Thursday, August 26, 2021

FOSSILS

Analysis of fossil by Harvard researcher’s team sheds light on reptile evolution

New species of fossil reptile identified from 231 million years ago

Peer-Reviewed Publication

HARVARD UNIVERSITY

Taytalura alcoberi 

IMAGE: ILLUSTRATION OF TAYTALURA ALCOBERI view more 

CREDIT: JORGE BLANCO

It’s not uncommon for scientists to have to run experiments numerous times to see whether they have a big discovery on their hands. Every once in a while, though, a researcher makes a big find by more or less eyeballing it. That’s essentially what Tiago R. Simões did when he was shown pictures of a 231-million-year-old reptile skull.

“I knew right away because of its age, locality, and some of its anatomical aspects that it was extremely important,” said Simões, a researcher in the lab of Harvard paleontologist Stephanie Pierce. “I knew we needed to give this priority and get the CT scan data to see exactly what we have.”

His suspicion was right. Analysis of the scans showed the fossil belonged to a new species of a lizard-like reptile, representing the earliest evolving member of a lineage that today includes all lizards, snakes, and their closest relatives. That’s nearly 11,000 species altogether.

Unearthed in the moonlike desert landscape of Ischigualasto Provincial Park in northwest Argentina, the fossil is of a lepidosaur, one of the major evolutionary branches of reptiles. It is the first three-dimensionally intact skull of a primitive member of this lineage ever found, and its discovery can help researchers better understand the early evolutionary history of this vast group.

“We have very few fossils from 240 or 250 million years ago when this entire group is expected to have originated and the very few fossils that we have are extremely fragmented. You have only pieces of jaws and teeth here and there,” said Simões, who is a fellow at Harvard and funded by the National Sciences and Engineering Research Council of Canada. “The first thing that this provides is this missing piece of the puzzle, which is an amazingly well-preserved skull of a primitive member of this lineage that lived in Argentina.”

Results of his analysis were published Wednesday in the journal Nature and was a collaboration between Simões and scientists from Argentina and Germany.

Understanding the significance of this find requires a little background. There are two main branches of reptile: archosaurs and lepidosaurs. Archosaurs include all crocodile and dinosaur lineages while lepidosaurs include squamates (lizards, snakes) and sphenodontians, which have only one living species today, the tuatara of New Zealand.

The lepidosaur fossil was not just any lepidosaur, but the first member of this group that evolved away from the others. That puts it at the top of that lineage and provides key evidence as to how lizards first evolved from more primitive reptiles. That kind of respect is shown in the name the scientists chose for it, Taytalura alcoberi, meaning father of the lizards in the Quechua and Kakán languages of the native Andean people of Argentina.

Taytalura is the earliest evolving lepidosaur, but it is not the oldest lepidosaur fossil ever found. That honor belongs to a 242 million-year-old squamate and a 234 million-year-old sphenodontian. That suggests an older Taytalura fossil may one day be found.

Regardless, the age discrepancy shows that these very early lepidosaurs lived side-by-side with squamates and sphenodontians, known as “true” lepidosaurs, for at least 10 million years during the Triassic period, a fact that was previously unknown.

The researchers used micro-CT scans of the three dimensionally preserved head to analyze the fossil. It allowed them to compare this early lepidosaurian skull with later lepidosaur and other reptiles. The researchers, for instance, noticed the skull of the first lepidosaurs looked substantially more like those of sphenodontians than squamates and that squamates represent a major deviation from the older skull patterns. They also found Taytalura teeth differed from those in any living or extinct group of lepidosaurs.

Another surprising finding involved where the fossil was discovered. Till now, almost all fossils of Triassic lepidosaurs have been found in Europe. This is the first early lepidosaur found in South America. It suggests lepidosaurs were able to migrate across the planet (which then was all still one super continent) very early in their evolutionary history.

That type of mileage is impressive for such a small creature. While it’s impossible to accurately estimate the total body length of this lizard-like reptile, the one-inch head suggests it likely could fit in the palm of a human hand. The creature most likely fed on insects from desert environments that it shared with some of the oldest dinosaurs in the planet, said Simões. “[It] was most likely preyed upon by some of the first dinosaurs to walk on Earth,” he said.

The researchers hope to explore older rocks in Argentina or other parts of South America and find older members of this lineage. The hope is to get the exact time of when the entire group originated, which will be critical in understanding the long evolutionary history of reptiles to help those that exist today.

“Lepidosaurs survived across three out of the five big mass extinctions on earth’s history during the last 260 million years,” Simões said. “By accurately reconstructing the long evolutionary history of lepidosaurs, we may be able to tell in much greater detail how they successfully survived and flourished across major environmental shifts in Earth’s past and how they may be impacted by modern human-induced climate change.”

 

Young athletes with history of concussions may have more changes to their brains


Study Finds Changes in Brain Blood Flow and Microstructure


Peer-Reviewed Publication

AMERICAN ACADEMY OF NEUROLOGY

MINNEAPOLIS - A new study suggests athletes with a history of concussion may show more brain injury from a later concussion, particularly in middle regions of the brain that are more susceptible to damage, when compared to athletes with no history of concussion. The research is published in the August 25, 2021, online issue of Neurology®, the medical journal of the American Academy of Neurology. The athletes participated in sports like football, volleyball and soccer.

We know concussions may have long-term effects on the brain that last beyond getting a doctor’s clearance to return to play,” said study author Tom A. Schweizer, PhD, of St. Michael’s Hospital in Toronto, Canada. “It is unclear, however, to what extent the effects of repeated concussion can be detected among young, otherwise healthy adults. We found even though there was no difference in symptoms or the amount of recovery time, athletes with a history of concussion showed subtle and chronic changes in their brains.”

This study focused on changes within two areas in the middle of the brain that are especially vulnerable to concussion. Researchers focused on blood flow in the cingulate cortex and white matter microstructure in the corpus callosum. Changes in blood flow and microstructure that show up on brain scans can indicate underlying brain injury. The cingulate cortex is a layer of gray matter that coordinates sensory and motor skills. Below it is the corpus callosum, a broad band of nerve fibers linking the two hemispheres of the brain.

The study looked at 228 athletes with an average age of 20. This included 61 with a recent concussion and 167 without. Within the first group, 36 had a history of concussion. Within the second group, 73 had a history of concussion.

Researchers took up to five brain scans of each recently concussed athlete, from time of injury to one year after returning to play.

Researchers found that one year after a recent concussion, athletes with a history of concussion had sharper declines in blood flow within one area of the cingulate compared to those without a history of concussions. Those with a history of concussion had an average cerebral blood flow of 40 milliliters (mL) per minute, per 100 grams (g) of brain tissue. Those without a history of concussion had an average cerebral blood flow of 53 mL per minute, per 100g of brain tissue.

In athletes with a history of concussion, in the weeks after a new concussion, researchers also found microstructural changes in a region of the brain called the splenium, which is part of the corpus callosum.

“Our findings suggest that an athlete with a history of concussion should be watched closely, as these subtle brain changes may be worsened by repeated injury,” said Schweizer. “Additionally, our results should raise concern about the cumulative effects of repeated head injuries later in life.”

A limitation of the study is that athletes reported their own histories of concussion and could be inaccurate. Further research is needed that would follow athletes over time.

The study was supported by Canadian Institutes of Health Research, the Canadian Institute for Military and Veterans Health Research and Siemens Healthineers Canada.

Learn more about concussion at BrainandLife.org, home of the American Academy of Neurology’s free patient and caregiver magazine focused on the intersection of neurologic disease and brain health. Follow Brain & Life® on FacebookTwitter and Instagram.

When posting to social media channels about this research, we encourage you to use the hashtags #Neurology and #AANscience.

The American Academy of Neurology is the world’s largest association of neurologists and neuroscience professionals, with over 36,000 members. The AAN is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, concussion, Parkinson’s disease and epilepsy.

For more information about the American Academy of Neurology, visit AAN.com or find us on FacebookTwitterInstagramLinkedIn and YouTube.

Disclaimer: AAAS 

 

Largest real-world study of COVID-19 vaccine safety published by Israel's Clalit Research Institute in The New England Journal of Medicine


The Clalit Research Institute, in collaboration with researchers from Harvard University, analyzed one of the world’s largest integrated health record databases to examine the safety of the Pfizer/BioNTech BNT162B2 vaccine against COVID-19

Peer-Reviewed Publication

CLALIT RESEARCH INSTITUTE

The Clalit Research Institute, in collaboration with researchers from Harvard University, analyzed one of the world’s largest integrated health record databases to examine the safety of the Pfizer/BioNTech BNT162B2 vaccine against COVID-19. The study provides the largest peer-reviewed evaluation of the safety of a COVID-19 vaccine in a nationwide mass-vaccination setting. The study was conducted in Israel, an early global leader in COVID-19 vaccination rates.

Previous efforts to characterize vaccine safety have relied on voluntary active reporting by vaccinated individuals, which is known to be incomplete. The present study relies on the analysis of millions of anonymized electronic medical records, which are far more comprehensive.

Furthermore, in order to provide the necessary context for interpreting vaccine safety findings, this study is the first to examine a wide range of adverse events both among vaccinated individuals and among unvaccinated individuals who were infected with the coronavirus. Thus, two separate analyses were conducted:

  1. Vaccination Outcomes Analysis: 884,828 vaccinated individuals aged 16 and over were carefully matched with 884,828 unvaccinated individuals based on an extensive set of sociodemographic, geographic and health-related attributes. Individuals were assigned to each group dynamically based on their changing vaccination status (235,541 individuals moved from the unvaccinated cohort into the vaccinated cohort during the study). Rates of the 25 potential adverse events within three weeks following either vaccine dose were compared between the two groups. This analysis took place from December 20, 2020, the launch of Israel’s national vaccination campaign, through May 24, 2021.
  2. Infection Outcomes Analysis: To provide context for the vaccine safety findings above, a separate analysis was conducted that estimated the rates of the same 25 potential adverse events among 173,106 unvaccinated individuals who were infected with the coronavirus, compared to 173,106 carefully matched controls who were not infected with the coronavirus. This analysis took place from March 1, 2020 (the beginning of the COVID-19 pandemic in Israel) through May 24, 2021.

The vaccine was found to be safe: Out of 25 potential side effects examined, 4 were found to have a strong association with the vaccine.

Myocarditis was found to be associated with the vaccine, but rarely – 2.7 excess cases per 100,000 vaccinated individuals. (The myocarditis events observed after vaccination were concentrated in males between 20 and 34.) In contrast, coronavirus infection in unvaccinated individuals was associated with 11 excess cases of myocarditis per 100,000 infected individuals.

Other adverse events moderately associated with vaccination were swelling of the lymph nodes, a mild side effect that is part of a standard immune response to vaccination, with 78 excess cases per 100,000, appendicitis with 5 excess cases per 100,000 (potentially as a result of swelling of lymph nodes around the appendix), and herpes zoster with 16 excess cases per 100,000.

In contrast to the relatively small number of adverse effects associated with the vaccine, high rates of multiple serious adverse events were associated with coronavirus infection among unvaccinated patients, including: Cardiac arrhythmias (a 3.8-fold increase to an increase of 166 cases per 100,000 infected patients), kidney damage (14.8-fold increase; 125 excess cases per 100,000), pericarditis (5.4-fold increase; 11 excess cases per 100,000), pulmonary embolism (12.1-fold increase; 62 excess cases per 100,000), deep vein thrombosis (3.8-fold increase; 43 excess cases per 100,000), myocardial infarction (4.5-fold increase; 25 excess cases per 100,000), and stroke (2.1-fold increase; 14 excess cases per 100,000).

The research was conducted by Dr. Noam Barda, Dr. Noa Dagan, Yair Ben-Shlomo, Dr. Eldad Kepten, Dr. Jacob Waxman, Reut Ohana and Prof. Ran Balicer from the Clalit Research Institute, Dr. Doron Netzer of Clalit Health Services, as well as Prof. Miguel Hernán and Prof. Marc Lipsitch of the Harvard T.H. Chan School of Public Health, Prof. Isaac Kohane of the Department of Biomedical Informatics at Harvard Medical School, and Prof. Ben Reis of Boston Children’s Hospital and Harvard Medical School.

This study focused on adverse events that may develop in the short to medium term after vaccination, and those with clinical significance. The study did not focus on common immediate symptoms such as redness and discomfort at the injection site or fever. Symptoms that occurred within 6 weeks of the vaccine (three weeks after each vaccine dose) were defined as an adverse event of the vaccine if they occurred more frequently among the vaccinated group compared to the control group.

The results of this study validate and complement the previously reported findings of the Pfizer/BioNTech Phase-III randomized clinical trial, which, with 21,720 vaccinated individuals, could not precisely and comprehensively assess vaccine safety. The present study’s large size allows a more detailed assessment of the vaccine’s safety across a wider range of adverse events.

“The extensive nationwide rollout of Israel’s COVID-19 vaccination campaign provided the Clalit Research Institute with a unique opportunity to assess, through its rich and comprehensive digital datasets, the safety of the vaccine in a real-world setting, without needing to rely on individual-driven active reporting of side-effects” said Prof. Ran Balicer, senior author of the study, Director of the Clalit Research Institute and Chief Innovation Officer for Clalit. “These results show convincingly that this mRNA vaccine is very safe and that the alternative of ‘natural’ morbidity caused by the coronavirus puts a person at significant, higher and much more common risk of serious adverse events. These data should facilitate informed individual risk-benefit decision-making, and, in our view, make a strong argument in favor of opting-in to get vaccinated, especially in countries where the virus is currently widespread,” added Prof. Balicer, who also serves as Chairman of Israel's National Expert Advisory Team on COVID-19 response.

“This study sheds light for the first time on the significant side effects of the coronavirus vaccine. Since this is a more comprehensive analysis based on electronic medical records, these are more reliable assessments than those published to date which have relied on voluntary active reporting systems,” explains Doron Netzer, Chief Medical Officer of Clalit’s Community Health Division.

Prof. Ben Reis, Director of the Predictive Medicine Group at the Boston Children’s Hospital Computational Health Informatics Program and Harvard Medical School, said, “To date, one of the main drivers of vaccine hesitancy has been a lack of information regarding potential side effects of the vaccine. This careful epidemiological study provides reliable information on vaccine safety, which we hope will be helpful to those who have not yet decided about vaccination.” He continued, “Those who have hesitated until now to get vaccinated due to concerns about very rare side effects - such as myocarditis – should be aware that the risks for this very same side effect are actually higher among unvaccinated infected individuals."

Prof. Miguel Hernán, Director of the CAUSALab and Professor at the Harvard T.H. Chan School of Public Health, said, “This research is a perfect example of how randomized trials and observational healthcare databases complement each other. The original trial of the Pfizer/BioNTech vaccine provided evidence of its safety, but the estimates were too imprecise given the small sample size. This analysis of Clalit’s high-quality database emulates the design of the original trial, uses its findings as a benchmark, and expands upon them to confirm the vaccine’s safety on a wide range of adverse events. This combination of evidence from randomized trials and observational studies is a model for efficient medical research, something which is especially important in COVID times.”

Prof. Marc Lipsitch, Director of the Center for Communicable Disease Dynamics and Professor at the Harvard T.H. Chan School of Public Health, said, “In all studies of vaccine safety, a major challenge is to ensure that those we are comparing to identify the vaccine’s side effects are similar in the other characteristics that may predict whether they will experience these side effects. This is especially hard in the context of a rapidly growing, age-targeted vaccine campaign. Clalit’s extraordinary database made it possible to design a study that addressed these challenges in a way that provides tremendous confidence in the inferences that come out of the study.”

The research was funded in part by the newly announced Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute. “The strengthening of the scientific collaboration between Harvard and Clalit made possible by the Berkowitz Living Laboratory Collaboration is already bearing fruit and giving us a foretaste of the value of healthcare systems instrumented for research,” said Prof. Isaac Kohane, Chair of the Department of Biomedical Informatics at Harvard Medical School and co-Director of the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration along with Professor Balicer. “Israel offers a unique environment in which to study the vaccine and its effects, and this study is an excellent example of what can be accomplished through such close scientific collaborations.”

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Greenhouse warming intensifies north tropical Atlantic sea surface temperature anomalies


Peer-Reviewed Publication

CHINESE ACADEMY OF SCIENCES HEADQUARTERS

Observed NTA warming events and their impact 

IMAGE: OBSERVED NTA WARMING EVENTS AND THEIR IMPACT view more 

CREDIT: IAP

North Tropical Atlantic (NTA) sea surface temperature anomalies are among the dominant and most consequential climate variations on Earth.

NTA warming events increase occurrences of extreme hurricanes and their landfall frequency along the U.S. East coast, induce severe droughts in Northeast Brazil, boost phytoplankton blooms in the Guinea Dome, and trigger La Niña events the following winter. Up until now, future changes in NTA variability and its underlying mechanisms have remained unknown.

A new study, however, has recently revealed that NTA variability is projected to increase in a warming climate. The research was conducted by an international team of 12 scientists from nine institutes around the world and results were published in Science Advances on August 25.

"The increase in NTA variability means not only strengthening of sea surface temperature anomalies but also increasing occurrences of extreme NTA events," said YANG Yun, associate professor at the College of Global Change and Earth System Science of Beijing Normal University and lead author of the study.

The increase in NTA variability and occurrences of extreme events mainly arises from an intensification of El Niño-Southern Oscillation (ENSO) influence, including ENSO-forced Pacific-North American pattern and tropospheric temperature anomalies.

ENSO-forced Pacific-North American pattern is enhanced in a warming climate because of the eastward shift of ENSO-related equatorial Pacific convection. This enhancement is further amplified by an increase in ENSO variability.

Co-author HUANG Gang from the Institute of Atmospheric Physics (IAP) of the Chinese Academy of Sciences further explained that "the strengthening of ENSO-induced temperature anomalies is due to combined effects of an increase in ENSO variability and amplified vapor response to ENSO."

"The consequence of an increase in ENSO variability and its teleconnections under greenhouse warming is more severe than previously thought, as the increase can energize dominant modes of climate variability remote from the Pacific, such as the NTA," said co-author CAI Wenju from the Centre for Southern Hemisphere Oceans Research, CSIRO Oceans and Atmosphere, Australia.

Given the profound climatic impact of NTA in inducing droughts, floods, and extreme hurricanes, this study adds to the urgency of reducing emissions of greenhouse gases.

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Sea level rise will harm coastal wetlands in the Chesapeake—A bad sign for people and property


Due to a combination of sea level rise and changing wetland distribution, even relatively weak storms in 2100 could have a greater impact on the Chesapeake Bay region than high-intensity storms today

Peer-Reviewed Publication

RESOURCES FOR THE FUTURE (RFF)

As the planet warms, the severity and frequency of hurricanes is increasing—and with it, economic losses from storm surge–related flooding. A new paper, published earlier this month in the journal Natural Hazards Review, assesses the impacts of rising seas and wetland change on storm surge flooding in a region expected to be a “hot spot” for sea level rise—the Chesapeake Bay.

The study results suggest that, particularly for strong storms in the future, the combination of wetland loss and sea level rise spurs significantly more property damage and affects more people than sea level rise alone.

“In low-elevation communities, even a small change in sea level can have a big impact,” said Margaret Walls, study coauthor and senior fellow at Resources for the Future (RFF). “Wetlands provide an important buffer to storm surge. In combination, wetland loss and sea level rise can create, almost literally, conditions for a perfect storm. This has serious repercussions for insurance markets, developers, and people living in this highly populated region.”

To quantify damages, the study authors model two historic hurricanes that hit the Chesapeake Bay region at the turn of the century: a relatively weak storm—Hurricane Dennis, in 1999—and a relatively strong storm—Hurricane Isabel, in 2003. By running computer simulations of these storms, in combination with coastal land use change tools from the National Ocean and Atmospheric Administration (NOAA), the team could model the combined and isolated impacts of sea level rise and wetland loss on coastal flooding in 2100.

They came to the following conclusions:

  • Under maximum sea level rise scenarios, even relatively weak storms in 2100 are projected to have a greater impact on the Chesapeake Bay region than high-intensity storms today.
  • The loss of wetlands significantly increases the amount of flooding in the region during strong storms—flooded area increases by a factor of 3.6–6.0 compared to current conditions. Without considering wetland loss, flooded area increases by a factor of 1.3–2.3.
  • In a scenario in which wetland loss is considered alongside sea level rise, a strong storm could put 789,000–1,971,000 people at risk of coastal inundation in the future.
  • Wetland loss combined with sea level rise would create $2.5 billion–$13 billion in property damage during a strong storm in 2100.
     

Notably, the modeling also shows that Virginia is likely to lose more wetlands than Maryland. However, Anne Arundel County, Maryland—which is located between Washington, DC, and Baltimore—has the highest number of people at risk from coastal flooding.

“The results show that coastal communities should be braced for a future marked by climate change and sea level rise,” Walls said. “Hopefully, our research will support efforts to develop adaptation measures that include conservation, restoration, and floodplain management measures. Natural infrastructure can go a long way to protect us in an uncertain future.”

For more, read the article, “Quantifying the Impacts of Storm Surge, Sea Level Rise, and Potential Reduction and Changes in Wetlands in Coastal Areas of the Chesapeake Bay Region,” in the journal Natural Hazards Review. The paper was authored by Ali Mohammed Rezaire from George Mason University, Celso M. Ferreira from George Mason University, Margaret Walls from Resources for the Future, and Ziyan Chu from First Street Foundation.

Artificial intelligence to help predict Arctic sea ice loss


Peer-Reviewed Publication

BRITISH ANTARCTIC SURVEY

IceNet_fig_ 

IMAGE: ICENET FIGURE view more 

CREDIT: BRITISH ANTARCTIC SURVEY

A new AI (artificial intelligence) tool is set to enable scientists to more accurately forecast Arctic sea ice conditions months into the future. The improved predictions could underpin new early-warning systems that protect Arctic wildlife and coastal communities from the impacts of sea ice loss.

Published this week (Thursday 26 August) in the journal Nature Communications, an international team of researchers led by British Antarctic Survey (BAS) and The Alan Turing Institute describe how the AI system, IceNet, addresses the challenge of producing accurate Arctic sea ice forecasts for the season ahead – something that has eluded scientists for decades.

Sea ice, a vast layer of frozen sea water that appears at the North and South poles, is notoriously difficult to forecast because of its complex relationship with the atmosphere above and ocean below. The sensitivity of sea ice to increasing temperatures has caused the summer Arctic sea ice area to halve over the past four decades, equivalent to the loss of an area around 25 times the size of Great Britain. These accelerating changes have dramatic consequences for our climate, for Arctic ecosystems, and Indigenous and local communities whose livelihoods are tied to the seasonal sea ice cycle.

IceNet, the AI predictive tool, is almost 95% accurate in predicting whether sea ice will be present two months ahead - better than the leading physics-based model.

Lead author Tom Andersson, Data Scientist at the BAS AI Lab and funded by The Alan Turing Institute, explains:

“The Arctic is a region on the frontline of climate change and has seen substantial warming over the last 40 years. IceNet has the potential to fill an urgent gap in forecasting sea ice for Arctic sustainability efforts and runs thousands of times faster than traditional methods.”

Dr Scott Hosking, Principal Investigator, Co-leader of the BAS AI Lab and Senior Research Fellow at The Alan Turing Institute, says:

“I’m excited to see how AI is making us rethink how we undertake environmental research. Our new sea ice forecasting framework fuses data from satellite sensors with the output of climate models in ways traditional systems simply couldn't achieve.”

Unlike conventional forecasting systems that attempt to model the laws of physics directly, the authors designed IceNet based on a concept called deep learning. Through this approach, the model ‘learns’ how sea ice changes from thousands of years of climate simulation data, along with decades of observational data to predict the extent of Arctic sea ice months into the future.

Tom Andersson concludes:

“Now we’ve demonstrated that AI can accurately forecast sea ice, our next goal is to develop a daily version of the model and have it running publicly in real-time, just like weather forecasts. This could operate as an early warning system for risks associated with rapid sea ice loss.”

 

Publication details:

Seasonal Arctic sea ice forecasting with probabilistic deep learning by Tom Andersson, Scott Hosking, Maria Pérez-Ortiz, Brooks Paige, Andrew Elliott, Chris Russell, Stephen Law, Dan Jones, Jeremy Wilkinson, Tony Phillips, James Byrne, Steffen Tietsche, Beena Sarojini, Eduardo Blanchard-Wrigglesworth, Yevgeny Aksenov, Rod Downie, and Emily Shuckburgh is published in the journal Nature Communications on Thursday 26 August. Read the paper here: http://dx.doi.org/10.1038/s41467-021-25257-4 

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