“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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But the carbon fixing champs are not plants, but soil bacteria. Some bacterial enzymes carry out a key step in carbon fixation 20 times faster than plant enzymes do, and figuring out how they do this could help scientists develop forms of artificial photosynthesis to convert the greenhouse gas into fuels, fertilizers, antibiotics and other products.

Now a team of researchers from the Department of Energy’s SLAC National Accelerator Laboratory, Stanford University, Max Planck Institute for Terrestrial Microbiology in Germany, DOE’s Joint Genome Institute (JGI) and the University of Concepción in Chile has discovered how a bacterial enzyme — a molecular machine that facilitates chemical reactions — revs up to perform this feat.

Rather than grabbing carbon dioxide molecules and attaching them to biomolecules one at a time, they found, this enzyme consists of pairs of molecules that work in sync, like the hands of a juggler who simultaneously tosses and catches balls, to get the job done faster. One member of each enzyme pair opens wide to catch a set of reaction ingredients while the other closes over its captured ingredients and carries out the carbon-fixing reaction; then, they switch roles in a continual cycle.

A single spot of molecular “glue” holds each pair of enzymatic hands together so they can alternate opening and closing in a coordinated way, the team discovered, while a twisting motion helps hustle ingredients and finished products in and out of the pockets where the reactions take place. When both glue and twist are present, the carbon-fixing reaction goes 100 times faster than without them.

“This bacterial enzyme is the most efficient carbon fixer that we know of, and we came up with a neat explanation of what it can do,” said Soichi Wakatsuki, a professor at SLAC and Stanford and one of the senior leaders of the study, which was published in ACS Central Science this week.

“Some of the enzymes in this family act slowly but in a very specific way to produce just one product,” he said. “Others are much faster and can craft chemical building blocks for all sorts of products. Now that we know the mechanism, we can engineer enzymes that combine the best features of both approaches and do a very fast job with all sorts of starting materials.”

Improving on nature

The enzyme the team studied is part of a family called enoyl-CoA carboxylases/reductases, or ECRs. It comes from soil bacteria called Kitasatospora setae, which in addition to their carbon-fixing skills can also produce antibiotics.

Wakatsuki heard about this enzyme family half a dozen years ago from Tobias Erb of the Max Planck Institute for Terrestrial Microbiology in Germany and Yasuo Yoshikuni of JGI. Erb’s research team had been working to develop bioreactors for artificial photosynthesis to convert carbon dioxide (CO₂) from the atmosphere into all sorts of products.

As important as photosynthesis is to life on Earth, Erb said, it isn’t very efficient. Like all things shaped by evolution over the eons, it’s only as good as it needs to be, the result of slowly building on previous developments but never inventing something entirely new from scratch.

What’s more, he said, the step in natural photosynthesis that fixes CO₂ from the air, which relies on an enzyme called Rubisco, is a bottleneck that bogs the whole chain of photosynthetic reactions down. So using speedy ECR enzymes to carry out this step, and engineering them to go even faster, could bring a big boost in efficiency.

“We aren’t trying to make a carbon copy of photosynthesis,” Erb explained. “We want to design a process that’s much more efficient by using our understanding of engineering to rebuild the concepts of nature. This ‘photosynthesis 2.0’ could take place in living or synthetic systems such as artificial chloroplasts — droplets of water suspended in oil.”

Portraits of an enzyme

Wakatsuki and his group had been investigating a related system, nitrogen fixation, which converts nitrogen gas from the atmosphere into compounds that living things need. Intrigued by the question of why ECR enzymes were so fast, he started collaborating with Erb’s group to find answers.

Hasan DeMirci, a research associate in Wakatsuki’s group who is now an assistant professor at Koc University and investigator with the Stanford PULSE Institute, led the effort at SLAC with help from half a dozen SLAC summer interns he supervised. “We train six or seven of them every year, and they were fearless,” he said. “They came with open minds, ready to learn, and they did amazing things.”

The SLAC team made samples of the ECR enzyme and crystallized them for examination with X-rays at the Advanced Photon Source at DOE’s Argonne National Laboratory. The X-rays revealed the molecular structure of the enzyme — the arrangement of its atomic scaffolding — both on its own and when attached to a small helper molecule that facilitates its work.

Further X-ray studies at SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL) showed how the enzyme’s structure shifted when it attached to a substrate, a kind of molecular workbench that assembles ingredients for the carbon fixing reaction and spurs the reaction along.

Finally, a team of researchers from SLAC’s Linac Coherent Light Source (LCLS) carried out more detailed studies of the enzyme and its substrate at Japan’s SACLA X-ray free-electron laser. The choice of an X-ray laser was important because it allowed them to study the enzyme’s behavior at room temperature — closer to its natural environment — with almost no radiation damage.

Meanwhile, Erb’s group in Germany and Associate Professor Esteban Vo?hringer-Martinez’s group at the University of Concepción in Chile carried out detailed biochemical studies and extensive dynamic simulations to make sense of the structural data collected by Wakatsuki and his team.

The simulations revealed that the opening and closing of the enzyme’s two parts don’t just involve molecular glue, but also twisting motions around the central axis of each enzyme pair, Wakatsuki said.

“This twist is almost like a rachet that can push a finished product out or pull a new set of ingredients into the pocket where the reaction takes place,” he said. Together, the twisting and synchronization of the enzyme pairs allow them to fix carbon 100 times a second.

The ECR enzyme family also includes a more versatile branch that can interact with many different kinds of biomolecules to produce a variety of products. But since they aren’t held together by molecular glue, they can’t coordinate their movements and therefore operate much more slowly.

“If we can increase the rate of those sophisticated reactions to make new biomolecules,” Wakatsuki said, “that would be a significant jump in the field.”

From static shots to fluid movies

So far the experiments have produced static snapshots of the enzyme, the reaction ingredients and the final products in various configurations.

“Our dream experiment,” Wakatsuki said, “would be to combine all the ingredients as they flow into the path of the X-ray laser beam so we could watch the reaction take place in real time.”

The team actually tried that at SACLA, he said, but it didn’t work. “The CO₂ molecules are really small, and they move so fast that it’s hard to catch the moment when they attach to the substrate,” he said. “Plus the X-ray laser beam is so strong that we couldn’t keep the ingredients in it long enough for the reaction to take place. When we pressed hard to do this, we managed to break the crystals.”

An upcoming high-energy upgrade to LCLS will likely solve that problem, he added, with pulses that arrive much more frequently — a million times per second — and can be individually adjusted to the ideal strength for each sample.

Wakatsuki said his team continues to collaborate with Erb’s group, and it’s working with the LCLS sample delivery group and with researchers at the SLAC-Stanford cryogenic electron microscopy (cryo-EM) facilities to find a way to make this approach work.

Researchers from the RIKEN Spring-8 Center and Japan Synchrotron Radiation Research Institute also contributed to this work, which received major funding from the DOE Office of Science. Much of the preliminary work for this study was carried out by SLAC summer intern Yash Rao; interns Brandon Hayes, E. Han Dao and Manat Kaur also made key contributions. DOE’s Joint Genome Institute provided the DNA used to produce the ECR samples. SSRL, LCLS, the Advanced Photon Source and the Joint Genome Institute are all DOE Office of Science user facilities.

Citation: Hasan DeMirci et al., ACS Central Science, 25 April 2022 (10.1021/acscentsci.2c00057)

SLAC is a vibrant multiprogram laboratory that explores how the universe works at the biggest, smallest and fastest scales and invents powerful tools used by scientists around the globe. With research spanning particle physics, astrophysics and cosmology, materials, chemistry, bio- and energy sciences and scientific computing, we help solve real-world problems and advance the interests of the nation.

SLAC is operated by Stanford University for the U.S. Department of Energy’s Office of Science. The Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time.

Described in a paper in Cell on April 27, 2022, the new method, called CATCH, attaches fluorescent tags to drug molecules and uses chemical techniques to improve the fluorescent signal. The researchers demonstrated the method with several different experimental drugs, revealing where — even within individual cells — the drug molecules hit their targets.

“This method ultimately should allow us, for the first time, to see relatively easily why one drug is more potent than another, or why one has a particular side effect while another one doesn’t,” says study senior author Li Ye, PhD, assistant professor of neuroscience at Scripps Research and The Abide-Vividion Chair in Chemistry and Chemical Biology.

The study’s first author, Zhengyuan Pang, is a graduate student in the Ye lab. The study also was a close collaboration with the laboratory of Ben Cravatt, PhD, Gilula Chair of Chemical Biology at Scripps Research.

“The unique environment at Scripps Research, where biologists routinely work together with chemists, is what made the development of this technique possible,” Ye says.

Understanding where drug molecules bind their targets to exert their therapeutic effects — and side effects — is a basic part of drug development. However, drug-target interaction studies traditionally have involved relatively imprecise methods, such as bulk analyses of drug-molecule concentration in entire organs.

The CATCH method involves the insertion of tiny chemical handles into drug molecules. These distinct chemical handles don’t react with anything else in the body, but do allow the addition of fluorescent tags after the drug molecules have bound to their targets. In part because human or animal tissue tends to diffuse and block the light from these fluorescent tags, Ye and his team combined the tagging process with a technique that makes tissue relatively transparent.

In this initial study, the researchers optimized and evaluated their method for “covalent drugs,” which bind irreversibly to their targets with stable chemical bonds known as covalent bonds. This irreversibility of binding makes it particularly important to verify that such drugs are hitting their intended targets.

The scientists first evaluated several covalent inhibitors of an enzyme in the brain called fatty acid amide hydrolase (FAAH). FAAH inhibitors have the effect of boosting levels of cannabinoid molecules, including the “bliss molecule” anandamide, and are being investigated as treatments for pain and mood disorders. The scientists were able to image, at the single-cell level, where these inhibitors hit their targets within large volumes of mouse brain tissue, and could easily distinguish their different patterns of target engagement.

In one experiment, they showed that an experimental FAAH inhibitor called BIA-10-2474, which caused one death and several injuries in a clinical trial in France in 2016, engages unknown targets in the midbrain of mice even when the mice lack the FAAH enzyme — offering a clue to the source of the inhibitor’s toxicity.

In other tests demonstrating the unprecedented precision and versatility of the new method, the scientists showed that they could combine drug-target imaging with separate fluorescent-tagging methods to reveal the cell types to which a drug binds. They also could distinguish drug-target engagement sites in different parts of neurons. Finally, they could see how modestly different doses of a drug often strikingly affect the degree of target engagement in different brain areas.

The proof-of-principle study is just the beginning, Ye emphasizes. He and his team plan to develop CATCH further for use on thicker tissue samples, ultimately perhaps whole mice. Additionally, they plan to extend the basic approach to more common, non-covalently-binding drugs and chemical probes. On the whole, Ye says, he envisions the new method as a basic tool not only for drug discovery but even for basic biology.

“In situ Identification of Cellular Drug Targets in Mammalian Tissue” was co-authored by Zhengyuan Pang, Michael Schafroth, Daisuke Ogasawara, Yu Wang, Victoria Nudell, Neeraj Lal, Dong Yang, Kristina Wang, Dylan Herbst, Jacquelyn Ha, Carlos Guijas, Jacqueline Blankman, Benjamin Cravatt and Li Ye — all of Scripps Research during the study.

The study was funded in part by the National Institutes of Health (DP2DK128800, DK114165, DK124731, DA033760), the Whitehall Foundation, the Baxter Foundation, and the Dana Foundation.

Scientists exploring Blick Mead, a Mesolithic archaeological site within a chalkland spring area about a mile from the iconic standing-stones, have found evidence the land was not covered in dense, closed canopy forests during the later Mesolithic period, as had previously been thought. Rather, it was partially wooded and populated by aurochs (cattle), red deer, elk and wild boar — making it good hunting ground for humans who lived opportunistically off the land, prior to the arrival of early farmers.

Lead researcher, Samuel Hudson, of Geography and Environmental Science at Southampton explains: “There has been intensive study of the Bronze Age and Neolithic history of the Stonehenge landscape, but less is known about earlier periods. The integration of evidence recovered from previous excavations at Blick Mead, coupled with our own fieldwork, allowed us to understand more about the flora and fauna of the landscape prior to construction of the later world-famous monument complex.

“Past theories suggest the area was thickly wooded and cleared in later periods for farming and monument building. However, our research points to pre-Neolithic, hunting-gatherer inhabitants, living in open woodland which supported aurochs and other grazing herbivores.”

The research team analysed pollen, fungal spores and traces of DNA preserved in ancient sediment (sedaDNA), combined with optically stimulated luminescence (OSL) and radiocarbon dating to produce an environmental history of the site. Using this evidence, they built a picture of the habitat in the area from the later Mesolithic (5500 BC) to the Neolithic period (from 4,000 BC).

The study indicates that later Mesolithic populations at Blick Mead took advantage of more open conditions to repeatedly exploit groups of large ungulates (hoofed mammals), until a transition to farmers and monument-builders took place. In a sense, the land was pre-adapted for the later large-scale monument building, as it did not require clearance of woodland, due to the presence of these pre-existing open habitats. The researchers suggest there was continuity between the inhabitants of the two eras, who utilised the land in different ways, but understood it to be a favourable location.

The findings of the team from Southampton, working with colleagues at the universities of Buckingham, Tromsø and Salzburg, are published in the journal PLOS ONE.

The scientists plan further exploration of the Mesolithic history of this area, which they hope to begin at the end of this year.

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In the fall of 2019, all-electric buses were introduced on bus route 60 in Gothenburg. The implementation was linked to the ElectriCity project, with its participants from industry, research, and public agencies working for sustainable travel in an urban setting.

In places, the roads along this bus route in question are highly uneven. Noise levels from the preceding system of bus transportation had been perceived as disturbing, especially on the uphill stretches. Previous noise-level measurements had indicated that disturbance from low-frequency noise in indoor environments was present in the residential area.

How much the electric bus transportation would affect the noise levels was not clear, and the same applied to how people’s health would be influenced. The low-frequency noise was particularly important, since it has a high disturbance potential and it is further less well attenuated by façades or noise barriers.

Low-frequency noise hard to block

“We can be disturbed by different noises, but the issue with low-frequency noise is that it’s attenuated less well by facades or windows and therefore intrudes into people’s homes more easily. Even small increases in its level are perceived as very noticeable,” says Kerstin Persson Waye, Professor of Environmental Medicine at Sahlgrenska Academy, University of Gothenburg, who heads the Sound Environment and Health group that conducted the research.

The study involved questionnaire surveys of randomly selected residents in two phases, before and after the switch to electric buses. Half of the residents lived in homes that lined the bus route in two city districts: Masthugget and Lunden. The other half, who lived some distance away, made up the reference group.

In parallel, noise measurements were performed in several homes — including indoors, which is not otherwise standard procedure. These measurements required special rigging with 10-12 microphones in each dwelling unit to provide correct and representative data of the low-frequency noise.

The changes that took place between phases one and two were clear and statistically significant. They applied to changes of the sound levels especially in the low frequencies, what the residents themselves noticed, and their reported noise annoyance. For example, the proportion of respondents who noticed noise from buses fell from 75 to 39 percent, and the proportion who were noise annoyed to a very high degree decreased from 26 to 5 percent.

Distinct improvement in health

There was also a clear reduction of perceived health effects. The proportion who felt exhausted once or twice a week declined from 49 to 39 percent — that is, down to the same proportion as in the reference group. The proportion who were in a low mood decreased from 22 to 17 percent, and considerably fewer also stated that they were very sleepy in the daytime.

“So, there was an improvement: People felt significantly better. Although we can’t say with certainty that the results reflect the whole population and how lasting the positive health changes are, we think they may be generalizable in residential settings where bus transportation makes up a large share of the exposure. Given, too, that other forms of transportation in the urban environment are getting more silent, this could influence public health,” Persson Waye concludes.

Respondents in the study numbered 1,326 in Phase 1, June-September 2019 (response rate: 34 percent) and 1,191 in Phase 2 the following year (response rate: 36 per cent). The response rate was as expected.

To investigate whether those who did not answer differed from the respondents, a follow-up study was conducted with a simplified questionnaire in the group who did not answer. No major differences in perceptions of the noise situation were found, but the level of education and the proportion who owned their home were lower in the group who had chosen not to participate in the large survey.

Yet, consistently achieving the deep, restorative sleep necessary for optimal physiologic health and peak cognitive performance can be difficult due to lifestyle, environmental, and biologic factors.

One of the most confounding questions in sleep biology has been how deep sleep is regulated by the brain. The answer could help illuminate new ways to mitigate sleep problems.

Now, a newly published study led by Harvard Medical School researchers at VA Boston Healthcare Systemoffers critical clues into this longstanding mystery.

The work, conducted in mice and published April 26 in Nature Communications, identifies an area in the brain that regulates the oscillations of delta waves — electrical signals transmitted across neurons that arise during the deepest phases of relaxation. They are a hallmark of restorative sleep.

The research team homed in on neurons in the thalamus, a region of the brain that regulates sleep and wakefulness, among other functions. Using CRISPR-Cas9 gene editing, the researchers disrupted a gene that codes for a protein that binds the inhibitory neurotransmitter GABA. The protein is a target of drugs that promote sleep. Disruption of this gene in mouse models boosted the activity of delta waves and enhanced deep sleep in the animals.

If replicated in further animal models, the findings could lay the groundwork for designing therapies that precision-target this protein to induce deep sleep.

“Our findings represent an important step forward in pinpointing the molecular basis of sleep regulation and point to an alternative pharmacologic strategy for promoting natural, restorative sleep,” said study senior investigator Radhika Basheer, associate professor of psychiatry at HMS and VA Boston.

New therapies are sorely needed. Commonly used insomnia medicines, while an important tool for treatment of persistent insomnia, have well-known drawbacks. Many of these medications work by getting people to fall asleep fast, but they also tend to dampen the activity of restorative delta waves. Thus, while such medications promote falling asleep, the slumber they induce is not necessarily restorative.

“We believe our findings set the stage for developing a new class of sleep medicines that can achieve this all-important maintenance of deep sleep by boosting delta wave oscillations,” added Basheer, who co-led the study with colleague Ritchie Brown, associate professor of psychiatry at HMS.

HMS co-authors include David Uygun, Chun Yang, Fumi Katsuki, Erik Hodges, James McKenna, and James McNally. Elena Tilli of Stonehill College was also a co-author on the study.

This work was supported by VA Biomedical Laboratory Research and Development Service Merit Awards and by National Institutes of Health grants R01 NS119227, R21 NS079866, R01 MH039683, T32 HL07901, K01 AG068366, R21 MH125242.

Disclosures: Uygun, McKenna, McNally, Brown, and Basheer are research health scientists at VA Boston Healthcare System. The contents of this work do not represent the views of the US Department of Veterans Affairs or the United States Government. McKenna received partial salary compensation and funding from Merck MISP (Merck Investigator Sponsored Programs) but has no conflict of interest with this work.

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