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New, more accurate way to deliver medicine to the brain

Houston Methodist researchers have discovered a more accurate and timely way to deliver life-saving drug therapies to the brain, laying the groundwork for more effective treatment of brain tumors and other neurological diseases than with the current convection-enhanced delivery (CED).

Delivering the correct dosage of drugs to the right place in the brain has long been a challenge. The natural blood-brain barrier that protects our brains from toxins and pathogens can also block the delivery of important medical treatments. And CED also follows the path of least resistance, so therapeutics don’t always hit the target.

Electric field infuses medicine accurately

So the researchers developed a new process called “electrokinetic convection-enhanced delivery” (ECED) that allows surgeons to design the appropriate delivery path and potentially reach brain lesions and tumors more accurately. ECED uses an electric field to infuse medicine from a reservoir outside the brain to specific targets inside the brain. It applies continuous pressure over time to inject a fluid containing therapeutics into the brain.

In the Springer Nature journal Communications Biology, Houston Methodist research scientist and co-author Jesus G. Cruz-Garza explains how ECED infuses macromolecules into the brain from a hydrogel reservoir placed at the brain’s surface. “The brain acts as a charged porous scaffold that in the presence of an electric field allows for electroosmosis—bulk fluid flow in a porous media.” From the hydrogel reservoir, Cruz-Garza explains, this bulk flow of fluid enables the delivery of therapeutic agents.

This invention improves on the 30-year-old process of injecting therapeutics into the brain via, say the researchers.

“Delivering therapeutics by way of ECED has many applications,” explained Dr. Amir Faraji, principal investigator and Houston Methodist neurosurgeon, in a statement. “It has the potential to “improve gene therapy and as a treatment for traumatic brain injury and degenerative diseases, and in a more targeted manner.”

The research was conducted at Houston Methodist Department of Neurosurgery, Houston Methodist Research Institute, Center for Neural Systems Restoration, Center for Neuroregeneration, in conjunction with Texas A&M University College of Medicine and School of Engineering.

Further research is needed before Faraji and team can bring this investigational therapy to humans, the researchers advise.

Citations:

Cruz-Garza, J.G., Bhenderu, L.S., Taghlabi, K.M. et al. (2024) Electrokinetic convection-enhanced delivery for infusion into the brain from a hydrogel reservoir. Commun Biol 7, 869. https://www.nature.com/articles/s42003-024-06404-1 (open access)

Eid, F., Chen, A. T., Chan, K. Y., Huang, Q., Zheng, Q., Tobey, I. G., Pacouret, S., Brauer, P. P., Keyes, C., Powell, M., Johnston, J., Zhao, B., Lage, K., Tarantal, A. F., Chan, Y. A., & Deverman, B. E. (2024). Systematic multi-trait AAV capsid engineering for efficient gene delivery. Nature Communications, 15(1), 1-14. https://www.nature.com/articles/s41467-024-50555-y (open-access)

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Tracking how psychedelics affect neurons

Researchers at the University of California, Davis have developed a rapid, noninvasive tool to track the neurons and biomolecules activated in the brain by psychedelic drugs.

The protein-based tool, called Ca2+-activated Split-TurboID, or CaST, is described in research published in Nature Methods. 

The new tool could help scientists unlock the benefits of psychedelic treatments for patients with brain disorders. 

There has been mounting interest in the value of psychedelic-inspired compounds as treatments for brain disorders, including depression, post-traumatic stress and substance use. Psychedelic compounds like LSD, DMT and psilocybin promote the growth and strengthening of neurons and their connections in the brain’s prefrontal cortex.

“It’s important to think about the cellular mechanisms that these psychedelics act upon,” said Christina Kim, an assistant professor of neurology at the UC Davis Center for Neuroscience and School of Medicine, and an affiliate of the UC Davis Institute for Psychedelics and Neurotherapeutics, in a statement.

The new technique could be used to track step-by-step the molecular signaling processes that are responsible for these compounds’ beneficial neuroplastic effects, taking 10 to 30 minutes, rather than the hours typical of other tagging methods.   

“We designed these proteins in the lab that can be packaged into DNA and then put into harmless adeno-associated viruses,” Kim said. “Once we deliver the CaST tool and these proteins into neurons, they incubate inside the cells and start expressing.”

A snapshot of the brain

The CaST tool measures changes in intracellular calcium concentrations, a nearly universal marker to track activity in a neuron. When neurons exhibit high activity, they exhibit high calcium levels. CaST uses this cue to tag the cell with a small biomolecule called biotin.

In the study, Kim and her colleagues dosed mice with the psychedelic psilocybin. They then used CaST in tandem with biotin to identify neurons with increased calcium in the prefrontal cortex (an area affected by many brain disorders and where psychedelics promote neuronal growth and strengthening).

The researchers also monitor the mouse head-twitch responses of a freely behaving animal. These are the primary behavioral correlates for hallucinations caused by psychedelics.

Next steps

Kim and her colleagues are now working on methods to enable brain-wide cellular labeling with the CaST tool and ways to enrich the signature of individual proteins produced by neurons affected by psychedelics. 

“We can send those samples to the UC Davis Proteomics Core Facility and they can give us an unbiased picture of all the proteins we identified,” Kim said.

The goal is to identify how psychedelics benefit the cellular profiles of those with brain disorders, elucidating the step-by-step cellular process of their therapeutic effects. 

The work was supported by grants from the Brain and Behavior Research Foundation, Kinship Foundation, Arnold and Mabel Beckman Foundation, NIH, NSF and the Boone Family Foundation. 

Citation: Zhang, R., Anguiano, M., Aarrestad, I. K., Lin, S., Chandra, J., Vadde, S. S., Olson, D. E., & Kim, C. K. (2024). Rapid, biochemical tagging of cellular activity history in vivo. Nature Methods, 1-11. https://doi.org/10.1038/s41592-024-02375-7 (open access)

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Sustainable AI for healthcare

High-speed development of AI has made its way into healthcare—particularly in the radiology field.

AI-based diagnostic systems are flourishing, with hospitals quickly adopting the technology to assist radiologists with AI-based diagnostic systems, for example. However, there are concerns about the environmental impact of increasingly complex AI models.

Energy consumption of medical AI systems

So Associate Professor Daiju Ueda of Osaka Metropolitan University’s Graduate School of Medicine led a research team to investigate energy consumption of AI systems in the medical field, carbon emissions of data centers, and electronic waste issues. The goal: developing energy-efficient AI models, implementing green computing and the use of renewable energy.

In the study, the researchers proposed specific guidelines for the sustainable deployment of AI in the medical field in an environmentally responsible manner.

“The challenge for the future will be to verify and further elaborate these recommendations in actual medical practice,” said Ueda in a statement. “They are also expected to contribute to the standardization of methods for assessing AI’s environmental impact and the development of an international regulatory framework.”

The results were published in Diagnostic and Interventional Imaging.

Citation: Ueda, D., Walston, S. L., Fujita, S., Fushimi, Y., Tsuboyama, T., Kamagata, K., Yamada, A., Yanagawa, M., Ito, R., Fujima, N., Kawamura, M., Nakaura, T., Matsui, Y., Tatsugami, F., Fujioka, T., Nozaki, T., Hirata, K., & Naganawa, S. (2024). Climate change and artificial intelligence in healthcare: Review and recommendations towards a sustainable future. Diagnostic and Interventional Imaging. https://doi.org/10.1016/j.diii.2024.06.002 (open access)

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Mapping the body’s internal sensory communication highway

Running from the brain to the large intestine, the vagus nerve is the body’s longest cranial nerve, encoding sensory information from the visceral organs. It plays a key role in respiratory, gastrointestinal, cardiovascular, endocrine and immune system functions.

Interoception—the body’s ability to sense its internal state in a timely and precise manner—is facilitated by the vagus sensory neurons, which independently code the three critical features of a body signal: the involved visceral organ, the tissue layer where the signal originates, and the type of sensory modality.

This was just discovered by Qiancheng Zhao, assistant professor in medicine-endocrinology and McNair Scholar at Baylor University School of Medicine, and Department of Medicine-Endocrinology, Baylor College of Medicine, and Department of Neuroscience, School of Medicine, Yale University.

Clinical applications

Zhao said his findings could provide potential new vagal targets, so future researchers might use this genetic information to help them access different visceral organs precisely.

The more detailed map also could help clarify the vagus nerve’s role in interception (the body’s ability to sense its internal state in a timely and precise manner) and find whether there might be neural modulatory applications for treating interoceptive disorders in respiratory, gastrointestinal, cardiovascular, endocrine and immune system functions.

Encoding sensory information

However, it has not been clear how the body’s longest cranial nerve, running from the brain to the large intestine, encodes sensory information from the visceral organs.

Applying a variety of techniques, Zhao discovered that vagal sensory neurons independently code the three critical features of a body signal: the involved visceral organ; the tissue layer where the signal originates; and the type of sensory modality.

Decoding vagal sensory nerve traffic

The vagal highway is crowded with traffic, with sensory and motor pathways intermingling in the nerve bundle. One of the potential challenges of expanding vagal nerve stimulation (VNS) is finding ways to identify and target specific vagal signals, instead of broadly stimulating the nerve—potentially creating unwanted side effects.

“We know that vagal sensory neurons can project to the visceral organs,” said Zhao. “So our question was: what signals from those visceral organs need to be sensed by vagal sensory neurons?”

To decipher the complexity of VNS traffic, Zhao and his colleagues focused on three aspects: the visceral organ sending the signal, the tissue layer in the organ where the signal originates and the kind of sensory stimulus.

To identify organ-projecting neurons, they have combined a viral tracing approach with single-cell RNA sequencing The analysis revealed that vagal sensory neurons use different gene modules to code specific visceral organs. They also traced neuronal projections in transparent, whole-mounted mouse organs to determine how vagal sensory neurons innervate the layers of specific tissues.

Zhao and his colleague Chuyue Yu at Yale University also developed an in vivo calcium imaging technique. It allowed them to identify the molecular features of vagal sensory neurons responding to different types of stimuli, such as mechanical inflation in the lung and chemical stimuli of nutrients from a protein shake in the mouse GI tract.

“When we have the anatomical map together with the molecular information and the inputs from functional imaging, then we can really have a full picture to understand the sensory logic,” Zhao said.

Clinical applications

Zhao’s research could inform future therapies that stimulate the vagus nerve to treat a variety of physical and psychiatric disorders, using VNS through an implantable electrical pulse generator (which has been approved by the U.S. Food and Drug Administration to treat drug-resistant epilepsy and depression).

Zhao said his findings could provide potential new vagal targets, so future researchers might use this genetic information to help them access different visceral organs precisely. The more detailed map also could help clarify the vagus nerve’s role in interoception and whether there might be neural modulatory applications for treating interoceptive disorders.

Aging

Zhao is also interested in discovering more about how vagal sensory neurons might behave differently across the lifespan and under different disease conditions. “We know that our physiological parameters, such as heart rate and blood pressure will change during aging so we might want to look, for example, at how the aging state changes the interaction between the sensory nerve and different organs.”

For his work investigating and mapping this internal information highway, Zhao is the 2024 grand prize winner of the Science & PINS Prize for Neuromodulation.

Citation: Zhao, Q. (2024). Navigating internal senses: A road map for the vagal interoceptive system. Science. https://www.science.org/doi/10.1126/science.adq8578 (open access)

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Smithsonian scientists devise method to secure Earth’s biodiversity on the moon

New research led by scientists at the Smithsonian proposes a plan to safeguard Earth’s imperiled biodiversity by cryogenically preserving biological material on the moon.

The moon’s permanently shadowed craters are cold enough for cryogenic preservation without the need for electricity or liquid nitrogen, according to the researchers. 

The paper, published today in BioScience and written in collaboration with researchers from the Smithsonian’s National Zoo and Conservation Biology Institute (NZCBI), Smithsonian’s National Museum of Natural History, Smithsonian’s National Air and Space Museum and others, outlines a roadmap to create a lunar biorepository.

The paper includes ideas for governance, the types of biological material to be stored and a plan for experiments to understand and address challenges such as radiation and microgravity. The study also demonstrates the successful cryopreservation of skin samples from a fish, which are now stored at the National Museum of Natural History. 

“Initially, a lunar biorepository would target the most at-risk species on Earth today, but our ultimate goal would be to cryopreserve most species on Earth,” said Mary Hagedorn, a research cryobiologist at NZCBI and lead author of the paper in a statement,

Global Seed Vault model

The proposal was inspired by the Global Seed Vault in Svalbard, Norway, which contains more than 1 million frozen seed varieties 400 feet underground and functions as a backup for the world’s crop biodiversity in case of global disaster. However, in 2017, thawing permafrost threatened the collection with a flood of meltwater. The seed vault has since been waterproofed, but the incident showed that even an Arctic subterranean bunker could be vulnerable to climate change. 

Cryopreservation storage temperatures

Unlike seeds, animal cells require much lower storage temperatures for preservation (-320 degrees Fahrenheit or -196 degrees Celsius). On Earth, cryopreservation of animal cells requires a supply of liquid nitrogen, electricity and human staff potentially vulnerable to disruptions that could destroy an entire collection, Hagedorn said.

To reduce these vulnerabilities, scientists needed a way to passively maintain cryopreservation storage temperatures. Since such cold temperatures do not naturally exist on Earth, Hagedorn and her co-authors looked to the moon. 

Moon’s polar regions: ideal for cryopreservation storage

The moon’s polar regions feature numerous craters that never receive sunlight due to their orientation and depth. These “permanently shadowed regions” can be −410 degrees Fahrenheit (−246 degrees Celsius)—more than cold enough for passive cryopreservation storage. To block out the DNA-damaging radiation present in space, samples could be stored underground or inside a structure with thick walls made of moon rocks. 

Fibroblasts cryopreserved easily

At the Hawaiʻi Institute of Marine Biology, the research team cryopreserved skin samples from a reef fish called the starry goby. The fins contain a type of skin cell called fibroblasts, the primary material to be stored in the National Museum of Natural History’s biorepository.

The team says fibroblasts have several advantages over other types of commonly cryopreserved cells such as sperm, eggs and embryos. Science cannot yet reliably preserve the sperm, eggs and embryos of most wildlife species. However, for many species, fibroblasts can be cryopreserved easily. In addition, fibroblasts can be collected from an animal’s skin, which is simpler than harvesting eggs or sperm. For species that do not have skin per se, such as invertebrates, Hagedorn said the team may use a diversity of types of samples depending on the species, including larvae and other reproductive materials.   

The next steps are to begin a series of radiation exposure tests for the cryopreserved fibroblasts on Earth to help design packaging that could safely deliver samples to the moon. The team is actively seeking partners and support to conduct additional experiments on Earth and aboard the International Space Station. Such experiments would provide robust testing for the prototype packaging’s ability to withstand the radiation and microgravity associated with space travel and storage on the moon. 

“We aren’t saying what if the Earth fails—if the Earth is biologically destroyed this biorepository won’t matter,” Hagedorn said. “This is meant to help offset natural disasters and, potentially, to augment space travel. Life is precious and, as far as we know, rare in the universe. This biorepository provides another, parallel approach to conserving Earth’s precious biodiversity.”    

Citation: Mary Hagedorn, Smithsonian National Zoological Park Library, Lynne Parenti, Smithsonian National Museum of Natural History, Robert A. Craddock, Smithsonian Institution, Pierre Comizzoli, Smithsonian National Zoological Park Library, Paula Mabee, National Ecological Observatory Network, Bonnie Meinke, University Corporation for Atmospheric Research, Susan M. Wolf, University of Minnesota, John Bischof, University of Minnesota. Rebecca Sandlin, Harvard Medical School, Shannon N. Tessier, Harvard Medical School, Mehmet Toner, Harvard-MIT Division of Health Sciences and Technology. Safeguarding Earth’s Biodiversity By Creating a Lunar Biorepository. BioScience, Oxford University Press. DOI: 10.1093/biosci/biae058

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Wearable blood pressure monitor uses ultrasound to capture a continuous record of blood pressure

Continuous, noninvasive blood pressure monitoring has been a longtime goal of medicine because of blood pressure’s utility as a metric for clinicians.

However, options have been limited to internally placed arterial catheters or inflatable pressure cuffs, requiring frequent calibration with an inflatable cuff.

Ultrasound-based measurement

Raymond Jimenez and colleagues propose a new method based on “resonance sonomanometry,” in which the artery is stimulated by an acoustic transducer (similar to a medical ultrasound scanner) and the resonant response and dimensions are measured using ultrasound.

Similar to how a guitar string changes pitch as its tension is manipulated, changing circumferential tension (by blood pulses) of the arterial wall changes its resonant frequency through the continuous phases of the cardiac cycle.

The method was tested on humans on the carotid artery in the neck and the axillary, brachial, and femoral arteries. Measurements were compared with those from a blood pressure cuff.

Not limited to an arm

All four sites produced measurements in a single subject that were broadly in line with those obtained from a cuff. Additional testing on the carotid arteries of six volunteers showed promising results, albeit with lower systolic values (predictable, given the carotid being closer to the heart than the brachial artery measured by the cuff).

According to the authors, their proposed device could be worn over any ultrasound-accessible artery, even including the radial (back of arm near hand), where the device could be worn like a watch.

Citation: Jimenez, R., Yurk, D., Dell, S., Rutledge, A. C., Fu, M. K., Dempsey, W. P., Rajagopal, A., & Brinley Rajagopal, A. (2024). Resonance sonomanometry for noninvasive, continuous monitoring of blood pressure. PNAS Nexus, 3(7). https://academic.oup.com/pnasnexus/article/3/7/pgae252/7717708 (open access)

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How to make AI more energy-efficient

The International Energy Agency (IEA) issued a global energy use forecast in March 2024 warning that global energy consumption for AI is likely to double from 460 terawatt-hours (TWh) in 2022 to 1,000 TWh in 2026—roughly equivalent to the electricity consumption of the entire country of Japan. 

The reason: machine or AI processes transfer data between logic (where information is processed within a system) and memory (where the data is stored)—consuming a large amount of power and energy in the process. 

Significant energy savings

So engineering researchers at the University of Minnesota Twin Cities have developed a state-of-the-art hardware device in which data never leaves computational random-access memory (CRAM). Compared to traditional methods, the new CRAM-based machine-learning inference accelerator can achieve 1,700 to 2,500 times energy savings, the researchers estimate.

The research is published in npj Unconventional Computing, a peer-reviewed scientific journal published by Nature. The work was supported by grants from the U.S. Defense Advanced Research Projects Agency (DARPA), the National Institute of Standards and Technology (NIST), the National Science Foundation (NSF) and Cisco Inc.

Citation: Lv, Y., Zink, B. R., Bloom, R. P., Cılasun, H., Khanal, P., Resch, S., Chowdhury, Z., Habiboglu, A., Wang, W., Sapatnekar, S. S., Karpuzcu, U., & Wang, J. (2024). Experimental demonstration of magnetic tunnel junction-based computational random-access memory. Npj Unconventional Computing, 1(1), 1-10. https://doi.org/10.1038/s44335-024-00003-3 (open access)

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Scientists build powerful energy-storage systems from carbon nanotubes

An international team of scientists has found that twisted carbon nanotubes can store high densities of energy to power sensors and other technologies.

The researchers suggest that this finding could advance carbon nanotubes as a promising solution for storing energy in devices that need to be lightweight, compact, and safe; and could also work in a wide range of futuristic technologies, such as space elevators.

Single-walled carbon nanotubes

The researchers at the University of Maryland Baltimore County studied single-walled carbon nanotubes. These are like straws, made from pure carbon sheets that are only one-atom thick. They are lightweight, relatively easy to manufacture and about 100 times stronger than steel, as recently described in an open-access Nature Nanotechnology paper.

To investigate carbon nanotubes’ potential for storing energy, the UMBC researchers and colleagues manufactured carbon nanotube “ropes” from bundles of commercially available nanotubes. After pulling and twisting the tubes into a single thread, they coated the ropes with substances that increased the ropes’ strength and flexibility. 

Higher and safer energy storage

By twisting them up and measuring the energy that was released as the ropes unwound, they found that the ropes could store 15,000 times more energy per unit mass than steel springs and about three times more energy than lithium-ion batteries.

They also note that materials in the carbon nanotube ropes are safer for the human body than those used in batteries. This stored energy also remains consistent and accessible at temperatures ranging from -60 to +100 °C (-76 to +212 °F). 

The team is currently working to incorporate twisted carbon nanotubes as an energy source for a prototype sensor they are developing.

Citation: Utsumi, S., Ujjain, S. K., Takahashi, S., Shimodomae, R., Yamaura, T., Okuda, R., Kobayashi, R., Takahashi, O., Miyazono, S., Kato, N., Aburamoto, K., Hosoi, Y., Ahuja, P., Furuse, A., Kawamata, Y., Otsuka, H., Fujisawa, K., Hayashi, T., Tománek, D., . . . Kaneko, K. (2024). Giant nanomechanical energy storage capacity in twisted single-walled carbon nanotube ropes. Nature Nanotechnology, 1-9. 10.1038/s41565-024-01645-x (open access)

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Cool invention for hot AI data centers

Artificial intelligence (AI) is hot right now. Also hot: the data centers that power that technology, which require a tremendous amount of energy.

In 2022, data centers used more than 4% of all electricity in the U.S., with 40% of that energy spent to keep equipment cool. As demand on data centers increases, even more energy will be required.

To mitigate that, the U.S. Department of Energy has awarded more than $40 million to researchers to find new ways to cool data centers. University of Missouri researcher Chanwoo Park recently received nearly $1.65 million from that initiative, known as COOLERCHIPS.

Two-phase cooling system designed to efficiently dissipate heat

Currently, data centers are cooled with either air-moving fans or liquid that moves heat away from computer racks. But Park and his team are developing a new two-phase cooling system designed to efficiently dissipate heat from server chips through phase change, such as boiling a liquid into vapor in a thin, porous layer. The new system can operate passively without consuming any energy when less cooling is needed.

“Even in active mode, where a pump is used, it consumes only a negligible amount of energy. The liquid goes in different directions and evaporates on a thin metal surface,” Park said in a statement. “Using this boiling surface, we’re able to achieve very efficient heat transfer with low thermal resistance.”

“Drastically reduce” cooling energy needed

The system also includes a mechanical pump that is activated to absorb more heat only when needed. Early tests show that two-phase cooling techniques “drastically reduce” the amount of energy needed to keep equipment cool.

“Eventually, there will be limitations under current cooling systems, and that’s a problem,” Park said. “We’re trying to get ahead of the curve and have something ready and available for the future of AI computing.”

Citation: R. Kokate and C. Park (2024). Experimental analysis of subcooled flow boiling in a microchannel evaporator of a pumped two-phase loop. Applied Thermal Engineering, 249, 123154. https://www.sciencedirect.com/science/article/abs/pii/S1359431124008226?via%3Dihub (open-access)

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AI and satellite predict a wildfire’s next move

Researchers at USC have developed a new model that combines generative AI and satellite data to accurately forecast wildfire spread—a potential breakthrough in wildfire management and emergency response.

The model uses satellite data to track a wildfire’s real-time progression, then feeds this information into a sophisticated computer algorithm that can accurately forecast the fire’s likely path, intensity and growth rate.

Detailed in an early study proof published in Artificial Intelligence for the Earth Systems, the study comes as California and much of the western US continue to grapple with an increasingly severe wildfire season.

Training generative AI model

The researchers began by gathering historical wildfire data from high-resolution satellite images of past wildfires, tracking how each fire started, spread and was eventually contained. Their comprehensive analysis revealed patterns influenced by different factors like weather, fuel (for example, trees, brush, etc.) and terrain.

They then trained a generative AI-powered computer model known as a conditional Wasserstein Generative Adversarial Network, or cWGAN, to simulate how these factors influence how wildfires evolve over time. They taught the model to recognize patterns in the satellite images that match up with how wildfires spread in their model.

Anticipating future fire spread

They then tested the cWGAN model on real wildfires that occurred in California between 2020 and 2022 to see how well it predicted where the fire would spread.

“By studying how past fires behaved, we can create a model that anticipates how future fires might spread,” said Assad Oberai, Hughes Professor and Professor of Aerospace and Mechanical Engineering at USC Viterbi and co-author of the study, in a statement.

“Fuel-like grass, shrubs or trees ignites, leading to complex chemical reactions that generate heat and wind currents. Factors such as topography and weather also influence fire behavior. Fires don’t spread much in moist conditions but can move rapidly in dry conditions,” he said. “These are highly complex, chaotic and nonlinear processes. To model them accurately, you need to account for all these different factors. You need advanced computing.”

The research was funded by the Army Research Office, NASA and the Viterbi CURVE program.

Citation: Bryan Shaddy et al., 23 Apr 2024, Generative Algorithms for Fusion of Physics-Based Wildfire Spread Models with Satellite Data for Initializing Wildfire Forecasts, Artificial Intelligence for the Earth Systems, https://journals.ametsoc.org/view/journals/aies/aop/AIES-D-23-0087.1/AIES-D-23-0087.1.xml (open access)

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