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Cells that normally nourish healthy brain cells called neurons release toxic fatty acids after neurons are damaged, a new study in rodents shows. This phenomenon is likely the driving factor behind most, if not all, diseases that affect brain function, as well as the natural breakdown of brain cells seen in aging, researchers say.
Previous research has pointed to astrocytes — a star-shaped glial cell of the central nervous system — as the culprits behind cell death seen in Parkinson’s disease and dementia, among other neurodegenerative diseases. While many experts believed that these cells released a neuron-killing molecule to “clear away” damaged brain cells, the identity of this toxin has until now remained a mystery.
Led by researchers at NYU Grossman School of Medicine, the new investigation provides what they say is the first evidence that tissue damage prompts astrocytes to produce two kinds of fats, long-chain saturated free fatty acids and phosphatidylcholines. These fats then trigger cell death in damaged neurons, the electrically active cells that send messages throughout nerve tissue.
Publishing Oct. 6 in the journal Nature, the study also showed that when researchers blocked fatty acid formation in mice, 75 percent of neurons survived compared with 10 percent when the fatty acids were allowed to form. The researchers’ earlier work showed that brain cells continued to function when shielded from astrocyte attacks.
“Our findings show that the toxic fatty acids produced by astrocytes play a critical role in brain cell death and provide a promising new target for treating, and perhaps even preventing, many neurodegenerative diseases,” says study co-senior author Shane Liddelow, PhD.
Liddelow, an assistant professor in the Department of Neuroscience and Physiology at NYU Langone Health, adds that targeting these fats instead of the cells that produce them may be a safer approach to treating neurodegenerative diseases because astrocytes feed nerve cells and clear away their waste. Stopping them from working altogether could interfere with healthy brain function.
Although it remains unclear why astrocytes produce these toxins, it is possible they evolved to destroy damaged cells before they can harm their neighbors, says Liddelow. He notes that while healthy cells are not harmed by the toxins, neurons become susceptible to the damaging effects when they are injured, mutated, or infected by prions, the contagious, misfolded proteins that play a major role in mad cow disease and similar illnesses. Perhaps in chronic diseases like dementia, this otherwise helpful process goes off track and becomes a problem, the study authors say.
For the investigation, researchers analyzed the molecules released by astrocytes collected from rodents. They also genetically engineered some groups of mice to prevent the normal production of the toxic fats and looked to see whether neuron death occurred after an acute injury.
“Our results provide what is likely the most detailed molecular map to date of how tissue damage leads to brain cell death, enabling researchers to better understand why neurons die in all kinds of diseases,” says Liddelow, also an assistant professor in the Department of Ophthalmology at NYU Langone.
Liddelow cautions that while the findings are promising, the genetic techniques used to block the enzyme that produces toxic fatty acids in mice are not ready for use in humans. As a result, the researchers next plan is to explore safe and effective ways to interfere with the release of the toxins in human patients. Liddelow and his colleagues had previously shown these neurotoxic astrocytes in the brains of patients with Parkinson’s, Huntington’s disease, and multiple sclerosis, among other diseases.
Funding for the study was provided by National Institutes of Health grants P30 CA124435, S10 RR027425, UL1 TR002529, and P30 CA023168. Further funding support was provided by the Cure Alzheimer’s Fund, The Blas Frangione Foundation, the U.S. Department of Defense, the Purdue Integrative Data Science Institute award, the Stark Neurosciences Research Institute, the Indiana Alzheimer Disease Center, and Eli Lilly. Liddelow maintains a financial interest in AstronauTx Ltd, a company targeting astrocytes as a possible treatment target for Alzheimer’s disease. The terms and conditions are being managed in accordance with the policies of NYU Langone.
In addition to Liddelow, other NYU Langone investigators involved in the study included Philip Hasel, PhD, and Uriel Rufen-Blanchette. Other study authors were first author Kevin Guttenplan, PhD; Maya Weigel, BA; Aaron Gilter, PhD; and co-senior author Ben Barres, MD, PhD; at Stanford University in Palo Alto, Calif.; Priya Prakash, PhD; Prageeth Wijewardhane; Jonathan Fine, PhD; and Guarav Chopra, PhD, at Purdue University in West Lafayette, Ind.; and Mikaela Neal, BS, and Kimberley Bruce, PhD, at the University of Colorado in Aurora.

Open any introductory biology textbook, and you’ll see a familiar diagram: A blobby-looking cell filled with brightly colored structures — the inner machinery that makes the cell tick.
Cell biologists have known the basic functions of most of these structures, called organelles, for decades. The bean-shaped mitochondria make energy, for example, and lanky microtubules help cargo zip around the cell. But for all that scientists have learned about these miniature ecosystems, much remains unknown about how their parts all work together.
Now, high-powered microscopy — plus a heavy dose of machine learning — is helping to change that. New computer algorithms can automatically identify some 30 different kinds of organelles and other structures in super high-resolution images of entire cells, a team of scientists at the Howard Hughes Medical Institute’s Janelia Research Campus reports October 6, 2021 in the journal Nature.
The detail in these images would be nearly impossible to parse by hand throughout the entire cell, says Aubrey Weigel, who led the Janelia Project Team, called COSEM (for Cell Organelle Segmentation in Electron Microscopy). The data for just one cell is made up of tens of thousands of images; tracing all a cell’s organelles through that collection of pictures would take one person more than 60 years. But the new algorithms make it possible to map an entire cell in hours, rather than years.
“By using machine learning to process the data, we felt we could revisit the canonical view of a cell,” Weigel says.
In addition to two companion articles in Nature, Janelia scientists also released a data portal, OpenOrganelle, where anyone can access the datasets and tools they’ve created.

In order to fulfill their many tasks, cells need energy. In the cell’s power plants, known as mitochondria, the energy contained in our food is converted into the molecule ATP. It serves as a kind of fuel that drives most cellular processes — from muscle contraction to the assembly of our DNA. Professor Leonid Sazanov and Irene Vercellino are now the first scientists to precisely show what a protein assembly essential for this process looks like in mammalian cells.
Like a fishhook
Using cryo-electron microscopy, a technique that allows researchers to look at extremely small samples in their natural state, first author Irene Vercellino and Prof. Sazanov show the exact structure of the so-called supercomplex CIII2CIV. This assembly of protein building blocks pumps charged particles, protons, through the mitochondrial membrane, which is needed to start the energy conversion process in the cells. It therefore fulfills a similar task as the starter battery of cars. Up to now, this supercomplex has only been described in plant and yeast cells where it takes on a very different form, as the researchers now discovered. In order to understand how exactly energy production works in animal cells like our own, the scientists now took a close look at mice and sheep cells and were surprised.
“Nobody could have predicted the way SCAF1 acts,” says Sazanov. Previous studies already showed that the molecule SCAF1 plays a role in assembling the two protein complexes that together form supercomplex CIII2CIV. Instead of interacting with the two protein complexes on the surface only, the molecule goes deep inside complex III while being attached to complex IV. “It is like a hook swallowed by a fish. Once it’s swallowed it can’t get out,” the structural biologist explains.
Close, but not too close
Furthermore, the scientists show that supercomplex CIII2CIV takes on two different forms — a locked and an unlocked or mature one. “In its locked state some parts of complex III are still missing and the interaction between the two complexes is very intimate,” describes Sazanov. Once it is fully assembled, however, the two complexes are connected by SCAF1 without getting in each other’s way. “In order to fulfill its tasks, complex III probably prefers to be free from interference in its movements,” the Belarusian-British scientist assumes.
Being assembled into a supercomplex, on the other hand, speeds up their chemical reactions, which has great advantages for the animal. It has been shown, that mice and zebrafish missing the SCAF1 molecule are significantly smaller, less fit, and less fertile. In their recent study, Vercellino and Sazanov describe the molecule’s role in forming supercomplex CIII2CIV, which optimizes the cellular metabolism. It has been the final piece of the puzzle: together with their previous studies, Sazanov and his team now determined the structures of all supercomplexes in mammalian mitochondria. The team is thus laying the foundation for new treatments for mitochondrial disease.
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Researchers at the KU Leuven Rega Institute and CD3 have developed an ultrapotent inhibitor of the dengue virus, which causes the tropical disease known as dengue. The teams collaborated closely with Janssen Pharmaceutica, N.V. The antiviral molecule is exceptionally effective against all known dengue variants and could be used for therapeutic and prevention purposes. The teams have published their findings in Nature.
Each year, dengue infects up to 400 million people, sickens up to 100 million, and kills thousands. Symptoms of the disease include a high fever and severe muscle and joint pain. Some patients also suffer from subcutaneous bleeding or capillary leakage.
The disease is caused by the mosquito-borne dengue virus, which is found in nearly all (sub)tropical regions, but especially in Latin America and Asia. The frequency of outbreaks continues to grow, and the virus is expected to impact billions more in the coming decades as the virus spreads to other regions due to climate change and other global trends. In 2019, the World Health Organization already included dengue in its list of ten threats to global health.
No antiviral drugs are currently available to prevent or treat dengue. This may change thanks to the breakthrough discovery of teams led by Johan Neyts (Rega Institute at KU Leuven) and Patrick Chaltin (CD3/CISTIM Leuven vzw), which was carried forward in partnership with a team led by Marnix van Loock (Janssen Pharmaceutica, N.V.).
Blocking the ‘copier’ of the virus
The antiviral has a unique mechanism, explains Professor Johan Neyts of the Rega Institute at KU Leuven. “Together with the research group of Professor Ralf Bartenschlager from Heidelberg University, we demonstrated that our inhibitor prevents the interaction between two viral proteins that are part of a kind of copier for the genetic material of the virus. If this interaction is blocked, the virus can no longer copy its genetic material. As a result, no new virus particles are produced.”
Together with Professor Xavier de Lamballerie (Aix-Marseille University), the team proved that the antiviral is very effective against all known variants of the dengue virus.

A UCLA study using mice reveals new insights into the wiring of a major circuit in the brain that is attacked by Parkinson’s and Huntington’s disease. The findings could hone scientists’ understanding of how these disorders arise in the human brain and pinpoint new therapeutic targets.
Published today in Nature, the research is part of a special package of 17 articles written by a consortium of neuroscientists nationwide. The work was conducted under the auspices of the BRAIN Initiative Cell Census Network (BICCN) as part of a massive effort to compile a complete atlas of cells in the brain.
The ambitious project aims to unlock the mysteries of the primary motor cortex, a part of the mammalian brain that controls movement.
With funding from the National Institute of Mental Health and the National Institutes of Health’s BRAIN Initiative, the UCLA team meticulously investigated how the mouse brain is wired. Their research analyzed 600 pathways and catalogued nerve-cell connectivity to create a wiring diagram of critical brain circuits.
“Like any explorer traveling deep into uncharted territory, we make maps to guide future visitors,” said Dr. Hong-Wei Dong, the study’s lead author and a professor of neurobiology at the David Geffen School of Medicine at UCLA. “My lab mapped out the circuitry of the mouse brain to enable other scientists to conduct more accurate experiments in mouse models of diseases like Parkinson’s or Huntington’s disease.”
Dong and his colleagues labeled a small number of individual neurons with a green dye, enabling the team to track their connections with other neurons through arm-like projections called axons and dendrites. These connections, called circuits, process and communicate distinct types of sensory information in the brain.

When you clicked to read this story, a band of cells across the top of your brain sent signals down your spine and out to your hand to tell the muscles in your index finger to press down with just the right amount of pressure to activate your mouse or track pad.
A slew of new studies now shows that the area of the brain responsible for initiating this action — the primary motor cortex, which controls movement — has as many as 116 different types of cells that work together to make this happen.
The 17 studies, appearing online Oct. 6 in the journal Nature, are the result of five years of work by a huge consortium of researchers supported by the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative to identify the myriad of different cell types in one portion of the brain. It is the first step in a long-term project to generate an atlas of the entire brain to help understand how the neural networks in our head control our body and mind and how they are disrupted in cases of mental and physical problems.
“If you think of the brain as an extremely complex machine, how could we understand it without first breaking it down and knowing the parts?” asked cellular neuroscientist Helen Bateup, a University of California, Berkeley, associate professor of molecular and cell biology and co-author of the flagship paper that synthesizes the results of the other papers. “The first page of any manual of how the brain works should read: Here are all the cellular components, this is how many of them there are, here is where they are located and who they connect to.”
Individual researchers have previously identified dozens of cell types based on their shape, size, electrical properties and which genes are expressed in them. The new studies identify about five times more cell types, though many are subtypes of well-known cell types. For example, cells that release specific neurotransmitters, like gamma-aminobutyric acid (GABA) or glutamate, each have more than a dozen subtypes distinguishable from one another by their gene expression and electrical firing patterns.
While the current papers address only the motor cortex, the BRAIN Initiative Cell Census Network (BICCN) — created in 2017 — endeavors to map all the different cell types throughout the brain, which consists of more than 160 billion individual cells, both neurons and support cells called glia. The BRAIN Initiative was launched in 2013 by then-President Barack Obama.

It takes billions of cells to make a human brain, and scientists have long struggled to map this complex network of neurons. Now, dozens of research teams around the country, led in part by Salk scientists, have made inroads into creating an atlas of the mouse brain as a first step toward a human brain atlas.
The researchers, collaborating as part of the National Institute of Health’s BRAIN Initiative Cell Census Network (BICCN), report the new data today in a special issue of the journal Nature. The results describe how different cell types are organized and connected throughout the mouse brain.
“Our first goal is to use the mouse brain as a model to really understand the diversity of cells in the brain and how they’re regulated,” says Salk Professor and Howard Hughes Medical Institute Investigator Joseph Ecker, co-director of the BICCN. “Once we’ve established tools to do this, we can move to working on primate and human brains.”
The NIH Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative is “a large-scale effort that seeks to deepen understanding of the inner workings of the human mind and to improve how we treat, prevent and cure disorders of the brain.” Since its initial funding in 2014, the BRAIN Initiative has awarded more than $1.8 billion in research awards.
The BICCN, one subset of the BRAIN Initiative, specifically focuses on creating brain atlases that describe the full plethora of cells — as characterized by many different techniques — in mammalian brains. Salk is one of three institutions that were given U19 awards to act as central players in generating data for the BICCN.
“This is not just a phone book for the brain,” says Margarita Behrens, a Salk associate research professor who helped lead the new BICCN papers. “In the long run, to treat brain diseases, we need to be able to hone in on exactly which cell types are having trouble.”
The special issue of Nature has 17 total BICCN articles, including five co-authored by Salk researchers that describe approaches to studying brain cells and new characterizations of subtypes of brain cells in mice. Some highlights include: DNA Methylation Analysis

The circuits of the human brain contain more than 100 billion neurons, each linked to many other neurons via thousands of synaptic connections, resulting in a three-pound organ that is profoundly more complex than the sum of its innumerable parts.
In recent years, however, transformative advances in imaging, sequencing and computational technologies have opened the possibility of mapping a human brain truly at the resolution of its molecular and cellular components. While that ultimate goal remains to be achieved, researchers have steadily progressed with a smaller, but no less momentous, effort: an atlas of the mouse brain.
In a special issue of Nature, publishing online October 7, 2021, researchers at the University of California San Diego, with colleagues across the country, describe their progress in collection of papers. Two of the papers, in which UC San Diego scientists served as senior authors, further refine the organization of cells within key regions of the mouse brain and, more critically, the organization of transcriptomic, epigenomic and regulatory factors and elements that provide these brain cells with function and purpose.
“To truly understand how the brain functions, and from that knowledge develop new drugs and therapies to improve human lives and health, we need to see and quantify brain structure, organization and function down to the level of single cells,” said Bing Ren, PhD, director of the Center for Epigenomics, professor of cellular and molecular medicine at UC San Diego School of Medicine and member of the Ludwig Institute for Cancer Research at UC San Diego.
“Depth and specificity are essential,” agreed Eran A. Mukamel, PhD, director of the Computational Neural DNA Dynamics Lab and associate professor in the Department of Cognitive Science at UC San Diego. “We want a comprehensive parts list for the brain, including not just the locations and connections of the neurons, but also the molecular and epigenetic fingerprints that give them their specialized identity.”
Gene regulatory elements
Since 2006, there has been a concerted, international effort to create a three-dimensional atlas of the mouse brain, which is roughly the size of a pea and comprised of approximately eight to 14 million neurons and glial cells. Though the mouse brain is not a miniature version of the human brain, it has proven to be a powerful model for studying many human brain functions, diseases and mental disorders, in part because the genes responsible for building and operating both human and rodent organs are 90 percent identical.

Researchers at the Centre for Genomic Regulation (CRG) and Pulmobiotics S.L have created the first ‘living medicine’ to treat antibiotic-resistant bacteria growing on the surfaces of medical implants. The researchers created the treatment by removing a common bacteria’s ability to cause disease and repurposing it to attack harmful microbes instead.
The experimental treatment was tested on infected catheters in vitro, ex vivo and in vivo, successfully treating infections across all three testing methods. According to the authors, injecting the therapy under the skin of mice treated infections in 82% of the treated animals.
The findings are an important first step for the development of new treatments for infections affecting medical implants such as catheters, pacemakers and prosthetic joints. These are highly resistant to antibiotics and account for 80% of all infections acquired in hospital settings.
The study is published today in the journal Molecular Systems Biology. This work has been supported by the “la Caixa” Foundation through the CaixaResearch Health call, the European Research Council (ERC), the MycoSynVac project under the EU’s Horizon 2020 research and innovation programme, the Generalitat de Catalunya and the Instituto de Salud Carlos III.
The new treatment specifically targets biofilms, colonies of bacterial cells that stick together on a surface. The surfaces of medical implants are ideal growing conditions for biofilms, where they form impenetrable structures that prevent antibiotics or the human immune system from destroying the bacteria embedded within. Biofilm-associated bacteria can be a thousand times more resistant to antibiotics than free-floating bacteria.
Staphylococcus aureus is one of the most common species of biofilm-associated bacteria. S. aureus infections do not respond to conventional antibiotics, requiring patients to surgically remove any infected medical implants. Alternative therapies include the use of antibodies or enzymes, but these are broad-spectrum treatments that are highly toxic for normal tissues and cells, causing undesired side effects.
The authors of the study hypothesised that introducing living organisms that directly produce enzymes in the local vicinity of biofilms is a safer and cheaper way of treating infections. Bacteria are an ideal vector, as they have small genomes that can be modified using simple genetic manipulation.
The researchers chose to engineer Mycoplasma pneumoniae, a common species of bacteria that lacks a cell wall, making it easier to release the therapeutic molecules that fight infection while also assisting it in evading detection from the human immune system. Other advantages of using M. pneumoniae as a vector include its low risk of mutating new abilities, and its inability to transfer any of its modified genes to other microbes living nearby.
M. pneumoniae was first modified so that it would not cause illness. Further tweaks made it produce two different enzymes that dissolve biofilms and attacks the cell walls of the bacteria embedded within. The researchers also modified the bacteria so that it secretes antimicrobial enzymes more efficiently.
The researchers first aim to use the modified bacteria to treat biofilms building around breathing tubes, as M. pneumoniae is naturally adapted to the lung. “Our technology, based on synthetic biology and live biotherapeutics, has been designed to meet all safety and efficacy standards for application in the lung, with respiratory diseases being one of the first targets. Our next challenge is to address high-scale production and manufacturing, and we expect to start clinical trials in 2023,” says María Lluch, co-corresponding author of the study and Chief Science Officer of Pulmobiotics.
The modified bacteria may also have long-term applications for other diseases. “Bacteria are ideal vehicles for ‘living medicine’ because they can carry any given therapeutic protein to treat the source of a disease. One of the great benefits of the technology is that once they reach their destination, bacterial vectors offer continuous and localised production of the therapeutic molecule. Like any vehicle, our bacteria can be modified with different payloads that target different diseases, with potentially more applications in the future,” says ICREA Research Professor Luis Serrano, Director of the CRG and co-author of the study.
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Exposure to air pollution and road traffic noise over the course of many years may be associated with an increased risk of developing heart failure, and the correlation appears to be even greater in people who are former smokers or have high blood pressure, according to new research published today in the Journal of the American Heart Association, an open access journal of the American Heart Association.
“We found that long-term exposure to specific air pollutants and road traffic noise increased the risk of incident heart failure, especially for former smokers or people with hypertension, so preventive and educational measures are necessary,” said Youn-Hee Lim, Ph.D., lead author of the study and assistant professor in the section of environmental health within the department of public health at the University of Copenhagen in Copenhagen, Denmark. “To minimize the impact of these exposures, broad public tactics such as emissions control measures should be implemented. Strategies like smoking cessation and blood pressure control must be encouraged to help reduce individual risk.”
This analysis examined the impact of long-term environmental exposure, specifically from air pollution and road traffic noise, on the development of heart failure in a group of female nurses in Denmark over a 15-to-20-year period.
Researchers collected data from a prospective study of over 22,000 members of the all-female Danish Nurse Cohort study. The women were 44 years of age and older at study enrollment and living in Denmark. Participants were recruited in 1993 or 1999, and when they enrolled, each woman completed a comprehensive questionnaire on body mass index, lifestyle factors (smoking, alcohol consumption, physical activity and dietary habits), pre-existing health conditions, reproductive health and working conditions. Information on heart failure diagnoses was gathered throughout the 20-year follow by linking study participants to the Danish National Patient Register, which includes records on all health care provided at hospitals in Denmark. Patient data was collected through December 31, 2014.
The study group lived in rural, urban and suburban areas throughout Denmark. To best measure individual exposure to air pollution and road traffic noise, researchers maintained records of each individual’s residential addresses, including any moves to new residences from 1970 and 2014. To determine levels of air pollution, the yearly average concentrations of two components, fine particulate matter (PM2.5) and nitrogen dioxide (NO2), were measured using a Danish air pollution modeling system. Road traffic noise levels within a three-kilometer radius from the participants’ residential addresses were estimated using a validated model system called Nord2000 and measured in decibels (dB), the standard unit for the intensity of sound.
The analysis of various pollutants and their effects on incident heart failure found: For every 5.1 µg/m3 increase in fine particulate matter exposure over three years, the risk of incident heart failure increased by 17%; For every 8.6 µg/m3 increase in NO2 exposure over three years, the risk of incident heart failure increased by 10%; For every 9.3 dB increase in road traffic noise exposure over three years, the risk of incident heart failure increased by 12%; and, Increased exposure to fine particulate matter and status as a former smoker were associated with a 72% increased risk of incident heart failure.”We were surprised by how two environmental factors — air pollution and road traffic noise — interacted,” Lim said. “Air pollution was a stronger contributor to heart failure incidence compared to road traffic noise; however, the women exposed to both high levels of air pollution and road traffic noise showed the highest increase in heart failure risk. In addition, about 12% of the total study participants had hypertension at enrollment of the study. However, 30% of the nurses with heart failure incidence had a previous history of hypertension, and they were the most susceptible population to air pollution exposure.”
The study has several limitations. Researchers did not have information on additional variables that may have affected the results of the analysis, such as measures for each individual’s exposure to indoor air pollution or occupational noise; the amount of time spent outdoors; glass thickness of the windows of their home, which may influence noise pollution levels; if they had a hearing impairment; or individual socioeconomic status. Additionally, almost one-fourth of the original participants in the Danish Nurse Cohort were excluded from the final analysis because information was missing at the beginning of the study or at the study’s completion, so selection bias may be a contributing factor. The researchers also note that since they investigated Danish female nurses’ exposure levels and health outcomes, a generalization of the results to men or other populations warrants caution.
Previous research has shown an association between air pollution and cardiovascular disease, and the American Heart Association detailed a collection of research on the risks of pollution in a scientific statement in 2004, with additional updated findings added in 2010. In 2020 the American Heart Association American Heart Association published a scientific statement and policy guidance to address the implications of air pollution amid the COVID-19 pandemic and beyond. The policy statement discusses policy guidance at the local, state and federal levels to improve the health of our communities. Short-term exposure to high levels of some air pollutants has also been linked to heart failure.
Co-authors are Jeanette Therming Jørgensen, M.Sc., Ph.D.; Rina So, Ph.D. student; Tom Cole-Hunter, Ph.D.; Amar Mehta, Sc.D.; Heresh Amini, Ph.D.; Elvira Bräuner, Ph.D.; Rudi Westendorp, M.D., Ph.D.; Shuo Liu, M.P.H.; Laust Mortensen, Ph.D.; Barbara Hoffmann; Steffen Loft, D.M.Sc.; Matthias Ketzel, Ph.D.; Ole Hertel, D.Sc.; Jørgen Brandt, Ph.D.; Steen Solvang Jensen, Ph.D.; Claus Backalarz; Mette K. Simonsen, M.Sc.; Nebojsa Tasic; Matija Maric; and Zorana J. Andersen, Ph.D. Authors’ disclosures are in the manuscript.
The study was funded by the Danish Council for Independent Research, the Region Zealand Fund and the Novo Nordisk Foundation Challenge Programme.