervention mice.

Godbout said these combined findings suggest that the repopulating microglia returned in a less “primed” state of readiness, lowering chances for a lifetime of exaggerated inflammatory responses in the brain to any challenge to the immune system — that brain inflammation being the likely culprit behind the neuropsychiatric complications that follow a head injury.

“If microglia in the human brain don’t return to normal and chronic inflammation persists after a head injury, it’s not just a secondary brain injury that causes problems. Even getting a viral infection after concussion recovery can progress into a cognitive or behavioral issue or amplify some other part of behavior, like depression,” Godbout said. “There is a real connection between a head injury and mental health, and the risk doesn’t go away.

“Now we’re looking more closely at the pathways that cause changes in microglia, and targeting something specific in that pathway. That is a way forward.”

This work was supported by the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the National Institute of Dental and Craniofacial Research, an Ohio State University Presidential Fellowship and the Thailand Research Fund-Royal Golden Jubilee Program.

Co-authors include Chelsea Bray, Kristina Witcher, Dunni Adekunle-Adegbite, Michelle Ouvina, Mollie Witzel, Emma Hans, Zoe Tapp, Jonathan Packer, Ethan Goodman, Fangli Zhao, Shane O’Neil, John Sheridan, Olga Kokiko-Cochran and Candice Askwith, all of Ohio State, and Titikorn Chunchai and Siriporn Chattipakorn of Chiang Mai University in Thailand.

A team of researchers has developed a simple yet powerful strategy for creating new enzymes with novel reactivity that can produce valuable chemical compounds, building on their previous work using light to repurpose naturally occurring enzymes.

The study, published in Nature Catalysis, was led by Xiaoqiang Huang, a former postdoctoral researcher in the University of Illinois Urbana-Champaign’s Department of Chemical and Biomolecular Engineering (ChBE) and the Center for Advanced Bioenergy and Bioproducts Innovation (CABBI), a U.S. Department of Energy-funded Bioenergy Research Center. Huang, currently an Assistant Professor at the Nanjing University in China, carried out this work in the laboratory of ChBE Professor Huimin Zhao, CABBI’s Conversion Theme Leader and an affiliate of the Carl R. Woese Institute for Genomic Biology (IGB).

In the study, visible light was used to excite an engineered ketoreductase enzyme, enabling a new-to-nature biocatalytic reaction known as an asymmetric radical conjugate addition, which is extremely difficult to achieve by chemical catalysis.

Catalysts are substances used to speed up chemical reactions. In living organisms, protein molecules called enzymes catalyze reactions in a process called biocatalysis. Scientists have begun using biocatalysis to synthesize valuable compounds, as its high selectivity allows them to deploy enzymes to act on specific substrates and create target products. Another advantage is that enzymatic reactions are highly sustainable. They are relatively inexpensive, consume low levels of energy, and do minimal damage to the environment — as opposed to chemical catalysts, which typically require organic solvents, heat, and high pressure to function.

Still, enzymes are complicated to work with. They are normally limited to catalyzing reactions found in nature, meaning scientists often struggle to track down the perfect biocatalyst to meet their needs. Zhao’s lab has focused on steering biocatalysis with visible light, a process known as “photobiocatalysis,” to produce new enzyme reactivity. In a previous study, Zhao and Huang developed a visible light-induced reaction using an enzyme named ene-reductase (ER) as a biocatalyst to produce high yields of valuable chiral carbonyl compounds, which have potential applications for production of high value chemicals.

The new study builds on that work, using photobiocatalysis on a different enzyme family — nicotamide-dependent ketoreductases produced by bacteria — and a different chemical mechanism to produce another type of chiral carbonyl compounds known as α-chiral esters. Through the illumination and evolution of ketoreductase, the team achieved an enantioselective biocatalytic Giese-type radical conjugate addition to transform fatty acids to α-chiral esters, Zhao said.

Enantioselectivity is the degree to which an enantiomer — one of a pair of molecules that are mirror images of each other — is preferentially produced in a chemical reaction. Chirality is a fundamental feature of organic compounds, which greatly influences the properties of molecules, and its implications are enormous in many areas, including biology, medicine, and material science. For example, the diverse stereochemistry of organic molecules (the spatial arrangement of atoms and its effect on chemical reactions) not only significantly enhances the richness of the biological world, but also plays a profound role in many biological activities such as molecular communication, he said.

The findings offer practical applications for CABBI’s work to develop biofuels and biochemicals from crops like miscanthus, sorghum, and energycane instead of petroleum. The new biocatalytic transformation could use the fatty acids that CABBI is generating from those plants as starting materials to synthesize value-added bioproducts — such as ingredients for soaps or skin-care products — in an environmentally friendly way.

“Although we did not target a specific product for further application, this work provides a practical new method that could be potentially applied to upgrading fatty acids,” Zhao said. “Enzymes are the workhorses for biological synthesis of fuels and chemicals from renewable biomass.

“One of the major scientific changes in CABBI’s Conversion research, or bioenergy research in general, is the lack of known enzymes with the desired activity and substrate specificity for the synthesis of target fuels and chemicals. Therefore, there is an urgent need to develop new strategies to discover or engineer enzymes with desired activity or reactivity.”

Co-authors on the study included CABBI Postdoctoral Fellow Guangde Jiang of ChBE; CABBI’s Wesley Harrison, a Ph.D. candidate in ChBE and IGB; Jianqiang Feng and Binju Wang of Xiamen University, China; and Jiawen Cui, Xin Zang, and Jiahai Zhou of Shanghai Institute of Organic Chemistry, China. Zhou is also affiliated with the Chinese Academy of Sciences Shenzhen Institute of Advanced Technology, China.

“As the planet continues to warm, we expect a number of species to move out of some protected areas and into others as they shift their ranges in response to climate change,” says lead-author Sean Parks, a research ecologist with the USDA Forest Service Rocky Mountain Research Station, Aldo Leopold Wilderness Research Institute.

The researchers found that some species currently in protected areas may have to cross international boundaries to find more suitable climate conditions. As they move, they may face physical barriers, such as border fences, and non-physical barriers, such as inconsistent conservation policies in different areas and countries.

Climate conditions are expected to change in over a quarter of the current land-based global network of protected areas under a scenario of 2°C warming. The study found that more than a third of protected lands could gain new climates. Understanding these shifts away from known to new climate conditions within protected areas helps the international conservation community forecast planning needs and make more strategic investment decisions for limited conservation funding.

“The Rocky Mountain Research Station is committed to addressing the threat of climate change, by providing research needed to support new strategies for stewarding protected areas and other wildlands within the United States and internationally,” says Jason Taylor, Director of the Aldo Leopold Wilderness Research Institute.

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