Culture

Youth brain activation data from the largest longitudinal neuroimaging study to date provides valuable new information on the cognitive processes and brain systems that underlie adolescent development and might contribute to mental and physical health challenges in adulthood. The study published today online in Nature Neuroscience.

Because of the notable brain, cognitive, and emotional maturation - and emergence of many mental health disorders - that occurs between the ages of 10 and 20, understanding neurodevelopment and how it is impacted by the numerous risk factors that emerge during this timeframe is a critical area of interest. However, to date, most human neuroimaging studies have focused on adult functioning.

The Adolescent Brain Cognitive Development Study (ABCD) Study, which launched in 2016, is a multisite, 10-year-long longitudinal study that has enrolled nearly 12,000 youth aged 9 to 10 at 21 research sites around the country.

These latest findings demonstrate which brain regions are involved in a range of important psychological processes, including cognitive control, reward processing, working memory, and social/emotional function.

Using functional magnetic resonance imaging (fMRI) technology, the researchers observed brain activation during a battery of three different tasks and identified how differences in the patterns of activity related to individual differences in these processes.

"This study - likely the biggest task activation paper ever - shows the brain regions activated by each task, how well they capture individual differences, and will likely serve as a baseline for all the subsequent papers that will track the kids as they age," says Hugh Garavan, Ph.D., professor of psychiatry at the University of Vermont, and a senior author on the study.

The brain maps aim to improve scientists' understanding of the psychological processes that put young people at higher risk for developing mental and physical health challenges and, by identifying the brain correlates of factors that influence development, can give guidance on which interventions could help improve outcomes.

"These brain activation maps and spatial reproducibility findings will serve as a gold standard for the neuroscientific community and could help inform study design," says Bader Chaarani, Ph.D., assistant professor of psychiatry at the University of Vermont and the study's first author.

The study's authors state that these brain activation maps will allow for "cross-sectional analyses of inter-individual and group differences," as well as "offer the potential for examining baseline predictors of future development and behavior and for quantifying changes in brain function that may arise from the numerous influences expected to affect development and behavior."

To investigate factors that can jeopardize pregnancy success in cattle, researchers at the University of São Paulo (USP) in Brazil used a kind of chip to mimic the environment of the endometrium, the tissue that lines the inside of the uterus. 

The study was conducted by biologist Tiago Henrique Camara de Bem, a postdoctoral fellow at the University of São Paulo’s School of Animal Science and Food Engineering (FZEA-USP), in collaboration with four researchers at the University of Leeds in the UK. Their findings are reported in an article in the journal Endocrinology.

The researchers focused on analyzing alterations in levels of insulin and glucose in maternal epithelial and stromal cells, and the possible consequences for initial development of the pregnancy. Epithelial cells are the most external in the endometrium. They interface with the lumen and are in direct contact with the embryo. Stromal cells are further inside, acting as support cells that guide epithelial cell growth, differentiation and development, among other functions.

The group discovered that high levels of glucose altered 21 protein-encoding genes in epithelial cells and 191 in stromal cells, as well as triggering quantitative changes in the protein secretome (proteins secreted in the culture medium, which in this case mimicked the endometrial fluid). “As we changed the amount of glucose and insulin in the culture medium, stressing the cells, we were able to switch genes on or off, determining whether they were or weren’t expressed,” Camara de Bem said. 

Changes in insulin levels altered the quantitative secretion of 196 proteins but resulted in limited alteration of gene transcription. “The key factor may be the protein composition of the uterine fluid, in which these cells secrete protein into the embryo,” he explained. “We found this group of proteins to be associated with signaling pathways that play an important role in early pregnancy success in cattle, relating to metabolism, cellular matrix and other factors. All these discoveries evidence a mechanism whereby maternal glucose and insulin alterations can affect uterine functioning.”

Camara de Bem was supported by FAPESP via a postdoctoral fellowship for a project conducted at the Molecular Morphophysiology and Development Laboratory under the supervision of Professor Flávio Vieira Meirelles, and a scholarship for a research internship abroad (BEPE). 

Stress

According to Camara de Bem, Brazil is a world leader in the production of bovine embryos, but nevertheless has a high rate of lost pregnancies. “A large proportion of our embryos are produced by in vitro fertilization. Oocytes are collected, matured, fertilized, cultured and transferred to synchronized recipients. However, 40% of pregnancies are lost in the third or fourth week,” he said, recalling that a bovine pregnancy lasts about nine months, as in humans. 

Reproductive success depends on a number of conditions. “Pregnancy is an interaction between the mother and the embryo that develops in the maternal uterus,” Camara de Bem said. “It involves cross-talk between the embryo’s cells and the mother’s. This communication is influenced by multiple processes. Pregnancy loss can occur when the communication isn’t right – when the embryo can’t signal its presence or the mother doesn’t recognize the developing embryo.”

Stress due to environmental or nutritional problems or even to the production process itself can lead to instability in maternal-embryo communication and disrupt the pregnancy, he continued. In the case of cattle, pregnancy in high-yield dairy cows is the main problem, with the initial post-partum period often involving metabolic stress due to a negative energy balance in the dam.

“Glucose, for example, is a basic substrate for cell metabolism,” Camara de Bem said. “Cells need glucose to perform their functions. Lactating cows undergo a metabolic challenge to produce milk. They consume a lot of energy because they need to maintain the basic functions of the organism as well as all the functions involved in milk production. The state of the mother’s metabolism significantly influences reproduction. Hence our focus on understanding the factors that cause metabolic stress in the environment that receives the embryo.” 

Endometrium on a chip

Camara de Bem stressed that the study was conducted in partnership with the group led by Niamh Forde, a professor at the University of Leeds’ Medical School and last author of the article. “She’s investigating maternal recognition of pregnancy in cattle. I’m interested in investigating the signals sent by the embryo to the mother. We thought it would be a good collaboration and had this idea of developing an ‘endometrium on a chip’ that could be used for multicellular culture, i.e. growing more than one type of cell from the endometrium,” he said. 

The chip resembles a histology slide, except that it is divided into chambers – compartments in which the scientists seeded two types of cell. The partitions are made of a porous membrane that enables information to be exchanged between the two cell types cultured in the different chambers but does not permit the cell types to switch positions. The device can be considered a commercial chip adapted to simulate an endometrium. 

“Epithelial cells were seeded in the upper chamber, stromal cells in the lower,” Camara de Bem said. “Both cell types are abundant in the endometrium. The upper chamber’s culture medium became enriched with factors produced and secreted by the epithelial cells, representing the endometrial secretome.”

The chip enabled the scientists to infuse the cells constantly with a culture medium. “We cultured the cells for three days, injecting medium the whole time [one microliter per minute for 72 hours] with three different concentrations of glucose or two different concentrations of insulin,” he said. “Nutrients were administered very slowly, in a flow mimicking the best medium physiology. This ensured that the cells were exposed to the same levels of glucose and insulin throughout the experiment.”

Future

The method was innovative and had never been used before to mimic the bovine endometrium. Conventional cell culture is too simple to simulate all endometrial conditions. “The endometrium is three-dimensional, with several types of cells and glands producing factors and nutrients to maintain the pregnancy,” Camara de Bem recalled. “In vitro embryo culture using the traditional method is static and involves a single cell type in an environment that doesn’t reflect the richness of the animal organism. You can grow cells, transfer embryos to a recipient and produce healthy animals, but we set out to recreate the process in a manner that was as close as possible to the physiological reality.” 

Camara de Bem noted that his partners at the University of Leeds are developing other kinds of chip for embryo insertion. “The methodology opens up a wealth of opportunities, and in future we hope to be able to culture cells and embryos together in order to find out exactly what happens when there are changes in the medium and in communication with maternal cells. This is an opening for more applied research,” he said.

The group’s work also offers a potential model for the study of pregnancy in mammals, including humans. “Except for non-human primates, mice are the main model for studying humans. Placenta formation in mice is the most similar to the process in humans. On the other hand, unlike us mice have many offspring. In cattle, placentation is very different from what it is in humans, but the gestational period is similar and cows also have only one offspring per pregnancy. There will never be an ideal model, because of the differences between species, but this can be one more model,” he said.

The emerald ash borer, an invasive beetle native to Southeast Asia, threatens the entire ash tree population in North America and has already changed forested landscapes and caused tens of billions of dollars in lost revenue to the ash sawtimber industry since it arrived in the United States in the 1990s. Despite the devastating impact the beetle has had on forests in the eastern and midwestern parts of the U.S., climate change will have a much larger and widespread impact on these landscapes through the end of the century, according to researchers.

"We really wanted to focus on isolating the impact of the emerald ash borer on biodiversity, forest composition, biomass and other factors," said Stacey Olson, program coordinator and legal assistant at Resources Legacy Fund. Olson completed the research as part of her master's thesis at Penn State. "We found that emerald ash borer and its impact on ash trees has serious implications for forest change at the site level, but at the broad landscape level, the climatic changes over the next century were much more important in terms of forest composition and species diversity."

The researchers used a forest simulation model to examine the effects of the emerald ash borer and climate change on a forested area of northeast Wisconsin through the year 2100. The area includes the Menominee Reservation. The Menominee Indian Tribe of Wisconsin has been sustainably harvesting timber from the forest for more than 150 years. The scientists reported their findings in the journal Ecosystems.

The model took into account how trees grow, disperse seeds, die and interact with disturbances such as climatic changes. It also accounted for emerald ash borer infestation and pre-emptive ash tree removal, an Indigenous forest management strategy.

"When we run the model, all of these components work simultaneously and interact with one another across the landscape and across time," said Olson, who was also an Environmental Scholar in the Earth and Environmental Systems Institute (EESI) at Penn State. "The model gives us a picture of what all these interacting disturbance and succession processes look like."

The researchers looked at moderate and high-level climate change scenarios based on a business-as-usual approach that fails to curb greenhouse gas emissions within the next decade. The landscape itself partly drove the team's decision to study these scenarios, Olson said. The forest sits in what scientists call a tension zone, where vegetation, soil type and climate variability can shift quickly as one moves across the landscape. In these areas, changes in climate can result in drastic changes on the ground.

The model showed a shift in the types of trees present in the study area by 2100. Northern hardwoods, like beech and birch trees, decreased by approximately 12%, to 35% of the total biomass of all species in the forest. Under climate change conditions, southern hardwoods, like black cherry trees, increased from 4% to 23% by mid-century and became the dominant species in the southern part of the study area.

The model showed that in some areas, the emerald ash borer would completely remove ash trees, clearing the way for other species to replace them. Ash, however, is not the dominant species in the forest, and its removal cannot account for the large shift in tree composition from northern to southern hardwoods. The researchers attributed this shift to climatic changes, such as warmer temperatures and periods of drought or water scarcity, identified in the models.

The study led by Olson is part of a larger project, Visualizing Forest Futures (ViFF), led by Erica Smithwick, distinguished professor of geography and EESI associate, and done in collaboration with the Menominee. The project combines Indigenous forest-management practices with cutting-edge modeling and visualization techniques to better understand the connections between human values and forests and how to sustainably manage forest resources.

"Our project seeks to guide decision-making about forest management strategies while also accounting for uncertainties in forest changes under future climates," Smithwick said. "Stacey's paper provides key information to help guide that process."

The team's research demonstrates the importance of focusing more resources on climate change mitigation rather than on a very specific, targeted threat like the emerald ash borer.

"Some of the research I found said that the ash will likely become functionally extinct within the next couple of decades," said Olson. "While this is clearly a serious problem that deserves attention, a big takeaway for me is that climate is an even larger driver of forest change over the next century, and addressing these challenges must be a top priority."

An experimental, lab-made antibody can completely prevent nonhuman primates from being infected with the monkey form of HIV, new research published in Nature Communications shows.

The results will inform a future human clinical trial evaluating leronlimab as a potential pre-exposure prophylaxis, or PrEP, therapy to prevent human infection from the virus that causes AIDS.

"Our study findings indicate leronlimab could be a new weapon against the HIV epidemic," said the study's lead researcher and co-corresponding author of this paper, Jonah Sacha, Ph.D., an Oregon Health & Science University professor at OHSU's Oregon National Primate Center and Vaccine & Gene Therapy Institute.

"The results of this pre-clinical study, targeting the HIV co-receptor CCR5, have the potential to be groundbreaking as we essentially have a tool that can mimic the genetic mutations of CCR5 that render some individuals immune to infection and have led in part to two cases of a cure of HIV," said the other co-corresponding author, Lishomwa Ndhlovu, M.D., Ph.D., a professor of immunology in medicine at Weill Cornell Medicine in New York.

Made by Vancouver, Washington-based CytoDyn, the monoclonal antibody blocks HIV from entering immune cells through a surface protein called CCR5. The injectable drug has already been studied in a Phase 3 trial as a potential treatment for people living with HIV when used in combination with standard antiretroviral medications. CytoDyn is in the process of submitting information to the FDA to request its approval for that use. This study, however, specifically examined preventing HIV infection to begin with.

Some PrEP drugs are already available, but they can lead to adverse side effects such as liver, heart and bone problems, and some people are resistant to them due to genetic mutations in HIV. Existing PrEP options typically require frequent use, such as a pill daily, or are infusions that must be given in a clinic. Leronlimab is designed to be a self-administered injection.

To study leronlimab's effectiveness as a potential PrEP drug, the research team created three groups of six rhesus macaques at OHSU's Oregon National Primate Research Center. Two groups received different doses of leronlimab, while the third served as a control that didn't receive the experimental drug.

Macaques that received the higher dose of 50 milligrams per kilogram of the animal's weight every other week were completely protected from the monkey form of HIV. In contrast, two of the animals that received the lower dose of 10 milligrams per kilogram per week became infected, and every animal in the control group became infected. Researchers concluded the low-dose group's partial protection was likely due to monkey immune responses against the human antibody.

Following this study's results, CytoDyn is planning to conduct an early clinical trial investigating leronlimab as a potential PrEP drug in people within the next year. Human doses would likely be lower than those given in this study, as rhesus macaque cells have more surface CCR5 protein than humans.

In the meanwhile, Sacha is already trying to make leronlimab easier to use. He received a five-year, $3-million NIH grant in August 2020 to develop a concentrated, longer-lasting formulation of leronlimab that could allow it to be injected every three months. Less-frequent injections can increase drug regimen adherence, and therefore improve drug effectiveness.

The research team dedicated this study to Timothy Ray Brown, who died Sept. 29, 2020, and was known as the Berlin patient for being the first person to be cured of HIV. While living in Berlin in 2007, Brown underwent a bone morrow transplant to treat his blood cancer. The procedure eliminated HIV in Brown because the transplanted bone marrow came from a donor who had a rare mutation that eliminated the CCR5 gene, which makes the surface protein through which HIV enters cells. Sacha became friends with Brown after meeting him at an AIDS conference in 2015. Brown is also a co-author on the paper, and inspired scientists working on this research.

Heart attacks and strokes -- the leading causes of death in human beings -- are fundamentally blood clots of the heart and brain. Better understanding how the blood-clotting process works and how to accelerate or slow down clotting, depending on the medical need, could save lives.

New research by the Georgia Institute of Technology and Emory University published in the journal Biomaterials sheds new light on the mechanics and physics of blood clotting through modeling the dynamics at play during a still poorly understood phase of blood clotting called clot contraction.

"Blood clotting is actually a physics-based phenomenon that must occur to stem bleeding after an injury," said Wilbur A. Lam, W. Paul Bowers Research Chair in the Department of Pediatrics and the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. "The biology is known. The biochemistry is known. But how this ultimately translates into physics is an untapped area."

And that's a problem, argues Lam and his research colleagues, since blood clotting is ultimately about "how good of a seal can the body make on this damaged blood vessel to stop bleeding, or when this goes wrong, how does the body accidentally make clots in our heart vessels or in our brain?"

How Blood Clotting Works

The workhorses to stem bleeding are platelets -- tiny 2-micrometer cells in the blood in charge of making the initial plug. The clot that forms is called fibrin, which acts as a glue scaffold that the platelets attach to and pull against. Blood clot contraction arises when these platelets interact with the fibrin scaffold. To demonstrate the contraction, researchers embedded a 3-millimeter Jell-O mold of a LEGO figure with millions of platelets and fibrin to recreate a simplified version of a blood clot.

"What we don't know is, 'How does that work?' 'What's the timing of it so all these cells work together -- do they all pull at the same time?' Those are the fundamental questions that we worked together to answer," Lam said.

Lam's lab collaborated with Georgia Tech's Complex Fluids Modeling and Simulation group headed by Alexander Alexeev, professor and Anderer Faculty Fellow in the George W. Woodruff School of Mechanical Engineering, to create a computational model of a contracting clot. The model incorporates fibrin fibers forming a three-dimensional network and distributed platelets that can extend filopodia, or the tentacle-like structures that extend from cells so they can attach to specific surfaces, to pull the nearby fibers.

Model Shows Platelets Dramatically Reducing Clot Volume

When the researchers simulated a clot where a large group of platelets was activated at the same time, the tiny cells could only reach nearby fibrins because the platelets can extend filopodia that are rather short, less than 6 micrometers. "But in a trauma, some platelets contract first. They shrink the clot so the other platelets will see more fibrins nearby, and it effectively increases the clot force," Alexeev explained. Due to the asynchronous platelet activity, the force enhancement can be as high as 70%, leading to a 90% decrease of the clot volume.

"The simulations showed that the platelets work best when they're not in total sync with each other," Lam said. "These platelets are actually pulling at different times and by doing that they're increasing the efficiency (of the clot)."

This phenomenon, dubbed by the team asynchronous mechanical amplification, is most pronounced "when we have the right concentration of the platelets corresponding to that of healthy patients," Alexeev said.

Research Could Lead to Better Ways to Treat Clotting, Bleeding Issues

The findings could open medical options for people with clotting issues, said Lam, who treats young patients with blood disorders as a pediatric hematologist in the Aflac Cancer and Blood Disorders Center at Children's Healthcare of Atlanta.

"If we know why this happens, then we have a whole new potential avenue of treatments for diseases of blood clotting," he said, emphasizing that heart attacks and strokes occur when this biophysical process goes wrong.

Lam explained that fine tuning the contraction process to make it faster or more robust could help patients who are bleeding from a car accident or, in the case of a heart attack, make the clotting less intense and slow it down.

"Understanding the physics of this clot contraction could potentially lead to new ways to treat bleeding problems and clotting problems."

Alexeev added that their research also could lead to new biomaterials such as a new type of Band-Aid that could help augment the clotting process.

First author and Georgia Tech Ph.D. candidate Yueyi Sun noted the simplicity of the model and the fact that the simulations allowed the team to understand how the platelets work together to contract the fibrin clot as they would in the body.

"When we started to include the heterogeneous activation, suddenly it gave us the correct volume contraction," she said. "Allowing the platelets to have some time delay so one can use what the previous ones did as a better starting point was really neat to see. I think our model can potentially be used to provide guidelines for designing novel active biological and synthetic materials."

Sun agreed with her research colleagues that this phenomenon might occur in other aspects of nature. For example, multiple asynchronous actuators can fold a large net more effectively to enhance packaging efficiency without the need of incorporating additional actuators.

"It theoretically could be an engineered principle," Lam said. "For a wound to shrink more, maybe we don't have the chemical reactions occur at the same time -- maybe we have different chemical reactions occur at different times. You gain better efficiency and contraction when one allows half or all of the platelets to do the work together."

Building on the research, Sun hopes to examine more closely how a single platelet force converts or is transmitted to the clot force, and how much force is needed to hold two sides of a graph together from a thickness and width standpoint. Sun also intends to include red blood cells in their model since they account for 40% of all blood and play a role in defining the clot size.

"If your red blood cells are too easily trapped in your clot, then you are more likely to have a large clot, which causes a thrombosis issue," she explained.

The concrete world that surrounds us owes its shape and durability to chemical reactions that start when ordinary Portland cement is mixed with water. Now, MIT scientists have demonstrated a way to watch these reactions under real-world conditions, an advance that may help researchers find ways to make concrete more sustainable.

The study is a "Brothers Lumière moment for concrete science," says co-author Franz-Josef Ulm, professor of civil and environmental engineering and faculty director of the MIT Concrete Sustainability Hub, referring to the two brothers who ushered in the era of projected films. Likewise, Ulm says, the MIT team has provided a glimpse of early-stage cement hydration that is like cinema in Technicolor compared to the black and white photos of earlier research.

Cement in concrete contributes about 8 percent of the world's total carbon dioxide emissions, rivaling the emissions produced by most individual countries. With a better understanding of cement chemistry, scientists could potentially "alter production or change ingredients so that concrete has less of an impact on emissions, or add ingredients that are capable of actively absorbing carbon dioxide," says Admir Masic, associate professor of civil and environmental engineering.

Next-generation technologies like 3D printing of concrete could also benefit from the study's new imaging technique, which shows how cement hydrates and hardens in place, says Masic Lab graduate student Hyun-Chae Chad Loh, who also works as a materials scientist with the company Black Buffalo 3D Corporation.
Loh is the first author of the study published in ACS Langmuir, joining Ulm, Masic, and postdoc Hee-Jeong Rachel Kim.

Cement from the start

Loh and colleagues used a technique called Raman microspectroscopy to get a closer look at the specific and dynamic chemical reactions taking place when water and cement mix. Raman spectroscopy creates images by shining a high-intensity laser light on material and measuring the intensities and wavelengths of the light as it is scattered by the molecules that make up the material.

Different molecules and molecular bonds have their own unique scattering "fingerprints," so the technique can be used to create chemical images of molecular structures and dynamic chemical reactions inside a material. Raman spectroscopy is often used to characterize biological and archaeological materials, as Masic has done in previous studies of nacre and other biomineralized materials and ancient Roman concretes.

Using Raman microspectroscopy, the MIT scientists observed a sample of ordinary Portland cement placed underwater without disturbing it or artificially stopping the hydration process, mimicking the real-world conditions of concrete use. In general, one of the hydration products, called portlandite, starts as a disordered phase, percolates throughout the material, and then crystallizes, the research team concluded.

Before this, "scientists could only study cement hydration with average bulk properties or with a snapshot of one point in time," says Loh, "but this allowed us to observe all the changes almost continuously and improved the resolution of our image in space and time."

For instance, calcium-silicate-hydrate, or C-S-H, is the main binding ingredient in cement that holds concrete together, "but it's very difficult to detect because of its amorphous nature," Loh explains. "Seeing its structure, distribution, and how it developed during the curing process was something that was amazing to watch."

Building better

Ulm says the work will guide researchers as they experiment with new additives and other methods to reduce concrete's greenhouse gas emissions: "Rather than 'fishing in the dark,'" we are now able to rationalize through this new approach how reactions occur or do not occur, and intervene chemically."

The team will use Raman spectroscopy as they spend the summer testing how well different cementitious materials capture carbon dioxide, Masic says. "Tracking this up to now has been almost impossible, but now we have the opportunity to follow carbonation in cementitious materials that helps us understand where the carbon dioxide goes, which phases are formed, and how to change them in order to potentially use concrete as a carbon sink."

The imaging is also critical for Loh's work with 3D concrete printing, which depends on extruding concrete layers in a precisely measured and coordinated process, during which the liquid slurry turns into solid concrete.

"Knowing when the concrete is going to set is the most critical question that everyone is trying to understand" in the industry, he says. "We do a lot of trial and error to optimize a design. But monitoring the underlying chemistry in space and time is critical, and this science-enabled innovation will impact the concrete printing capabilities of the construction industry."

This work was partially supported by the scholarship program of the Kwanjeong Educational Foundation.

A new technology could dramatically improve the safety of lithium-ion batteries that operate with gas electrolytes at ultra-low temperatures. Nanoengineers at the University of California San Diego developed a separator—the part of the battery that serves as a barrier between the anode and cathode—that keeps the gas-based electrolytes in these batteries from vaporizing. This new separator could, in turn, help prevent the buildup of pressure inside the battery that leads to swelling and explosions.

“By trapping gas molecules, this separator can function as a stabilizer for volatile electrolytes,” said Zheng Chen, a professor of nanoengineering at the UC San Diego Jacobs School of Engineering who led the study.

The new separator also boosted battery performance at ultra-low temperatures. Battery cells built with the new separator operated with a high capacity of 500 milliamp-hours per gram at -40 C, whereas those built with a commercial separator exhibited almost no capacity. The battery cells still exhibited high capacity even after sitting unused for two months—a promising sign that the new separator could also prolong shelf life, the researchers said.

The team published their findings June 7 in Nature Communications.

The advance brings researchers a step closer to building lithium-ion batteries that can power vehicles in the extreme cold, such as spacecraft, satellites and deep-sea vessels.

This work builds on a previous study published in Science by the lab of UC San Diego nanoengineering professor Ying Shirley Meng, which was the first to report the development of lithium-ion batteries that perform well at temperatures as low as -60 C. What makes these batteries especially cold hardy is that they use a special type of electrolyte called a liquefied gas electrolyte, which is a gas that is liquefied by applying pressure. It is far more resistant to freezing than a conventional liquid electrolyte.

But there’s a downside. Liquefied gas electrolytes have a high tendency to go from liquid to gas. “This is the biggest safety issue with these electrolytes,” said Chen. In order to use them, a lot of pressure must be applied to condense the gas molecules and keep the electrolyte in liquid form.

To combat this issue, Chen’s lab teamed up with Meng and UC San Diego nanoengineering professor Tod Pascal to develop a way to liquefy these gassy electrolytes easily without having to apply so much pressure. The advance was made possible by combining the expertise of computational experts like Pascal with experimentalists like Chen and Meng, who are all part of the UC San Diego Materials Research Science and Engineering Center (MRSEC).

Their approach makes use of a physical phenomenon in which gas molecules spontaneously condense when trapped inside tiny, nanometer-sized spaces. This phenomenon, known as capillary condensation, enables a gas to become liquid at a much lower pressure.

The team leveraged this phenomenon to build a battery separator that would stabilize the electrolyte in their ultra-low temperature battery—a liquefied gas electrolyte made of fluoromethane gas. The researchers built the separator out of a porous, crystalline material called a metal-organic framework (MOF). What’s special about the MOF is that it is filled with tiny pores that are able to trap fluoromethane gas molecules and condense them at relatively low pressures. For example, fluoromethane typically condenses under a pressure of 118 psi at -30 C; but with the MOF, it condenses at just 11 psi at the same temperature.

“This MOF significantly reduces the pressure needed to make the electrolyte work,” said Chen. “As a result, our battery cells deliver a significant amount of capacity at low temperature and show no degradation.”

The researchers tested the MOF-based separator in lithium-ion battery cells—built with a carbon fluoride cathode and lithium metal anode—filled with fluoromethane gas electrolyte under an internal pressure of 70 psi, which is well below the pressure needed to liquefy fluoromethane. The cells retained 57% of their room temperature capacity at -40 C. By contrast, cells with a commercial separator exhibited almost no capacity with fluoromethane gas electrolyte at the same temperature and pressure.

The tiny pores of the MOF-based separator are key because they keep more electrolyte flowing in the battery, even under reduced pressure. The commercial separator, on the other hand, has large pores and cannot retain the gas electrolyte molecules under reduced pressure.

But tiny pores are not the only reason the separator works so well in these conditions. The researchers engineered the separator so that the pores form continuous paths from one end to the other. This ensures that lithium ions can still flow freely through the separator. In tests, battery cells with the new separator had 10 times higher ionic conductivity at -40 C than cells with the commercial separator.

Chen’s team is now testing the MOF-based separator on other electrolytes. “We are seeing similar effects. We can use this MOF as a stabilizer to adsorb various kinds of electrolyte molecules and improve the safety even in traditional lithium batteries, which also have volatile electrolytes.”

Citizen opposition to COVID-19 vaccination has emerged across the globe, prompting pushes for mandatory vaccination policies.  But a new study based on evidence from Germany and on a model of the dynamic nature of people's resistance to COVID-19 vaccination sounds an alarm: mandating vaccination could have a substantial negative impact on voluntary compliance.

Majorities in many countries now favor mandatory vaccination. In March, the government of Galicia in Spain made vaccinations mandatory for adults, subjecting violators to substantial fines. Italy has made vaccinations mandatory for care workers. The University of California and California State University systems announced in late April that vaccination would be required for anyone attending in the Fall.

The research, published in this week's Proceedings of the National Academy of Sciences (PNAS), extends an earlier PNAS study by first author Katrin Schmelz, a psychologist and behavioral economist at the University of Konstanz, documenting that a major source of vaccine hesitancy is distrust of government. She found that enforced vaccinations reduce people's desire to be vaccinated, particularly among those with low levels of trust in public institutions.

In the new study, Schmelz and economist Samuel Bowles of the Santa Fe Institute exploit a large panel survey implemented in Germany during the first and second waves of the pandemic. Despite infections in Germany being 15 times more common in the second wave of both the pandemic and the survey, the researchers observed increased opposition when they asked participants a hypothetical question about how they'd respond if vaccinations were to be legally required (the German government is publicly committed not to require vaccinations). In contrast, there was a higher and undiminished level of support for the voluntary vaccinations now in force. 

The authors also draw on evidence from the dynamics of diffusion of novel products and technologies such as TVs and washing machines in the last century. They reason that as those who are hesitant or opposed to vaccination see that others are getting vaccinated, they might change their mind. Learning from others' vaccination decisions - "conformism" in psychology - means that even if initial vaccination hesitancy is substantial, as more become vaccinated it may be possible to get to a herd immunity target without mandating vaccines.

They also use experimental evidence from behavioral economics showing that explicit incentives, whether in the form of carrots or sticks, may crowd out intrinsic or ethical motives. Policies that aim to incentivize a desired behavior, such as getting vaccinated, can actually undercut individuals' sense of a moral or ethical obligation to do the right thing. 

This is evident in their data. Mandating vaccinations by law directly reduces the desire to be vaccinated. Their model also suggests an adverse indirect effect: enforcement will reduce the extent to which others being vaccinated will induce vaccine hesitators to become willing, as this carries a weaker signal. Schmelz says "How people feel about getting vaccinated will be affected by enforcement in two ways -- it could crowd out pro-vaccine feelings, and reduce the positive effect of conformism if vaccination is voluntary."

Bowles says this should be a caution to governments considering mandated policies: "Costly errors may be avoided if policymakers reflect carefully on the costs of enforcement. These could not only increase opposition to vaccination, but also heighten social conflict by further alienating citizens from the government or scientific and medical elites," he says. Nonetheless, he says government enforcement "may still be necessary if the number wishing to be vaccinated is insufficient to control the pandemic."

Schmelz concludes that "Our findings have broad policy applicability beyond COVID-19. There are many cases in which voluntary citizen compliance to a policy is essential because state enforcement capacities are limited, and because results may depend on the ways that the policies themselves alter citizens' beliefs and preferences," adding that "... examples include policies to promote lifestyle changes to reduce carbon footprints or to sustain tolerance and mutual respect in a heterogeneous society."

Brazilian researchers have simultaneously demonstrated the mechanism linking high blood pressure to elevated intracranial pressure, validated a non-invasive intracranial pressure monitoring method, and proposed a treatment for high blood pressure that does not affect intracranial hypertension.

The study was supported by FAPESP and involved collaboration between researchers at São Paulo State University (UNESP) and Brain4care, a startup based in São Carlos. It could result in novel treatments for intracranial hypertension and its complications, including stroke. The main findings are reported in the journal Hypertension.

The researchers monitored blood pressure and intracranial pressure in rats for six weeks. “We set out to investigate what happened to intracranial pressure during the period in which the animals were becoming hypertensive. We were the first to succeed in monitoring this process non-invasively, tracking changes in the shape of the intracranial pressure curve. Our study suggests that intracranial hypertension can be prevented if diagnosed early and treated with losartan, a drug widely used by patients with high blood pressure. It blocks the action of angiotensin II [a naturally occurring peptide that can cause vasoconstriction and an increase in blood pressure], which we also show to be important to control intracranial pressure,” said Eduardo Colombari, principal investigator for the study. Colombari is a professor at UNESP’s Dental School in Araraquara (FOAr).

Intracranial pressure typically increases because of a tumor, encephalitis, meningitis, aneurysm or similar problems, but the researchers showed that chronic high blood pressure can also impair cerebral compliance, leading to a rise in intracranial pressure.

In the study the researchers used vascular clips to simulate renal artery obstruction in rats, restricting the flow of blood to one kidney. The reduced irrigation triggered the pressure-controlling renin-angiotensin system, leading the kidney to release peptides, enzymes and receptors that constrict the blood vessels and raise blood pressure throughout the organism. In the third week of monitoring, when the rats were considered hypertensive, blood pressure rose even more, causing fluid retention and above all boosting cerebral blood flow.

“If the hypertension isn’t treated, the disorder can worsen,” Colombari said. “The rise in intracranial pressure caused by systemic hypertension impairs the brain’s ability to stabilize the pressure [cerebral autoregulation]. This can also lead to blood-brain barrier rupture. Our study showed that the rats’ blood-brain barrier was compromised in the third week. When the barrier is breached, substances and products from the renin-angiotensin system as well as pro-inflammatory substances present in the blood vessels can enter the interstitial space, where the neurons reside, especially regions important to integrative neurohumoral adjustment, such as the cardiovascular, respiratory, and renal systems, among others.”

Treating intracranial hypertension

Blood-brain barrier disruption endangers areas of the nervous system that are important to control cardiovascular pressure as a whole. “How is intracranial hypertension treated now? By inducing a coma or administering a diuretic to resolve fluid retention in the skull. These methods are relatively unspecific and highly systemic. Deeper understanding of the link between high blood pressure and intracranial hypertension points to the possibility of a new field of study in pharmacology,” said Gustavo Frigieri, Brain4care’s Scientific Director.

Part of the study involved a comparison between intracranial pressure measured by the non-invasive sensor and by the invasive method. The wearable sensor developed by Brain4care has been used to measure intracranial pressure in patients with systemic impairments and has been licensed by the National Health Surveillance Agency (ANVISA) in Brazil and the Food and Drug Administration (FDA) in the United States.

Frigieri also sees plenty of opportunities for applications in basic research. “By comparing the non-invasive and invasive methods, we validated our technology for use in scientific research with small animals,” he said. “It can close gaps left open owing to the aggressiveness of the conventional method, which entails a significant risk of infection because a hole is drilled in the skull to insert a sensor.”

Blood flow and hormones

At the end of the study, the researchers treated the animals with losartan, reducing blood pressure and intracranial pressure. “It’s not a cause-and-effect relationship because intracranial pressure wasn’t affected when we lowered blood pressure with a vasodilator [hydralazine]. We observed a major impairment of the brain, and the angiotensin inhibitor [losartan] improved both blood pressure and cerebral blood flow,” Colombari said.

In the sixth week of the experiment, before administration of any drugs, blood pressure was high (190 per 100 mmHg) and intracranial pressure had risen significantly. The researchers discovered alterations in the intracranial pressure pulse waveforms. Each heartbeat (systolic or diastolic) pumps blood to the brain, originating the first peak (P1). A second wave (P2) correlates directly with intracranial arterial volume and cerebral compliance, important factors observed immediately before ventricular diastole.

According to the researchers, the second wave is associated with brain tissue compliance and arterial elasticity in the skull so that the energy of the first wave is absorbed. However, blood-brain barrier disruption and loss of cerebral compliance hinders control of P2, and the first wave becomes stronger than the second.

“At this point we found P2 to be higher than P1, which is the opposite of the normal situation. This is due to loss of protection by the blood-brain barrier so that the brain expands and fluid leaks into the interstitium,” Colombari said.

NEW YORK, NY--A new global study of 30-day outcomes in children and adolescents with COVID-19 found that while death was uncommon, the illness produced more symptoms and complications than seasonal influenza.

The study, "30-day outcomes of Children and Adolescents with COVID-19: An International Experience," published online in the journal Pediatrics, also found significant variation in treatment of children and adolescents hospitalized with COVID-19.

Early in the pandemic, opinions around the impact of COVID-19 on children and adolescents ranged from it being no more than the common flu to fear of its potential impact on lesser-developed immune systems. This OHDSI global network study compared the real-world observational data of more than 242,000 children and adolescents diagnosed with COVID-19, including nearly 10,000 hospitalized youths, to more than 2,000,000 diagnosed with influenza across five countries (France, Germany, South Korea, Spain, and the United States) to provide a clearer picture of its impact.

Asthma and obesity -- a common finding among a general pediatric population -- were the most common baseline comorbidities. There was also a higher prevalence of rare conditions, including congenital malformations, neurodevelopmental disorders, and heart disease, among those hospitalized with COVID-19. Pediatric patients with COVID-19 also showed higher rates of symptoms such as labored breathing, loss of smell and gastrointestinal symptoms than those with influenza, which could help improve early diagnosis of COVID-19 among this population.

Adjunctive therapies were the most common treatment options in children and adolescents, though there was global heterogeneity on which particular therapies were used (systemic corticosteroids and famotidine were most common).

The most common 30-day complications for hospitalized youths with COVID-19 were hypoxemia and pneumonia, both of which occurred at a higher rate than hospitalized influenza pediatric patients.

There was limited knowledge of the COVID-19 impact on children and adolescents around the world during the first half of 2020, when the OHDSI community collaborated on the CHARYBDIS Project. Findings at the time ranged from a 5.7 % hospitalization rate to another that reported a 63% hospitalization rate. There was a need for reliable evidence on the demographics, comorbidities, symptoms, in-hospital treatments, and health outcomes among children and adolescents to inform clinical decision-making.

"This study addressed critical questions that were weighing down on both the healthcare community and the general population -- how was COVID-19 impacting our youngest population," said study lead Talita Duarte-Salles, PhD, an epidemiologist at IDIAP Jordi Gol in Barcelona, Spain, and first author of the study. "While some last year claimed that COVID-19 was no different than the flu, the real-world evidence we generated through open science showed something quite different. It was a relief to see that fatality was rare, but clearly both complications and symptoms showed the COVID-19 was no flu in children and adolescents."

The study was developed and executed by the OHDSI (Observational Health Data Sciences and Informatics) community, a multi-stakeholder, interdisciplinary network that collaborates globally to bring out the value of health data through open science and large-scale analytics. This study resulted from the CHARYBDIS Project, which has resulted in several published studies, including ones on general COVID-19 phenotyping, patients with autoimmune disease, and use of repurposed and adjunctive drug therapies. Several others are undergoing peer review and have been posted to a preprint server; OHDSI's work on COVID-19 can be found here.

Columbia University serves as the Central Coordinating Center for the OHDSI community.

"Generating reliable evidence that can inform clinical decision-making for children and adolescents was so important, and it doesn't happen without collaboration and the foundation of open-source tools and practices developed for years in this network," Duarte-Salles said. "It was truly inspiring the way our OHDSI community rallied together globally in the face of this unprecedented pandemic and collaborated together."

Research Highlights:

Rates of Kawasaki disease - a condition that creates inflammation in blood vessels in the heart and is more common in children of Asian/Pacific Island descent - have substantially decreased in South Korea during the COVID-19 pandemic.

The decrease could be due to mask-wearing, hand-washing, school closures and physical distancing, suggesting Kawasaki disease may be prompted by infectious agents.

The cause of Kawasaki disease is unknown, though it may be an immune response to acute infectious illness.

DALLAS, June 7, 2021 -- The rate of Kawasaki disease in South Korea has substantially decreased during the COVID-19 pandemic, possibly due to pandemic prevention efforts, such as mask-wearing, hand-washing and physical distancing, according to new research published today in the American Heart Association's flagship journal Circulation.

Kawasaki disease is the most common cause of heart disease that develops after birth in children, creating inflammation in blood vessels, particularly heart arteries. Kawasaki disease usually occurs before age 5 and is more common among children of Asian descent, although it affects children of all races and ethnicities. South Korea has the second-highest incidence of Kawasaki disease in the world, after Japan.

According to the 2021 American Heart Association's heart disease and stroke statistics, the incidence of Kawasaki disease in 2006 was 20.8 per 100,000 U.S. children under age 5, the most recent national estimate available and is limited by reliance on weighted hospitalization data from 38 states. Although Kawasaki disease can occur into adolescence (and rarely beyond), 76.8% of U.S. children with the condition are age 5 or younger. Boys have a 1.5-fold higher incidence of Kawasaki disease than girls. The rate of Kawasaki disease appears to be rising worldwide, possibly due to improved awareness and recognition of the disease, more frequent diagnosis of incomplete Kawasaki disease and true increasing incidence.

Symptoms of Kawasaki disease include fever, rash, red lips and strawberry tongue (bumpy and red with enlarged taste buds). Prompt treatment is critical to prevent significant heart problems, and most children recover fully with treatment. Although the cause of Kawasaki disease is unknown, it may be an immune response to an acute infectious illness based in part on genetic susceptibilities.

South Korean researchers noted that efforts to prevent COVID-19 provided a unique opportunity to analyze the possible effects of mask-wearing and social distancing on Kawasaki disease. Since February 2020, South Korea has required strict mask-wearing, periodic school closures, physical distancing, and frequent testing and isolation for people with COVID-19 symptoms.

Researchers reviewed health records from January 2010 to September 2020 in a South Korean national health insurance database to identify Kawasaki disease cases among children from birth to 19 years old. They identified 53,424 cases of Kawasaki disease during the 10 years studied, and 83% of cases occurred in children younger than 5 years of age.

Researchers compared the rate of Kawasaki disease from February 2020 to September 2020, a time of significant COVID-19 prevention efforts, to pre-COVID-19 rates of Kawasaki disease. Their analysis found the number of Kawasaki disease cases dropped substantially -- by about 40% -- after COVID-19 prevention efforts were implemented in Feb. 2020. Before 2020, the average number of cases of Kawasaki disease between February and September was 31.5 per 100,000 people, compared to 18.8 per 100,000 people for the same months in 2020 during the COVID-19 pandemic. The greatest decrease in cases occurred among children up to age 9, while no decrease occurred among 10- to 19-year-olds.

"Our findings emphasize the possible impact of environmental triggers on the occurrence of Kawasaki disease," said study lead author Jong Gyun Ahn, M.D., Ph.D., associate professor of pediatrics at Severance Children's Hospital at Yonsei University College of Medicine in Seoul, South Korea. "The decrease in the incidence of Kawasaki disease after the implementation of non-pharmaceutical interventions is very clear, and it is unlikely that other independent interventions were accidentally involved.

"The broad and intensive COVID-19 prevention interventions had the additional effect of lowering the incidence of respiratory infections, which have previously been suggested as triggering agents for Kawasaki disease," Ahn noted. "Additionally, the seasonality of the Kawasaki disease epidemic disappeared in South Korea. It is usually most prevalent in the winter, with a second peak in late spring-summer."

American Heart Association volunteer expert Jane W. Newburger, M.D., M.P.H., FAHA, notes the research findings are consistent with the hypothesis that Kawasaki disease is an immunologic reaction elicited in genetically susceptible people when exposed to viruses or other infectious agents in the environment. Newburger is a member of the American Heart Association's Young Hearts Council, associate cardiologist-in-chief, academic affairs; medical director of the neurodevelopmental program; and director of the Kawasaki Program at Boston Children's Hospital; and Commonwealth Professor of Pediatrics at Harvard Medical School.

"During the COVID pandemic, children were exposed to fewer viruses and other infectious agents. So the 'natural experiment' that occurred from isolation and masking of children

supports the likelihood that Kawasaki disease is triggered by viruses or other infectious agents in the environment," Newburger said. "However, these dramatic changes in lifestyle would be difficult to sustain if the sole purpose was to prevent Kawasaki disease. Kawasaki disease is a very rare illness in children and does not represent a public health emergency like COVID."

Newburger also noted that many Kawasaki disease experts in the U.S. also have noticed fewer cases in their centers during the pandemic.

This study has some limitations: cases of Kawasaki disease among patients who did not submit insurance claims are not included in the national insurance database; and the study was observational and could not control for other factors such as whether or not patients sought and received health care including screening and treatment for Kawasaki disease.

It is also important to note that Kawasaki disease is not the same as multi-system inflammatory syndrome in children (MIS-C), the new condition identified this past year during the COVID-19 pandemic. While the two conditions have some overlapping symptoms, they also have some distinct differences including more profound inflammation and more gastrointestinal symptoms with MIS-C, and MIS-C is associated with COVID-19 infection.

CAMBRIDGE, MA -- MIT engineers have discovered a new way of generating electricity using tiny carbon particles that can create a current simply by interacting with liquid surrounding them.

The liquid, an organic solvent, draws electrons out of the particles, generating a current that could be used to drive chemical reactions or to power micro- or nanoscale robots, the researchers say.

"This mechanism is new, and this way of generating energy is completely new," says Michael Strano, the Carbon P. Dubbs Professor of Chemical Engineering at MIT. "This technology is intriguing because all you have to do is flow a solvent through a bed of these particles. This allows you to do electrochemistry, but with no wires."

In a new study describing this phenomenon, the researchers showed that they could use this electric current to drive a reaction known as alcohol oxidation -- an organic chemical reaction that is important in the chemical industry.

Strano is the senior author of the paper, which appears today in Nature Communications. The lead authors of the study are MIT graduate student Albert Tianxiang Liu and former MIT researcher Yuichiro Kunai. Other authors include former graduate student Anton Cottrill, postdocs Amir Kaplan and Hyunah Kim, graduate student Ge Zhang, and recent MIT graduates Rafid Mollah and Yannick Eatmon.

Unique properties

The new discovery grew out of Strano's research on carbon nanotubes -- hollow tubes made of a lattice of carbon atoms, which have unique electrical properties. In 2010, Strano demonstrated, for the first time, that carbon nanotubes can generate "thermopower waves." When a carbon nanotube is coated with layer of fuel, moving pulses of heat, or thermopower waves, travel along the tube, creating an electrical current.

That work led Strano and his students to uncover a related feature of carbon nanotubes. They found that when part of a nanotube is coated with a Teflon-like polymer, it creates an asymmetry that makes it possible for electrons to flow from the coated to the uncoated part of the tube, generating an electrical current. Those electrons can be drawn out by submerging the particles in a solvent that is hungry for electrons.

To harness this special capability, the researchers created electricity-generating particles by grinding up carbon nanotubes and forming them into a sheet of paper-like material. One side of each sheet was coated with a Teflon-like polymer, and the researchers then cut out small particles, which can be any shape or size. For this study, they made particles that were 250 microns by 250 microns.

When these particles are submerged in an organic solvent such as acetonitrile, the solvent adheres to the uncoated surface of the particles and begins pulling electrons out of them.

"The solvent takes electrons away, and the system tries to equilibrate by moving electrons," Strano says. "There's no sophisticated battery chemistry inside. It's just a particle and you put it into solvent and it starts generating an electric field."

Particle power

The current version of the particles can generate about 0.7 volts of electricity per particle. In this study, the researchers also showed that they can form arrays of hundreds of particles in a small test tube. This "packed bed" reactor generates enough energy to power a chemical reaction called an alcohol oxidation, in which an alcohol is converted to an aldehyde or a ketone. Usually, this reaction is not performed using electrochemistry because it would require too much external current.

"Because the packed bed reactor is compact, it has more flexibility in terms of applications than a large electrochemical reactor," Zhang says. "The particles can be made very small, and they don't require any external wires in order to drive the electrochemical reaction."

In future work, Strano hopes to use this kind of energy generation to build polymers using only carbon dioxide as a starting material. In a related project, he has already created polymers that can regenerate themselves using carbon dioxide as a building material, in a process powered by solar energy. This work is inspired by carbon fixation, the set of chemical reactions that plants use to build sugars from carbon dioxide, using energy from the sun.

In the longer term, this approach could also be used to power micro- or nanoscale robots. Strano's lab has already begun building robots at that scale, which could one day be used as diagnostic or environmental sensors. The idea of being able to scavenge energy from the environment to power these kinds of robots is appealing, he says.

"It means you don't have to put the energy storage on board," he says. "What we like about this mechanism is that you can take the energy, at least in part, from the environment."

Many modern fitness trackers and smartwatches feature integrated LEDs. The green light emitted, whether continuous or pulsed, penetrates the skin and can be used to measure the wearer's heart rate during physical activity or while at rest.

These watches have become extremely popular. A team of ETH researchers now wants to capitalise on that popularity by using the LEDs to control genes and change the behaviour of cells through the skin. The team is led by Martin Fussenegger from the Department of Biosystems Science and Engineering in Basel. He explains the challenge to this undertaking: "No naturally occurring molecular system in human cells responds to green light, so we had to build something new."

Green light from the smartwatch activates the gene

The ETH professor and his colleagues ultimately developed a molecular switch that, once implanted, can be activated by the green light of a smartwatch.

The switch is linked to a gene network that the researchers introduced into human cells. As is customary, they used HEK 293 cells for the prototype. Depending on the configuration of this network - in other words, the genes it contains - it can produce insulin or other substances as soon as the cells are exposed to green light. Turning the light off inactivates the switch and halts the process.

Standard software

As they used the standard smartwatch software, there was no need for the researchers to develop dedicated programs. During their tests, they turned the green light on by starting the running app. "Off-the-shelf watches offer a universal solution to flip the molecular switch," Fussenegger says. New models emit light pulses, which are even better suited to keeping the gene network running.

The molecular switch is more complicated, however. A molecule complex was integrated into the membrane of the cells and linked to a connecting piece, similar to the coupling of a railway carriage. As soon as green light is emitted, the component that projects into the cell becomes detached and is transported to the cell nucleus where it triggers an insulin-producing gene. When the green light is extinguished, the detached piece reconnects with its counterpart embedded in the membrane.

Controlling implants with wearables

The researchers tested their system on both pork rind and live mice by implanting the appropriate cells into them and strapping a smartwatch on like a rucksack. Opening the watch's running program, the researchers turned on the green light to activate the cascade.

"It's the first time that an implant of this kind has been operated using commercially available, smart electronic devices - known as wearables because they are worn directly on the skin," the ETH professor says. Most watches emit green light, a practical basis for a potential application as there is no need for users to purchase a special device.

According to Fussenegger, however, it seems unlikely that this technology will enter clinical practice for at least another ten years. The cells used in this prototype would have to be replaced by the user's own cells. Moreover, the system has to go through the clinical phases before it can be approved, meaning major regulatory hurdles. "To date, only very few cell therapies have been approved," Fussenegger says.

Levels of a protein called neurofilament light chain (NfL) in the blood can identify those who might have neurodegenerative diseases such as Down's syndrome dementia, motor neuron disease (ALS) and frontotemporal dementia, when clinical symptoms are not definitive.

Published in Nature Communications and part-funded by the NIHR Maudsley Biomedical Research Centre, the research determined a set of age-related cut-off levels of NfL which could inform its potential use in primary care settings through a simple blood test.

Joint Senior Author on the study, Dr Abdul Hye from the NIHR Maudsley Biomedical Research Centre at King's College London and South London and Maudsley NHS Foundation Trust said: 'For the first time we have shown across a number of disorders that a single biomarker can indicate the presence of underlying neurodegeneration with excellent accuracy. Though it is not specific for any one disorder, it could help in services such as memory clinics as a rapid screening tool to identify whether memory, thinking or psychiatric problems are a result of neurodegeneration.'

Neurodegenerative diseases are debilitating conditions that result in ongoing degeneration or death of nerve cells, leading to problems in thought, attention and memory. There are currently around 850,000 people with dementia in the UK which is projected to rise to 1.6 million by 2040. In order to help identify the onset of these debilitating diseases and put in place preventative measures as early as possible there has been a drive to develop reliable and accessible biomarkers that can recognise or rule out whether the processes in the brain that are responsible for neurodegeneration are occurring.

Current biomarkers used to identify neurodegenerative disorders are taken from the fluid that surrounds the brain and spinal column (cerebrospinal fluid - CSF) which has to be extracted using an invasive procedure called lumbar puncture. Advances have been made to use biomarkers from the blood which would provide a more accessible and comfortable assessment. A central and irreversible feature in many neurodegenerative disorders is damage to the nerve fibre which results in the release of neurofilament light chain (NfL). Using ultrasensitive tests, NfL can be detected in blood at low levels and is increased in a number of disorders, unlike phosphorylated tau which is specific for Alzheimer's disease. This means NfL can be of use in the diagnostic process of many neurodegenerative diseases most notably in this study Down's syndrome dementia, ALS and frontotemporal dementia.

Co-author Professor Ammar Al-Chalabi from at King's College London and co-lead of the Psychosis and Neuropsychiatry research theme at the NIHR Maudsley BRC. said
'For neurodegenerative diseases like Alzheimer's, Parkinson's or motor neuron disease, a blood test to allow early diagnosis and help us monitor disease progression and response to treatment would be very helpful. Neurofilament light chain is a promising biomarker that could speed diagnosis of neurodegenerative diseases and shorten clinical trials.'

The study examined 3138 samples from King's College London, Lund University and Alzheimer's Disease Neuroimaging Initiative, including people with no cognitive impairment, people with neurodegenerative disorders, people with Down syndrome and people with depression. The study showed that concentrations of NfL in the blood were higher across all neurodegenerative disorders compared to those with no cognitive problems, the highest being in people with Down's syndrome dementia, motor neuron disease and frontotemporal dementia.

The study also showed that although blood based NfL could not differentiate between all the disorders, it could provide insight into different groups within certain disorders. For example, in those with Parkinson's a high concentration of NfL indicated atypical Parkinson's disorder and in patients with Down syndrome, NfL levels differentiated between those with and without dementia.

Co-author Andre Strydom, Professor in Intellectual Disabilities at King's College London said: 'This study shows that neurofilament light chain levels were particularly increased in adults with Down syndrome who have a genetic predisposition for Alzheimer's disease. Furthermore, we showed that those individuals with a dementia diagnosis following onset of Alzheimer's disease had higher levels than those who did not. This suggests that the new marker could potentially be used to improve the diagnosis of Alzheimer's in people with Down syndrome, as well as to be used as biomarker to show whether treatments are effective or not. It is exciting that all that could be needed is a simple blood test, which is better tolerated in Down syndrome individuals than brain scans.'

The study assessed age-related thresholds or cut-offs of NfL concentrations that could represent the point at which an individual would receive a diagnosis. These age-related cut-off points were 90% accurate in highlighting neurodegeneration in those over 65 years of age and 100% accurate in detecting motor neurone disease and Down syndrome dementia in the King's College London samples, with a very similar result in the Lund samples. Importantly, NfL was able to distinguish individuals with depression from individuals with neurodegenerative disorders which commonly present with primary psychiatric disorder in the onset of disease development such as frontotemporal dementia.

Joint-Senior author Professor Oskar Hansson from Lund University said 'Blood tests have great potential to improve the diagnosis of dementia both in specialised memory clinics and in primary care. Plasma NfL can be extremely useful in a number of clinical scenarios which can greatly inform doctors, as shown in this large study'.

Dr Hye said 'Blood-based NfL offers a scalable and widely accessible alternative to invasive and expensive tests for dementia. It is already used as a routine assessment in some European countries such as Sweden or Netherlands, and our age-related cut-offs can provide a benchmark and quick accessible test for clinicians, to indicate neurodegeneration in people who are exhibiting problems in thinking and memory.'

Lead author Dr Nicholas Ashton from King's College London concludes 'We are entering an exciting period where blood tests like plasma NfL, in combination with other emerging blood biomarkers like phosphorylated tau (p-tau), are starting to give us a meaningful and non-invasive insight into brain disorders'.

The first double-blind experiment analysing the role of human decision-making in climate reconstructions has found that it can lead to substantially different results.

The experiment, designed and run by researchers from the University of Cambridge, had multiple research groups from around the world use the same raw tree-ring data to reconstruct temperature changes over the past 2,000 years.

While each of the reconstructions clearly showed that recent warming due to anthropogenic climate change is unprecedented in the past two thousand years, there were notable differences in variance, amplitude and sensitivity, which can be attributed to decisions made by the researchers who built the individual reconstructions.

Professor Ulf Büntgen from the University of Cambridge, who led the research, said that the results are "important for transparency and truth - we believe in our data, and we're being open about the decisions that any climate scientist has to make when building a reconstruction or model."

To improve the reliability of climate reconstructions, the researchers suggest that teams make multiple reconstructions at once so that they can be seen as an ensemble. The results are reported in the journal Nature Communications.

Information from tree rings is the main way that researchers reconstruct past climate conditions at annual resolutions: as distinctive as a fingerprint, the rings formed in trees outside the tropics are annually precise growth layers. Each ring can tell us something about what conditions were like in a particular growing season, and by combining data from many trees of different ages, scientists are able to reconstruct past climate conditions going back hundreds and even thousands of years.

Reconstructions of past climate conditions are useful as they can place current climate conditions or future projections in the context of past natural variability. The challenge with a climate reconstruction is that - absent a time machine - there is no way to confirm it is correct.

"While the information contained in tree rings remains constant, humans are the variables: they may use different techniques or choose a different subset of data to build their reconstruction," said Büntgen, who is based at Cambridge's Department of Geography, and is also affiliated with the CzechGlobe Centre in Brno, Czech Republic. "With any reconstruction, there's a question of uncertainty ranges: how certain you are about a certain result. A lot of work has gone into trying to quantify uncertainties in a statistical way, but what hasn't been studied is the role of decision-making.

"It's not the case that there is one single truth - every decision we make is subjective to a greater or lesser extent. Scientists aren't robots, and we don't want them to be, but it's important to learn where the decisions are made and how they affect the outcome."

Büntgen and his colleagues devised an experiment to test how decision-making affects climate reconstructions. They sent raw tree ring data to 15 research groups around the world and asked them to use it to develop the best possible large-scale climate reconstruction for summer temperatures in the Northern hemisphere over past 2000 years.

"Everything else was up to them - it may sound trivial, but this sort of experiment had never been done before," said Büntgen.

Each of the groups came up with a different reconstruction, based on the decisions they made along the way: the data they chose or the techniques they used. For example, one group may have used instrumental target data from June, July and August, while another may have only used the mean of July and August only.

The main differences in the reconstructions were those of amplitude in the data: exactly how warm was the Medieval warming period, or how much cooler a particular summer was after a large volcanic eruption.

Büntgen stresses that each of the reconstructions showed the same overall trends: there were periods of warming in the 3rd century, as well as between the 10th and 12th century; they all showed abrupt summer cooling following clusters of large volcanic eruptions in the 6th, 15th and 19th century; and they all showed that the recent warming since the 20th and 21st century is unprecedented in the past 2000 years.

"You think if you have the start with the same data, you will end up with the same result, but climate reconstruction doesn't work like that," said Büntgen. "All the reconstructions point in the same direction, and none of the results oppose one another, but there are differences, which must be attributed to decision-making."

So, how will we know whether to trust a particular climate reconstruction in future? In a time where experts are routinely challenged, or dismissed entirely, how can we be sure of what is true? One answer may be to note each point where a decision is made, consider the various options, and produce multiple reconstructions. This would of course mean more work for climate scientists, but it could be a valuable check to acknowledge how decisions affect outcomes.

Another way to make climate reconstructions more robust is for groups to collaborate and view all their reconstructions together, as an ensemble. "In almost any scientific field, you can point to a single study or result that tells you what to hear," he said. "But when you look at the body of scientific evidence, with all its nuances and uncertainties, you get a clearer overall picture."