Earth

Plant flowering in low-nitrogen soils: A mechanism revealed

image: Arabidopsis plants used in one of the experiments during the study (Photo: Takeo Sato).

Image: 
Takeo Sato

Scientists from Japan, Europe and the USA have described a pathway leading to the accelerated flowering of plants in low-nitrogen soils. These findings could eventually lead to increases in agricultural production.

Nitrogen is one of the three macronutrients required by plants for growth and development, along with phosphorus and potassium. Nitrogen-rich condition induces plant growth, particularly the growth of stems and leaves, while delaying flowering. On the other hand, in some plants, low-nitrogen conditions lead to a change from growth mode to reproductive mode, therefore accelerating flowering. However, the molecular mechanisms that regulate flowering under these conditions are not known.

A team of scientists led by Associate Professor Takeo Sato of Hokkaido University's Graduate School of Life Science has revealed the molecular mechanism responsible for the acceleration of flowering in Arabidopsis under low nitrogen conditions. Their findings were published in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS).

Arabidopsis, a cruciferous plant, is well known as a model plant in biology and has an extensive database of its protein expression. In the current study, the team first identified a set of proteins involved in flowering that became active as a result of changes in nitrogen level. One of these was the gene regulation factor FLOWERING BHLH 4 (FBH4). Through experiments using FBH4 deficient plants, this protein was found to be responsible for accelerated flowering under low-nitrogen conditions.

Further investigation suggested that FBH4 is extensively phosphorylated by another protein called SnRK1. Low-nitrogen conditions suppress SnRK1 activity, which in turn results in the dephosphorylation of FBH4. The dephosphorylated FBH4 moves to the nucleus to activate genes responsible for flowering. Dephosphorylated FBH4 is also responsible for controlling the expression of other genes vital for plant survival under low nitrogen conditions, particularly those related to nitrogen recycling and remobilization.

The scientists concluded that, in response to inadequate nitrogen, Arabidopsis plants appear to precisely control gene expression related to developmental and metabolic processes required for flowering through FBH4. "The FBH family of genes is present in major crop plants," says Takeo Sato. "Crop plants exhibit early flowering under low-nitrogen conditions; if we can control FBH activities in these crop plants, it might be an effective way to sustainably increase agricultural production."

Credit: 
Hokkaido University

Starting local

Corals are in trouble. All across the globe the diverse and dynamic ecosystems are taking huge hits year after year. The Great Barrier Reef has lost half of its coral since 1995. Scientists are seeing similar declines in reefs from Hawai'i to the Florida Keys and across the Indo-Pacific region.

The widespread decline is fueled in part by climate-driven heatwaves that induce coral bleaching -- the breakdown of the relationship between shallow-water coral and the symbiotic algae they rely upon for nutrients.

Climate change is a clear and present danger to the persistence of coral reefs, and global reductions in carbon emissions is critical for the future of reefs. But according to a new study published in the journal Science, managing local environmental conditions can help give coral a fighting chance.

"Some have argued that climate change is so overwhelming that conserving coral reefs on a local scale is futile," said lead author Mary Donovan, a former postdoctoral researcher at UC Santa Barbara, now an assistant professor at Arizona State University. "But our study found that local impacts on coral reefs magnified the effects of climate-driven heatwaves. This suggests that local action to conserve coral reefs can help reefs withstand the effects of climate change."

Scientists and trained community members have collected data from 223 sites across the world on behalf of Reef Check, a non-profit organization that promotes reef stewardship through citizen science initiatives. Donovan and her colleagues analyzed local data collected during and after climate-driven bleaching events to determine the health of reefs.

The researchers found that local factors could exacerbate coral loss in the year following bleaching. The presence of macroalgae, or seaweeds, was particularly associated with coral mortality, the researchers noted. Reefs with more macroalgae experienced up to 10 times more coral die-off, even at similar levels of heat stress, they found. And the effect increased at higher temperatures.

In addition to competing with coral for space on the reef, just the presence of macroalgae can change the water chemistry in ways that make coral more susceptible to bleaching, explained coauthor Deron Burkepile, a professor in UC Santa Barbara's Department of Ecology, Evolution, and Marine Biology. These changes can also make coral more vulnerable to disease, as can elevated temperatures. The two factors in concert could give coral a one-two punch.

"When we think about the impact of these big marine heatwaves, we often think it's all about the heat," Burkepile said. "We don't think about the local biotic interactions as much.

"But these local interactions matter," he continued, "and it's the local interactions that we can manage in a relatively effective way."

The abundance of macroalgae is highly receptive to local dynamics like overfishing and nutrient pollution. Overfishing depletes the number of fish that eat algae and keep the reef's ecosystem in balance. Meanwhile, nutrient pollution from land -- including runoff from golf courses, agriculture and coastal development -- threaten reefs by fostering the growth of algae, in addition to other threats to reefs such as disrupting coral microbiomes.

These issues can even allow algae to dominate over coral. And once that occurs, it can be challenging to restore the ecosystem to the way it was, according to a previous study out of UC Santa Barbara.

The importance of local conditions to reef survival in relation to the overwhelming effects of marine heatwaves is often dismissed, the authors argue, and can instill a sense of hopelessness in scientists, conservationists and those who rely on reefs for their livelihoods. However, local factors offer opportunities for management that could boost coral reefs' resistance to climate change, according to Burkepile.

"When we think where most coral reefs are, they're in parts of the world where the communities can do little about climate change," he said.

"These results imply that there is something that we all can do," Donovan added. "There are opportunities for us to take concerted action on climate change as well as local action."

Traditional fishery management techniques, like bag limits and regulations on gear, could promote the recovery of herbivorous fishes, she suggested, which could help remove macroalgae and help corals survive heat waves. Marine protected areas like the Kahekili Herbivore Fisheries Management Area in Hawai'i are another tool that communities could employ, as are better wastewater treatment methods that could reduce the nutrient runoff on which the algae thrive.

The researchers intend to continue their work investigating the effects of local conservation strategies on coral reef resilience. For instance, in summer 2022, they plan to remove algae from reefs around the island of Mo'orea, French Polynesia to examine how these removals impact corals' response to heat waves both as a potential conservation strategy as well as a controlled experiment.

"Coral reefs take up some of the smallest area on our planet, but harbor the most species of any ecosystem on Earth," Donovan said. "And people all over the world rely on reefs for food security, for coastal protection from storms and for other aspects of their livelihoods. In many parts of the world, it isn't only a question of beauty, but of survival." This only underscores the importance of identifying local actions that communities can take to protect and manage the natural resources coral reefs provide.

Credit: 
University of California - Santa Barbara

Shiny mega-crystals that build themselves

image: The nanocrystals arrange themselves to form structures familiar from the world of minerals such as perovskites or rock salt. All these structures, however, are 100-times larger than their counterparts in conventional crystals.
Such superlattices are potential candidates for use as highly energy-efficient,ultrafast light emitters.

Image: 
Gian Vaitl / Empa

To really appreciate what a team of researchers led by Maksym Kovalenko and Maryna Bodnarchuk has achieved, it is best to start with something mundane: Crystals of table salt (also known as rock salt) are familiar to anyone who has ever had to spice up an overtly bland lunch. Sodium chloride - NaCl in chemical terms - is the name of the helpful chemical; it consists of positively charged sodium ions (Na+) and negatively charged chloride ions (Cl-). You can imagine the ions as beads that strongly attract each other forming densely packed and rigid crystals like the ones we can see in a saltshaker.
Many naturally occurring minerals consist of ions - positive metal ions and negative ions, which arrange themselves into different crystal structures depending on their relative sizes. In addition, there are structures such as diamond and silicon: These crystals consist of only one kind of atoms - carbon in the case of diamond -, but, similar to minerals, the atoms are also held together by strong bonding forces.

Novel building blocks for a new kind of matter

What if all these strong bonding forces between atoms could be eliminated? In the realm of atoms, with all the quantum mechanics at play, this would not yield a molecule or a solid-state matter, at least at ambient conditions. "But modern chemistry can produce alternative building blocks that can indeed have vastly different interactions than those between atoms," says Maksym Kovalenko, Empa researcher and professor of chemistry at ETH Zurich. "They can be as hard as billiard balls in a sense that they sense each other only when colliding. Or they can be softer on the surfaces, like tennis balls. Moreover, they can be built in many different shapes: not just spheres, but also cubes or other polyhedra, or more anisotropic entities."
Such building blocks are made of hundreds or thousands of atoms and are known as inorganic nanocrystals. Kovalenko's team of chemists at Empa and ETH is able to synthesize them in large quantities with a high degree of uniformity. Kovalenko and Bodnarchuk, and some of their colleagues the world over, have been working for about 20 years now with these kinds of building blocks. The scientists call them "Lego materials" because they form long-range ordered dense lattices known as superlattices.
It had long been speculated that mixing different kinds of nanocrystals would allow the engineering of completely new supramolecular structures. The electronic, optical or magnetic properties of such multicomponent assemblies would be expected to be a mélange of the properties of the individual components. In the early years, the work had focused on mixing spheres of different sizes, resulting in dozens of various superlattices with packing structures that mimic common crystal structures, such as table salt - albeit with crystal unit cells ten- to 100-times larger.
With their latest article in "Nature", the team led by Kovalenko and Bodnarchuk now managed to expand the knowledge a great deal further: They set out to study a mixture of different shapes - spheres and cubes to start with. This seemingly simple deviation from the mainstream immediately led to vastly different observations. Moreover, the chosen cubes, namely colloidal cesium lead halide perovskite nanocrystals, are known as some of the brightest light emitters developed to date, ever since their invention by the same team six years ago. The superlattices the researchers obtained are not only peculiar as far as their structure is concerned, but also with respect to some of their properties. In particular, they exhibit superfluorescence - that is, the light is irradiated in a collective manner and much faster than the same nanocrystals can accomplish in their conventional state, embedded in a liquid or a powder.

Entropy as an ordering force?

Upon mixing spheres and cubes, wondrous things happen: The nanocrystals arrange themselves to form structures familiar from the world of minerals such as perovskites or rock salt. All these structures, however, are 100-times larger than their counterparts in conventional crystals. What's more: A perovskite-like structure had never before been observed in the assembly of such non-interacting nanocrystals.
Especially curious: These highly ordered structures are created solely by the force of entropy - that is, the perpetual endeavor of nature to cause maximum disorder. What a perfect joke of nature! This paradoxical assembly occurs because, during crystal formation, the particles tend to use the space around them most efficiently in order to maximize their freedom of motion during the late stages of solvent evaporation, i.e. before they are "frozen" in their eventual crystal lattice positions. In this regard, the shape of the individual nanocrystals plays a crucial role - soft-perovskite cubes allow for a much denser packing than what is attainable in all-spherical mixtures. Thus, the force of entropy causes the nanocrystals to always arrange in the densest possible packing - as long as they are designed such that they do not attract or repel each other by other means, such as electrostatics.

The dawn of a new science

"We have seen that we can make new structures with high reliability," says Maksym Kovalenko. "And this now raises many more questions; we are still at the very beginning: What physical properties do such weakly bonded superlattices exhibit and what is the structure-property relationship? Can they be used for certain technical applications, say, in optical quantum computing or in quantum imaging? According to what mathematical laws do they form? Are they truly thermodynamically stable or only kinetically trapped?" Kovalenko is now searching for theorists who might be able to predict what may yet happen.
"We will eventually discover completely new classes of crystals," he speculates, "ones, for which there are no natural models. They will then have to be measured, classified and described." Having written the first chapter in the textbook for a new kind of chemistry, Kovalenko is more than ready to deliver his share to make that happen as fast as possible. "We are now experimenting with disk- and cylinder-shaped nanocrystallites. And we're very excited to see the new structures they enable", he smiles.

Credit: 
Swiss Federal Laboratories for Materials Science and Technology (EMPA)

Recruiting bacteria to build catalysts atom by atom

image: The research team exploited the iron-breathing bacterium Geobacter sulfurreducens to synthesize single-atom catalysts, which could be used for various energy-related applications.

Image: 
© 2021 KAUST

Exploiting the unusual metal-reducing ability of the iron-breathing bacterium Geobacter sulfurreducens, KAUST researchers have demonstrated a cheap and reliable way to synthesize highly active single-atom catalysts. The innovation, which could dramatically improve the efficiency and cost of hydrogen production from water, highlights the role nature can play in the search for new energy systems.

Many chemical reactions require a catalyst as a reactive surface where atoms or molecules are brought together with the right amount of energy to spark a chemical change. Water, for example, can be split into hydrogen and oxygen atoms by reacting on a pair of electrodes made of platinum and iridium oxide. The efficiency of the reaction, however, depends largely on how many atoms can get involved.

"In a nanoparticle catalyst, only 20 percent of the metal atoms might be available for catalysis," says Srikanth Pedireddy, formerly at KAUST and now at the University of Exeter, U.K. "Single-atom catalysts, on the other hand, allow 100 percent atomic utilization and so are promising for various catalyst applications; however, conventional synthesis methods are expensive, involve high temperatures and only give low yields with poor atomic distribution."

In search of a more reliable and cost-effective approach, Pedireddy, Pascal Saikaly and their colleagues turned to nature. The anaerobic bacterium G. sulfurreducens is unusual in that it "breathes" iron, not oxygen, and has the remarkable ability to conduct electrons from inside to outside the cell.

"This bacterium has redox active proteins called c-type cytochromes that contain a heme complex -- a central iron atom coordinated to four nitrogen atoms of a porphyrin ring," says Pedireddy. "We envisaged that this heme site could be used to chemically reduce single atoms of catalytically active metals instead of iron."

After confirming the formation of single iron atoms at the cytochrome sites on the surface of bacterial cells, the team immersed the bacteria in a solution containing iridium, which produced a similar and very satisfying result.

"Seeing single atoms on the surface of bacteria was a major challenge," says Pedireddy. "With the high-resolution electron microscopy facilities at KAUST, we were able to visualize the atomically dispersed single atoms of metals on the bacteria surface."

The team found they could load the bacteria with up to 1 percent of well-dispersed single-atom iridium, giving a more reliable catalyst with comparable hydrogen-evolving activity to the platinum/carbon standard at a fraction of the cost of other single-atom methods.

"Our work could inspire the use of other efficient electroactive bacteria for synthesizing high-performing and low-cost electrocatalysts for various energy-related applications," Saikaly says.

Credit: 
King Abdullah University of Science & Technology (KAUST)

Sometimes, even 3-year-olds just want to fit in with the group

DURHAM, N.C. -- What makes preschoolers eat their veggies? Raise their hand? Wait their turn? "Because I say so" is a common refrain for many parents. But when it comes to getting kids to behave, recent research suggests that the voice of adult authority isn't the only thing that matters. Around age three, fitting in with the group starts to count big too.

That's the finding of a new study by Duke University researchers showing that, by their third birthday, children are more likely to go along with what others say or do for the sake of following the crowd, rather than acting out of a desire to kowtow to authority or heed that person's preferences per se.

"Every culture has its do's and don'ts," said first author Leon Li, a doctoral student in psychology and neuroscience at Duke.

We're not born knowing what to say when someone sneezes, the right and wrong time to wear a hat, or that we should eat with a fork and not with our hands. But most of us begin to pick up on these unwritten social rules when we are very young, and quickly figure out when and how to follow them.

The question, Li said, is what makes young children "behave"? What propels a 3-year-old to use their quiet voice when they'd rather sing and shout? What's really going on when a person covers their cough and a preschooler follows suit, against their own inclination?

Perhaps children this age are not really trying to conform to the accepted way of doing things, some have suggested, as much as they are trying to show regard for adults by doing what they say. Or the child's copycat behavior could be rooted in a desire to feel bonded with that person.

To better understand what motivates preschoolers to fall in line, the researchers conducted a study in the lab of professor Michael Tomasello at Duke, where Li and Duke undergraduate Bari Britvan invited 3.5-year-olds to help set up for a pretend tea party.

Each of the 104 children was given a blue sticker to wear at the start of the study, and told that the people with that color sticker were part of the same team.

Next the researchers watched as the children decided among different kinds of teas, snacks, cups and plates for the tea party, first on their own and then after listening to the choices of other team members.

Sometimes the other team member framed their choice as a matter of personal preference. ("For my tea party today, I feel like using this snack.") Other times they presented it as a norm shared by the whole group: ("For tea parties at Duke, we always use this kind of snack.")

After listening to the choices of others, most of the time the children stuck with their first choice. In other words, children who initially said they felt like using, say, the donut eventually wound up picking the donut no matter what the other person said they were using.

But 23% of the time the children switched their choice to settle for someone else's. And when they did, they were more likely to go along with the other person when an option was presented as a group norm rather than a mere personal preference.

The pattern held up even when the other person was another child, not an adult, suggesting that the preschoolers weren't simply acting out of a desire to imitate adults or obey authority.

Li says the findings lend support to an idea, proposed by Tomasello and colleagues, about how children develop the moral reasoning capacity that sets humans apart from other animals.

When an adult says to an infant or a toddler, "we don't hit," the child generally does as she's told out of deference to that person. But eventually, by around their third birthday, children start to think in a different way. They begin to understand cues such as "we don't hit" as something larger, coming from the group, and act out of a sense of connectedness and shared identity.

Credit: 
Duke University

Pertussis more common in Europe than previously thought

Although vaccination programmes against pertussis are very effective in Europe, new Finnish study shows that the disease is still very common among middle-aged adults in various European countries. At the same time, the results show that the disease is underdiagnosed as the annually reported figures are considerably lower than those discovered in the study.

The primary cause of pertussis, also known as whooping cough, is the Bordetella pertussis agent which spreads through the respiratory mucosa and produces toxins that damage the mucous membrane. These toxins incapacitate the body's defence mechanisms and the infection is marked by severe, spasmodic coughing episodes. Pertussis is often categorised as a childhood disease, but adults can also contract it.

Before the vaccination programmes, whooping cough was one of the deadliest childhood diseases. In Finland, the vaccinations started in 1952, and the pertussis vaccination is included in the national DTP vaccination programme. Even though the vaccination programmes are effective in Europe, the number of pertussis cases has increased in several countries. 200-500 whooping cough cases are reported in Finland each year, while globally there were over 150,000 reported cases in 2018.

The University of Turku in Finland leads an extensive European follow-up study on pertussis, diphtheria and tetanus. The study is part of the EUPert-LabNet laboratory network funded by the European Centre for Disease Prevention and Control (ECDC). The EUPert-LabNet network is led by the Head of Finnish National Reference Laboratory for Pertussis and Diphtheria, Professor Qiushui He from the University of Turku. 18 European countries have participated in the study.

"To our best knowledge, this is the largest follow-up study in Europe since the DTP vaccines were introduced. On the basis of the results, whooping cough seems to be more common in Europe than previously thought. The disease was most common in Norway, France and Denmark, and most uncommon in Finland and Hungary," says Professor He and continues:

"A very alarming finding in our research was the low levels of antibodies against diphtheria in many European countries. This clearly indicates that the herd immunity in middle-aged adults is decreasing. Attention should be paid to this matter in the entire Europe."

"On the other hand, antibodies against tetanus are on a sufficient level in different European countries," says He.

The pertussis research team works at the Institute of Biomedicine of the University of Turku, and in addition to He, it is led by Professor h.c., Docent Jussi Mertsola. Since 2005, Professors He and Mertsola have coordinated the European EUpertstrain network that studies how changes in pertussis strains impact the effectiveness of the vaccines.

The Turku Pertussis Team led by He and Mertsola is currently investigating immune responses in children and adults including how immunisations during pregnancy affect the immunity of newborn babies. The studies are part of the five-year European PERISCOPE project with €28 million funding from the EU's IMI2 and Horizon 2020 programmes.

Credit: 
University of Turku

Lead levels in urban soil are declining but hotspots persist

DURHAM, N.C. - Decades after federal bans ended widespread use of lead in paint and gasoline, some urban soils still contain levels of the highly toxic metal that exceed federal safety guidelines for children, a Duke University study finds.

To conduct their study, the researchers analyzed and mapped soil lead concentrations along 25 miles of streets in Durham, N.C., a city of about 270,000 people. They found that while soil lead levels have generally decreased since the 1970s, they have decreased much less near residential foundations than along streets.

The researchers collected soil samples near foundations of houses built before 1978. Samples within a meter of the older homes averaged 649 milligrams (mg) of lead per kilogram (kg) of soil, more than three times the average level detected near streets, which was 150 mg/kg.

EPA guidelines say exposure to soil lead concentrations above 400 mg/kg is associated with potential long-term health risks to children, including possible damage to the brain and nervous system, slowed growth and development, learning and behavior problems and hearing and speech problems.

"Urban soil processes are driving lead concentrations down over time, but it's alarming that lead levels in some locations -- typically older, poorer neighborhoods -- still far exceed safe levels decades after leaded gasoline and lead paint were phased out," said lead author Anna Wade, a postdoctoral researcher at the U.S. Environmental Protection Agency and a 2020 Ph.D. graduate of Duke's Nicholas School of the Environment.

The Duke team shared its findings with Durham public health groups and plans to conduct similar mapping studies in five or six other cities nationwide.

Determining where contamination risks persist, and why contamination is decreasing at different rates in different locations, is essential for mitigating those risks, she said. However, many cities lack the resources to conduct the regular city-wide sampling needed to obtain that data. "Our study had to go all the way back to the 1970s to find comparable data for portions of the 35-square-kilometer area we sampled," Wade said.

Daniel D. Richter, professor of soils at Duke, said, "There's been a lot of interest in mitigating lead exposure in cities, but most is focused on reducing risks within the home. Our study reminds us about the outdoor environment where exposure risks also exist."

Wade, Richter and their team published their peer-reviewed, open-access study May 21 in Environmental Science & Technology.

Curbside soil lead levels have dropped over time as the result of human and natural causes, the study suggests. Those causes include accelerated erosion and stormwater runoff, which has carried away some contaminated surface soils, depositing them in nearby floodplains.

Digging for road construction and repair also contributed to the drop by mixing and burying some contaminated soil deeper underground.

Foundation soils are less affected by these processes. Also, soils near many older homes continue to receive chips and dust from old leaded paint. Soil lead levels are thus decreasing more slowly near older homes, and those soils continue to pose a higher risk.

Traffic density also factors into the risk equation.

In larger cities that see more traffic, such as New York or Chicago, soil lead levels along heavily travelled streets have historically been high. In larger cities, those levels may still be unacceptably high, Wade said. Implementing regular, widespread soil testing is the only way to know for certain.

"Large-scale sampling reveals patterns of soil lead distribution that you miss through spot checking," Richter said. "That can make the problem more predictable and remediable and encourage cities to act on this issue rather than just letting it be."

Credit: 
Duke University

A deep dive into the brain

image: Left: Conventional fluorescence images of a mouse brain. Right: An image taken with the new diffuse optical localization imaging (DOLI) method.

Image: 
ETH Zurich, University of Zurich / Daniel Razansky

The way the human brain works remains, to a great extent, a topic of controversy. One reason is our limited ability to study neuronal processes at the level of single cells and capillaries across the entire living brain without employing highly invasive surgical methods. This limitation is now on the brink of change.

Researchers led by Daniel Razansky, Professor of Biomedical Imaging at ETH Zurich and the University of Zurich, have developed a fluorescence microscopy technique that facilitates high-resolution images of microcirculation without the need to open the skull or scalp. The technique has been named "diffuse optical localization imaging", or DOLI in short.

For Razansky, this brings us closer to achieving a long-standing goal in neuroscience: "Visualising biological processes deep in the intact living brain is crucial for understanding both its cognitive functions and neurodegenerative diseases such as Alzheimer's and Parkinson's," he says.

Enhanced fluorescence microscopy

A fluorescent contrast agent is set to glow when administered into the blood stream and irradiated with light of particular wavelength. Fluorescence microscopy makes use of this effect to visualise biological processes at the cellular and molecular level. Until now, researchers using this method on humans or animals have encountered the problem that living tissue scatters and absorbs light extensively, resulting in blurred images and the inability to identify the exact location of the fluorescent agent inside the brain.

By introducing several new techniques, Razansky and his team have now succeeded in significantly improving this method. "We opted for using a specific spectral region for imaging, the so-called second near-infrared window. This allowed us to greatly reduce the background scattering, absorption and intrinsic fluorescence of the living tissues," explains the professor. In addition, the research team used a recently developed, highly efficient infrared camera and a new quantum dot contrast agent that fluoresces strongly within the selected infrared range.

High-resolution images of the brain

The researchers first tested the new technique using synthetic tissue models that simulate the properties of brain tissue, demonstrating that it is possible to acquire microscopic images at four times the penetration depth of conventional fluorescence microscopy approaches. Razansky and his team then injected living mice with microdroplets encapsulating fluorescent quantum dots as a contrast agent. They were then able to localize these droplets individually in the living brain using the new technique.

"For the first time, we were able to clearly visualise the microvasculature and blood circulation deep in the mouse brain entirely noninvasively," says Razansky. In addition, the researchers from ETH Zurich and the University of Zurich observed that the size of the imaged microdroplets depends on how deep they are located in the brain. This makes the DOLI technique capable of three-dimensional imaging.

Compared with other biological imaging techniques, such as optoacoustic imaging, also developed by Razansky, the DOLI technique takes advantage of the high versatility and uncomplicated nature of established fluorescence imaging approaches. "You basically need a relatively simple and affordable camera setup without any pulsed lasers or sophisticated optics. This facilitates the dissemination in labs," explains Razansky.

A basis for new insights

Neurological disorders, ranging from epilepsy, strokes to various types of dementia, affect up to one billion people worldwide. Therefore, it is of paramount importance to better understand the biological causes of neurodegenerative and other brain diseases and to detect them at an early stage.

According to Razansky, the improved fluorescence microscopy based on the DOLI method offers a good basis for this: "We assume that this technique will also lead to new insights into brain function and, in the longer term, facilitate development of new therapeutic options." Until then, however, he and his team will most likely have to watch the brains of a few more mice.

Credit: 
ETH Zurich

Why is it so hard to withdraw from some antidepressants?

Researchers at the University of Illinois Chicago are a step closer to discovering why it is so difficult for people to withdraw from some antidepressant medications.

The paper "Antidepressants produce persistent Gαs associated signaling changes in lipid rafts following drug withdrawal," published in the journal Molecular Pharmacology, addresses the molecular and cellular mechanisms that cause antidepressant withdrawal syndrome.

The study's authors, Mark Rasenick, distinguished professor of physiology and biophysics and psychiatry at UIC and research career scientist at the Jesse Brown VA Medical Center, and Nicholas Senese, a postdoctoral fellow at UIC, explained that current antidepressants can take approximately two months to take effect in patients who then continue taking these drugs for years. Weaning patients from these drugs can result in unpleasant symptoms that can range from flu-like feelings and persistent pain or itch to Parkinson's-like conditions that can last for weeks.

One in six Americans have, or will, suffer from depression; for veterans, the estimated rate is twice that.

Previous research has demonstrated that antidepressant drugs collect gradually in cholesterol-rich membrane structures called lipid rafts. When a neurotransmitter (such as serotonin, which is involved with mood) binds to a receptor on the outside of a cell, a protein in the lipid raft --- called Gs alpha --- conveys the signal into the cell's interior where it can elicit a variety of actions. One of those actions is the production of an intracellular signaling molecule called cyclic AMP. In the brains of people with depression, cyclic AMP is low; but with effective antidepressant treatment, cyclic AMP is returned to normal.

For their new study, Rasenick and Senese looked at the activity of Gs alpha molecules by using fluorescent light to determine how they moved in and out of the lipid rafts. They found that while withdrawal of some antidepressant drugs balances Gs alpha action in and out of the lipid rafts, other drugs suppress the return of Gs alpha to rafts. This suppression, the researchers believe, is what causes persistent and undesired effects of some antidepressants.

Lipid rafts appear to be relevant for both the delayed therapeutic effects of antidepressants as well as the difficulty in weaning off from these drugs. It takes a long time for these drugs to sort into rafts and a long time for the drugs to exit --- some more than others. Curiously, rapid-acting antidepressants like ketamine have similar effects on Gs alpha and lipid rafts, but without the delay, Rasenick said.

"This validates the notion that intracellular molecules that result from an active Gs alpha protein are a very good biomarker for the functioning of antidepressants," Rasenick said. "We think we have achieved some clarity on this issue and we'd like to move forward toward using technology to create a personalized treatment for depression."

Rasenick explained that by looking at how an individual patient's cells metabolize Gs alpha proteins, they can better predict what antidepressant medication could work for them. This can be accomplished in days and not weeks and months of trial and error to find the right medication. A company using this UIC-developed technology, Pax Neuroscience, has been formed to develop the technology for the market.

Additionally, the cellular fluorescent indicators allow testing at a cellular level to develop new antidepressant medications.

Credit: 
University of Illinois Chicago

The new species of bacteria killing palms in Australia

image: Symptoms found in ornamental palms in Cairns. (a) Dypsis poivreana (RID7866) showing early symptoms of leaf yellowing and marginal necrosis; (b) Archontophoenix alexandrae (RID8088) showing mid stage symptoms of canopy browning. (c) Euterpe precatoria (RID7936), (d) Cocos nucifera (RID7941), (e) Euterpe sp. (LMJ1271) and (f) Phoenix sp. (RID8094) all displaying advanced symptoms in which all or most leaves have died, with older leaves retained and hanging like a skirt.

Image: 
Richard Davis et al.

The bacterium, which they named Candidatus Phytoplasma dypsidis was found to cause a fatal wilt disease. This new discovery was reported in the International Journal of Systematic and Evolutionary Microbiology.

In 2016, several ornamental palms within a conservatory in the Cairns Botanic Gardens, Queensland, died mysteriously. A sample was taken from one of the diseased plants and investigated by Dr Richard Davis and colleagues from the Australian Government Department of Agriculture, Water and the Environment, and state and local government. They compared the characteristics and genome of the bacterium identified as the cause of the disease and found the bacterium was similar to other species of Candidatus Phytoplasma, many of which are responsible for disease epidemics in palms elsewhere but was different enough to be an independent species. "When the laboratory testing indicated it was something close to, but not the same as, devastating palm pathogens overseas, we were very surprised," said Dr Davis.

"At first we thought it was most likely an unrelated fungal disease. Almost as an afterthought, I suggested we screen for phytoplasma because there are some very bad phytoplasma diseases of palms moving around the world, including in neighbouring Papua New Guinea," he explained.

So far, infection with Candidatus Phytoplasma dypsidis has been found to cause disease in 12 different species of palms, including Cocos nucifera, which produces coconuts. "Although palms are not grown as a cash crop in Australia, they are important ornamental garden and amenity plants. Coconuts and other palms are an economically significant component of Australia's tourism industry in the tropics," said Dr Davis.

'Palms take on a much greater significance in most of the countries near Australia, in south east Asia and the Pacific, where coconuts are 'the tree of life'. It is important to raise awareness of a new disease threat, such as this, so that regional biosecurity measures can be prioritised."

The bacterium is thought to be spread from plant-to-plant by insects which feed on phloem, the tissue which transports nutrients around the plant, said Dr Davis: "it seems certain from our observations of how this thing has spread through the local area, that there must be an insect vector. Finding out what vector species are involved is a vital next research priority."

Outbreaks of exotic plant pathogens in Australia are rare due to the country's stringent biosecurity measures. "Australia, New Zealand and the Pacific island countries and territories have an enviable plant and animal health status compared to much of the rest of the world. Because we are islands, we have escaped many significant plant disease threats that have travelled around the world, over history," explained Dr Davis, "As biosecurity plant pathologists for the Australian Government Department of Agriculture, Water and the Environment, our team's main role is to look out for and detect incursions of exotic plant pathogens. We usually do this in remote parts of Australia's north, so to come across something much closer to home in the suburbs of Cairns, in far North Queensland, Australia, was unusual. However, we have no evidence to suggest this is an incursion from overseas because it is a unique organism. It may well be indigenous to Australia and some as yet unknown factor has triggered a disease outbreak."

Dr Davis is concerned that this new disease could spread outside of Cairns and affect palm populations further north: "North of Cairns, we have threatened ecological communities of fan palms which are of great environmental significance," he said. It is important for Dr Davis and his team to continue to monitor the spread of Candidatus Phytoplasma dypsidis. A number of questions remain, including which insect vectors are spreading the disease, and whether the bacterium is capable of infecting other types of plant, including important crops such as bananas.

Credit: 
Microbiology Society

Atlas of malaria parasite gene activity provides new targets for drugs and vaccines

image: Transmission cycle of malaria parasites between human host and mosquito vector (upper) and map of gene activity of parasite cells at different stages of the cycle (bottom). Each colour represents a stage of the life cycle.

Image: 
Real et al.

Researchers have mapped in fine detail the genetic changes malaria parasites go through as they prepare to infect people.

The atlas maps the malaria parasite Plasmodium falciparum in unprecedented cellular detail as it develops inside a mosquito and prepares to infect humans through a bite. This detailed investigation could lead to new ways to block key stages in the parasite's development and prevent transmission through future drugs or vaccines.

Mosquitoes are increasingly resistant to pesticides, and the parasite that causes malaria is also becoming increasingly resistant to antimalarial drugs. This has created an urgent need for new ways to fight malaria, which in 2019 caused an estimated 229 million cases and 409,000 deaths, most of which were young children in sub-Saharan Africa.

To reinvigorate efforts in drug or vaccine discovery, a team from the lab of Professor Jake Baum at Imperial College London and the lab of Dr Mara Lawniczak from the Wellcome Sanger Institute have examined the human malaria parasite Plasmodium falciparum in unprecedented detail. Their results are published today in Nature Communications.

P. falciparum develops in the midgut of a mosquito before travelling to the mosquito's saliva glands, ready to infect a human when the bug bites. During these phases, the parasite goes through many stages important for its development and ability to transmit, including changing into different forms.

The team tracked how these stages were controlled by analysing the activity of genes throughout the process. They isolated the different forms of the parasite and produced 1467 'transcriptomes' - maps of which genes in single cells are turned on or off during the different stages.

When genes are turned on, they instruct the cell to make different proteins and drive developmental changes, such as causing the parasite to exit the midgut and colonise the salivary gland of the mosquito, or to travel through human cells to reach the liver, where the parasite prepares to invade more human cells.

Knowing how these processes work in detail at the cellular level reveals to researchers new targets that could be blocked to stop development, preventing transmission of the parasite.

Dr Eliana Real, from the Department of Life Sciences at Imperial, said: "Being directly based on the human-infective parasite, our new data have clear implications for malaria control, which has an increasing focus on transmission blocking strategies both in terms of drugs that kill the parasite as it moves between stages and protective vaccines. Understanding how parasites behave transcriptionally within the mosquito vector provides a found
dation from which new strategies will surely arise."

As well as surveying the whole transmission cycle of the parasite, the team focused on what is called the sporozoite stage: the form released into the human skin during a mosquito bite. They sorted parasites from within the mosquito during their development, and isolated sporozoites after an infectious bite as they interact with human skin cells. In doing so, they were able to find specific patterns of gene expression that define each of the critical stages in these processes.

Dr Virginia Howick, previously from the Wellcome Sanger Institute and now based at the University of Glasgow, said: "This fine granularity enables us to trace sporozoite developmental processes and to propose new mechanistic targets essential for each step and future vaccine targets for blocking malaria infection."

The team were also able to compare their data with a similar set from the related parasite Plasmodium berghei, a rodent malaria parasite that is often used as a model for studying malaria disease in the lab. This showed which genes are common between species, and which are specific to the human version of the parasite.

Dr Farah Dahalan, from the Department of Life Sciences at Imperial, said: "This level of gene surveillance at the individual parasite level throughout its life cycle will provide an invaluable resource for researchers to discover previously unexplored elements of Plasmodium cell biology, comparative Plasmodium species biology and the development of control methods that target particular pathways or lay the foundations for improving vaccines."

The researchers have made all their data available on an interactive website, where the transcriptional profile of any gene across any stage of the Plasmodium life cycle can be easily and freely viewed.

Credit: 
Imperial College London

Banning the sale of fossil-fuel cars benefits the climate when replaced by electric cars

image: Exhaust emissions are emissions within Sweden's borders, which need to reach zero by 2045 to fully contribute to Sweden's climate policy goals. Emissions from the production of cars and fuels encompass the manufacture of cars and batteries as well as fuel production, including the production of electricity for electric cars. The striped fields show the possibilities for emission reductions in the manufacture of batteries, vehicles and fuels. The diagram assumes a Swedish ban on new sales of petrol and diesel cars in 2030, as well as an increasing usage of biofuels in accordance with the revised Swedish "reduction obligation" until 2030.

Image: 
Illustration: Yen Strandqvist/Chalmers University of Technology

If a ban were introduced on the sale of new petrol and diesel cars, and they were replaced by electric cars, the result would be a great reduction in carbon dioxide emissions. That is the finding of new research from Chalmers University of Technology, Sweden, looking at emissions from the entire life cycle - from manufacture of electric cars and batteries, to electricity used for operation. However, the total effect of a phasing out of fossil-fuelled cars will not be felt until the middle of the century - and how the batteries are manufactured will affect the extent of the benefit.

A rapid and mandatory phasing in of electric cars could cause emissions from Swedish passenger cars' exhausts to approach zero by 2045. The Swedish government has proposed an outright ban on the sale of new fossil fuel cars from the year 2030 - but that alone will not be enough to achieve Sweden's climate targets on schedule.

"The lifespan of the cars currently on the roads and those which would be sold before the introduction of such a restriction mean that it would take some time - around 20 years - before the full effect becomes visible," says Johannes Morfeldt, researcher in Physical Resource Theory at Chalmers University of Technology and lead author of the recently published scientific study.

To have the desired effect, a ban would either need to be introduced earlier, by the year 2025, or, if the ban is not brought in until 2030, then the use of biofuels in petrol and diesel cars needs to increase significantly before then - in accordance with the revised Swedish "reduction obligation". The combination of these two measures would have the effect of achieving zero emissions from passenger vehicles and keeping to Sweden's climate targets.

"The results from our study show that rapid electrification of the Swedish car fleet would reduce life cycle emissions, from 14 million tonnes of carbon dioxide in 2020 to between 3 and 5 million tonnes by the year 2045. The end result in 2045 will depend mainly on the extent to which possible emission reductions in the manufacturing industry are realised," says Johannes Morfeldt.

A transition from petrol and diesel cars to electric cars will mean an increased demand for batteries. Batteries for electric cars are often criticised, not least for the fact that they result in high levels of greenhouse gas emissions during manufacture.

"There are relatively good opportunities to reduce emissions from global battery manufacturing. Our review of the literature on this shows that average emissions from global battery manufacturing could decrease by about two thirds per kilowatt hour of battery capacity by the year 2045. However, most battery manufacturing takes place overseas, so Swedish decision-makers have more limited opportunities to influence this question," says Johannes Morfeldt.

From a climate perspective, it does not matter where the emissions take place, and the risk with decisions taken at a national level for lowering passenger-vehicle emissions is that they could lead to increased emissions elsewhere - a phenomenon sometimes termed 'carbon leakage'. In this case, the increase in emissions would result from greater demand for batteries, and the risk is thus greater the higher the emissions from battery production.

In that case, the Swedish decision would not have as great an effect on reducing the climate impact as desired. The life-cycle emissions would end up in the upper range - around 5 million tonnes of carbon dioxide instead of around 3 million tonnes. Due to this, there may be reason to regulate emissions in both vehicle and battery production, from a life cycle perspective.

"Within the EU, for example, there is a discussion about setting a common standard for the manufacture of batteries and vehicles - in a similar way as there is a standard that regulates what may be emitted from exhausts," says Johannes Morfeldt.

But, given Sweden's low emissions from electricity production, a ban on sales of new fossil-fuel cars would indeed result in a sharp reduction of the total climate impact, regardless of how the manufacturing industry develops.

The results of the study are based on Swedish conditions, but the method used by the researchers can be used to obtain corresponding figures for other countries, based on each country's car fleet and energy system. The year 2045 is highlighted because that is when greenhouse gas emissions within Sweden should reach net zero according to the climate policy goals of the country.

Credit: 
Chalmers University of Technology

Salmon virus originally from the Atlantic, spread to wild Pacific salmon from farms: Study

video: Piscine orthoreovirus (PRV) - which is associated with kidney and liver damage in Chinook salmon - is continually being transmitted between open-net salmon farms and wild juvenile Chinook salmon in British Columbia, Canada waters, according to a new genomics analysis published today in Science Advances.

Image: 
Video Amy Romer

Piscine orthoreovirus (PRV) - which is associated with kidney and liver damage in Chinook salmon - is continually being transmitted between open-net salmon farms and wild juvenile Chinook salmon in British Columbia waters, according to a new genomics analysis published today in Science Advances.

The collaborative study from the University of British Columbia (UBC) and the Strategic Salmon Health Initiative (SSHI) -- a partnership between Fisheries and Oceans Canada (DFO), Genome BC and the Pacific Salmon Foundation -- traces the origins of PRV to Atlantic salmon farms in Norway and finds that the virus is now almost ubiquitous in salmon farms in B.C.

It also shows that wild Chinook salmon are more likely to be infected with PRV the closer they are to salmon farms, which suggests farms transfer the virus to wild salmon.

Genome sequencing of viruses from farms and wild fish further indicates that transmission occurs between farms and wild salmon.

"Both our genomic and epidemiological methods independently came to the same conclusion, that salmon farms act as a source and amplifier of PRV transmission," said Dr. Gideon Mordecai, a viral ecologist and Liber Ero fellow with UBC Science and researcher with UBC Medicine, who led the study. "Because separate lines of independent evidence all point to the same answer, we're confident in our finding."

Sequencing of 86 PRV genomes helped researchers track the history of PRV emergence in British Columbia. They estimate that the lineage of PRV in the North East Pacific diverged from PRV in the Atlantic Ocean approximately 30 years ago. This suggests that the introduction of PRV to B.C. and infection of wild Pacific salmon is a relatively recent phenomenon, coincident with the growth of salmon aquaculture in the province - not dating back to early attempts to introduce Atlantic salmon to the region, starting in 1874.

"There is much confusion about where PRV is originally from, whether it is transmitted between farmed and wild salmon, and how different lineages of the virus cause different severities of disease," said Dr. Mordecai. "This study's genome sequencing clearly indicates PRV is not native to B.C. waters--it originated in the Atlantic Ocean and has been spread around the world through salmon aquaculture."

The study highlights the role of aquaculture in introducing novel pathogens to new regions, where they then spread to wild fish, and integrates the expertise of the two senior authors, Dr. Kristi Miller, a DFO scientist and Professor Jeffrey Joy, a UBC evolutionary geneticist. It demonstrates the value of genomics in the surveillance of viral pathogens affecting important fisheries resources and how analytical methods derived from the epidemiology of human viruses can be adapted and applied to conserving wild salmon populations.

Further analysis of PRV genomes generated by the study suggested that there has been a growth in the number of PRV infections in B.C. over recent decades. This finding corresponds with the regional growth in salmon aquaculture and high rates of viral infection in salmon farms.

"Our finding that PRV is transmitted between farmed and wild salmon is particularly relevant given recent field and laboratory studies showing the lineage of PRV in B.C. is likely to cause disease in both Pacific and Atlantic salmon" says Dr. Mordecai. A recent Norwegian study found that a Canadian isolate of the virus causes heart lesions in Atlantic salmon. More importantly to the Pacific ecosystem, PRV has been associated with a different disease in Chinook salmon in which blood cells rupture, leading to kidney and liver damage. These are in contrast to the DFO's assessment that PRV is not a disease agent.

"Our study reaffirms that a more precautionary approach to managing salmon farming in BC is warranted," says study co-author Dr. Andrew Bateman, of the Pacific Salmon Foundation. "The PRV findings, in particular, support calls to transition from open-net salmon farming towards farming technology that doesn't allow disease transfer between farmed and wild salmon, protecting BC's wild Pacific salmon from serious risk in the process."

"The study provides foundational information necessary to assess the risk of salmon aquaculture on wild fish, as recommended by the Auditor General of Canada's 2018 Report on Salmon Farming, which criticized DFO's ability to manage aquaculture in a precautionary manner," says Professor Jeffrey Hutchings of Dalhousie University, a leading Canadian fisheries scientist who was not involved with the research. "The work by Mordecai, Miller, and colleagues on PRV provides the most compelling, scientifically objective evidence to date that wild salmon in BC are at increased risk of disease because of open net-pen Atlantic salmon aquaculture," adds Professor Hutchings.

Credit: 
University of British Columbia

Deep oceans dissolve the rocky shell of water-ice planets

image: Cut-away diagram of a water-rich sub-Neptune exo-planet highlighting, in orange color, the interaction region between a deep H2O layer and the underlying rocky mantle

Image: 
S. Speziale/ GFZ

What is happening deep beneath the surface of ice planets? Is there liquid water, and if so, how does it interact with the planetary rocky "seafloor"? New experiments show that on water-ice planets between the size of our Earth and up to six times this size, water selectively leaches magnesium from typical rock minerals. The conditions with pressures of hundred thousand atmospheres and temperatures above one thousand degrees Celsius were recreated in a lab and mimicked planets similar, but smaller than Neptune and Uranus.

The mechanisms of water-rock interaction at the Earth's surface are well known, and the picture of the complex cycle of H2O in the deep interior of our and other terrestrial planets is constantly improving. However, we do not know what happens at the interface between hot, dense H2O and the deep rocky shell of water-ice planets at pressures and temperatures orders of magnitude higher than at the bottom of the deepest oceans on Earth. In the solar system Neptune and Uranus are classified as ice-giants; they have a thick external water-ice layer, which is underlain by a deep rocky layer, and it is still discussed whether the temperature at the interface is high enough to form liquid water.

An international research team lead by Taehyun Kim of the Yonsei University of Seoul, Korea, including scientists from the University of Arizona, from DESY, from Argonne National Laboratory, and Sergio Speziale of the GFZ German Research Centre for Geosciences, conducted a series of challenging experiments both at PETRA III (Hamburg) and the Advanced Photon Source (Argonne, U.S.A.) showing how water strongly leaches magnesium oxide (MgO) from certain minerals, i.e. ferropericlase (Mg,Fe)O and olivine (Mg,Fe)2SiO4 at pressures between 20 and 40 Gigapascal (GPa). This equals 200,000 to 400,000 times the atmospheric pressure on Earth and temperatures above 1500 K (? 1230 °C), conditions which are present at the interface between deep oceans and the rocky mantle in sub-Neptune class of water planets. Sergio Speziale says: "These findings open new scenarios for the thermal history of large icy planets such as Neptune and Uranus." The results of this study are published in the scientific journal Nature Astronomy.

Tiny pellets of either ferropericlase or olivine powder were loaded together with water in a tiny sample chamber (less than a millimetre in diameter) drilled in a metal foil and squeezed between two gem-quality diamonds culets using a diamond anvil cell (DAC). The samples were heated by shining an infrared laser through the diamond anvils. Synchrotron x-ray diffraction was used to determine minerals transformation and breakdown induced by reactions with water. A sudden decrease of diffraction signal from the starting minerals, and the appearance of new solid phases including brucite (magnesium hydroxide) were observed across full heating and quenching cycles. Sergio Speziale explains: "This demonstrated the onset of chemical reactions and the dissolution of the magnesium oxide component of both ferropericlase and olivine; the dissolution was strongest in a specific pressure-temperature range between 20 to 40 Gigapascal and 1250 to 2000 Kelvin." The details of the reaction process and the consequent chemical segregation of MgO from the residual phases, were confirmed by thorough Scanning Electron Microscopy (SEM) and X-ray spectroscopy of the recovered samples. "At these extreme pressures and temperatures the solubility of magnesium oxide in water reaches levels similar to that of salt at ambient conditions", Sergio Speziale says.

The scientists conclude that the intensive dissolution of MgO at the interface between the H2O layer and underlying rocky mantle could produce, in water-rich sub-Neptune exo-planets with appropriate size and composition such as TRAPPIST-1f, chemical gradients in the early hot phases of the planets' history. These gradients with differentiated distribution of magnesium oxide at the planetary seafloor could be partially preserved across their long cooling evolution. Tracks of initial relatively shallow interactions between water and rocky material during planetary accretion could be also preserved for billions of years in large icy planets of the size of Uranus.

Credit: 
GFZ GeoForschungsZentrum Potsdam, Helmholtz Centre

Brain tumors caused by normal neuron activity in mice predisposed to such tumors

Seeing, hearing, thinking, daydreaming -- doing anything at all, in fact -- activates neurons in the brain. But for people predisposed to developing brain tumors, the ordinary buzzing of their brains could be a problem. A study by researchers at Washington University School of Medicine in St. Louis and Stanford University School of Medicine shows that the normal day-to-day activity of neurons can drive the formation and growth of brain tumors.

The researchers studied mice genetically prone to developing tumors of their optic nerves, the bundle of neurons that carries visual signals from the eyes to the brain. The mice served as a model for children with the genetic condition neurofibromatosis type 1 (NF1). About one in six children with NF1 develops low-grade optic nerve tumors by age 7. In this study, mice with Nf1 mutations raised under normal lighting developed tumors; those kept in the dark during a critical period of development did not.

The findings, published May 26 in the journal Nature, suggest that neuronal activity plays an underappreciated role in nervous system cancers. The research opens up new avenues to preventing brain tumors in children at high risk for them.

"Optic gliomas are very common in children with NF1, and they can cause vision loss," said co-senior author David H. Gutmann, MD, PhD, the Donald O. Schnuck Family Professor of Neurology at Washington University and the director of the university's NF Center. "We don't have a good way to predict who will develop tumors or any way to prevent them. But now that we know these brain tumors are caused by exposure to light and neuronal activity, we can start thinking of next-gen prevention strategies. Maybe we can give kids cool sunglasses to wear with filters or lenses to block out certain wavelengths of light, or repurpose drugs that suppress excessive neuronal activity, and protect these kids from developing brain tumors and losing their sight."

Co-senior author Michelle Monje, MD, PhD, an associate professor of neurology at Stanford Medicine, previously demonstrated that neuronal activity drives the growth of an aggressive form of brain cancer. But it wasn't clear whether neuronal activity itself sets in motion the process of tumor formation or if it only bolsters the growth of tumors initiated by other processes.

As part of this study, the researchers used mice with mutations in their Nf1 gene. Such mice start developing low-grade tumors of their optic nerves around 9 weeks of age, and virtually all have tumors by 12 weeks to 16 weeks old. Since the neurons in the optic nerve become active when exposed to light, the researchers investigated whether they could reduce neuronal activity -- and, thereby, tumor formation -- simply by keeping the mice away from light. They raised mice from age 9 weeks to 16 weeks in the dark and then checked for tumors.

"The results were so striking. Mice raised in the dark simply did not develop tumors, while all the mice raised in the light did, despite their identical genetic predisposition to develop optic nerve tumors," Monje said. "While we had previously found that neuronal activity is an important regulator of glioma growth, these findings showed how crucial neuronal activity can be for tumor formation."

Further experiments verified the crucial role of light exposure and narrowed down the critical window to age 6 weeks to 12 weeks. None of the mice reared in the dark during that time frame developed tumors by 24 weeks of age. Putting mice older than 12 weeks, when the tumors already had formed, into darkness slowed tumor growth but did not shrink them.

First author Pan Yuan, PhD, who first worked with Gutmann at Washington University and is now a postdoctoral researcher with Monje, showed that the link between light and tumors requires a protein called neuroligin 3. When their optic nerves are stimulated, mice with Nf1 mutations release abnormally high levels of neuroligin 3. Blocking the protein with a drug or genetically modifying mice to eliminate the neuroligin 3 gene resulted in fewer and smaller tumors.

Moreover, brain tumors from people are also high in neuroligin 3, which suggests the possibility of targeting the protein as a treatment for brain tumors. The researchers analyzed tissue samples from 19 people with low-grade brain tumors and found high levels of neuroligin 3, regardless of whether they arose in children with NF1 or not.

"All of this is teaching us that we may have ignored one really important cell type in nervous system cancers: the neuron," Gutmann said. "As neurologists, we have been treating overactive neurons for decades with drugs. One of the directions our laboratories are pursuing is repurposing some of those drugs to see if we can shut off unwanted activity, maybe just for a short developmental period, and prevent brain tumors from forming. And there are other points at which we could intervene as well: by limiting light exposure, by targeting neuroligin 3 or inhibiting some other step in the pathway. It has really opened our eyes."

Credit: 
Washington University School of Medicine