Culture

Researchers at the Francis Crick Institute have found that a protein which is initially helpful in the body's immune response to a virus, can later interfere with the repair of lung tissue. The work, published in Science, highlights the need for careful consideration regarding the use of this protein to treat viruses, including coronavirus.

When a virus infects the lungs, the body attempts to defend itself and fight off the infection. One defensive mechanism is the activation of a protein, called interferon lambda, which signals to surrounding lung tissue cells to switch on anti-viral defences.

Interferon lambda is currently being investigated in clinical trials as a potential treatment for COVID-19*, so understanding the biology underlying its anti-viral effects is important.

The research team investigated the effects of this protein in the lab and found that if it is active for an extended period, it inhibits the repair of the lung tissue. This could prolong lung damage and increase the risk of subsequent bacterial infections.

The Crick scientists observed that in mice with influenza, having increased levels of this protein in their lungs meant that their epithelial cells multiplied less. These cells make up the lining of the airspaces in the lung and need to multiply to replace damaged cells and repair damage. This was the case for mice treated with the protein experimentally and also mice that had produced the protein naturally, as a result of their response to the virus.

Furthermore, cultures of human lung epithelial cells treated with this protein were also less able to grow.

Andreas Wack, author and group leader of the Immunoregulation lab at the Crick says, "This is a really potent protein with many different functions. At the beginning of a viral infection, it is protective, triggering functions that help to fight the virus. However, if it remains in the tissue for too long, it could become harmful.

"This means, for any anti-viral treatment that uses this protein, there is a really careful balance that must be made. Clinicians should consider the timing of the treatment, the earlier this better, and the duration of treatment."

While this research studied mice infected with influenza, the effects of this protein should be similar for other viruses that also cause lung damage, including coronavirus.

The paper has been published alongside research from Harvard Medical School, which found that severe COVID-19 patients showed strong expression of this protein in their lungs.**

Jack Major, lead author and PhD student in the Immunoregulation lab at the Crick says, "Understanding how our bodies respond to infection has never been more important. Differences in our immune responses have huge implications for whether a treatment will work and what the side effects might be.

"Our results suggest that before pursuing treatment with interferon lambda, doctors should consider at what stage of the disease patients are, as treatment late in infection may increase the risk of prolonged damage."

The Crick researchers will continue to study inflammatory pathways in lung infections, including infection with coronavirus.

A new analysis of blood sera taken from 63 COVID-19 patients, 71 controls, and various coronavirus-exposed animals provides strong support for the use of the SARS-CoV-2 virus' receptor-binding domain (RBD) as an antigen for reliable tests to detect antibodies to the virus. The study confirms that, because the SARS-CoV-2 RBD is distinct from those in related coronaviruses, it is capable of inducing antibodies that are highly specific to SARS-CoV-2. Additionally, the researchers found that more than 95% of patients developed antibodies to a recombinant SARS-CoV-2 RBD antigen within nine days after the onset of symptoms. Together, these results suggest that RBD-based antigens could be used to develop serological tests for SARS-CoV-2 exposure that are both specific for, and sensitive to, the SARS-CoV-2 virus. Moreover, the presence of RBD-induced antibodies strongly correlated with higher levels of virus-neutralizing antibodies in the sampled patients. Thus, deployed at the population level, RBD-based antibody tests could provide an estimate of how many individuals have recovered from SARS-CoV-2 infections, a necessary first step for implementing policies to contain the pandemic and re-open communities. Lakshmanane Premkumar and colleagues probed the antibody specificity of the SARS-CoV-2 RBD, a critical portion of the virus' spike protein complex, in sera sampled from symptomatic human patients, control patients, and animals exposed to various zoonotic coronaviruses. The researchers found that the RBD antigen was 98% sensitive - meaning it detected SARS-CoV-2 antibodies in 98% of individuals who tested positive for the virus via PCR tests - and 100% specific in the COVID-19 patient cohort, meaning that all patients who had tested positive for RBD-targeting antibodies were also positive for SARS-CoV-2 in PCR tests. In some patients, the RBD antigen cross-reacted with antibodies for SARS-CoV-1 (a related coronavirus that causes SARS), but since SARS-CoV-1 prevalence is very low in humans, this cross-reactivity is unlikely to pose diagnostic challenges, the scientists say. The researchers say they plan to examine whether asymptomatic patients who carry the virus exhibit similar antibody responses as those who experience symptomatic infections.

Two separate studies in mice suggest that a class of interferons being evaluated in clinical trials as a therapy for COVID-19 may increase susceptibility to bacterial infections, depending on how long patients are exposed to it, and when they receive it. The results suggest that timing and duration of this treatment may need to be carefully selected, as trials move forward, to avoid deleterious effects. Interferons (IFNs) help fight viral infections in the lung. In particular, type III IFNs (IFN- λ) have attracted much attention, because, unlike other IFNs, they show antiviral effects without driving inflammatory responses. Already, a clinical trial exploring use of IFN-λ against SARS-CoV-2 has begun. Despite interest in the use of IFN-λ to treat viral infections, the long-term effects IFN-λ on lung physiology - and in possibly impairing bacterial control by the lung epithelium - remain largely overlooked. Here, to directly evaluate whether SARS-CoV-2 induces IFNs, Achille Broggi and colleagues tested swabs of COVID-19 patients and healthy controls, as well as the bronchoalveolar lavage fluid of severe SARS-CoV-2-positive patients. In the latter group, levels of type I and III interferons were high, they report. Next, to better understand the effects of IFN-λ signaling in the lung, Broggi and colleagues studied the lungs of mice exposed to synthetic viral RNA. In these animals, IFN-λ secreted by dendritic cells caused damage to the lung epithelium, which increases susceptibility to lethal bacterial superinfections. In a separate study using a mouse model to investigate the dynamics of influenza virus infection, Jack Major et al. report that IFN signaling (especially that of IFN-λ) hampered lung repair. This pair of papers suggests that the timing and duration of IFN-λ exposure are critical parameters underlying the success or failure of antiviral therapeutics, the authors say. "[O]ur data enjoin clinicians to carefully analyze the duration of IFN-λ administration and to take into consideration the severity of disease when IFN-λ is used as a therapeutic agent against lung viral infections," write Broggi and colleagues. "Optimal protection would be achieved by strong induction of IFN-stimulated genes early during infection to curb viral replication, followed by timely down-regulation of IFN responses, enabling efficient lung epithelial repair," say Major et al.

Viruses and other disease-causing microbes influence the type of immune response their hosts will develop against them. In some cases, the predominant response involves antibodies, proteins made by the immune system that specifically recognize parts of the invading microbe and mediate its destruction. In other cases, immune cells are trained to recognize the microbe and lead the attack against it.

Scientists have extensively investigated the mechanisms that lead to either an antibody or a cell-mediated response, and about 10 years ago, a novel signal was suggested as the trigger of a cell-mediated response. In a current study, Baylor researchers, Dr. William Decker, Dr. Matthew Halpert, Dr. Vanaja Konduri and their colleagues present comprehensive evidence that supports this phenomenon and propose a mechanism for its action.

The classic immune response

Research has shown that two factors related to microbes significantly affect the type of immune response that will predominate. On one hand are the microbial components (parts of proteins or genetic material, called pathogen-associated molecular patterns or PAMPs), and on the other is the location of the microbes, whether they tend to be inside or outside cells. Cells have means to recognize PAMPs ? some cellular proteins recognize PAMPs inside cells, while others detect PAMPs outside cells.

Research on viruses has shown that when viral genetic material is detected inside cells, a cell-mediated immune response develops, while the detection of viral proteins outside the cell triggers antibody-mediated responses.

The implementation of these immune responses involves cellular proteins called Pattern Recognition Receptors, or PRRs. Antigen-presenting cells, such as dendritic cells, are involved in the first steps of developing a specific immune response. During these first steps, antigen-presenting cells sample both the intracellular and extracellular environments by binding PAMPs to their PRRs. Recognition of a PAMP by a PRR turns on the danger alarm and alerts the rest of the immune system to the presence of a foreign microbial invader.

A novel mechanism that triggers a cell-mediated immune response

In addition to these well-studied signals that mediate classic immune responses, Baylor researchers have proposed and demonstrated a different mechanism that directs the immune response toward a cellular type. This new mechanism also involves surveillance of both the intracellular and extracellular environments but by a different class of proteins called the Major Histocompatibility Complex, or MHC. MHC Class I binds protein fragments found inside of cells whereas MHC Class II binds protein fragments present on the outside of cells.

"This mechanism appears to take place mostly when a fulminant viral infection occurs," said Decker, associate professor of pathology and immunology and corresponding author of this work.

When a virus avidly proliferates, parts of viral proteins can be found in abundance both inside and outside of cells. One possible outcome of this situation is that identical protein fragments bind to both MHC Class I and Class II proteins on antigen-presenting cells.

When this occurs in conjunction with other inflammatory cues, "a response is triggered that promotes a cell-mediated immunity against that virus," said Decker, who also is a member of Baylor's Dan L Duncan Comprehensive Cancer Center. "In this case, the response does not depend on any particular PAMP structure. Instead, it depends on the fact that the pieces of virus bound by MHC Class I and II have an identical amino acid sequence."

"In this study, we defined experimental model systems that enabled us to study this specific mechanism without interference from classical mechanisms. We found ample evidence that supports the novel mechanism and described a large molecular sensor complex we propose plays a central role in comparing the amino acids sequences of intracellular and extracellular protein fragments," said Halpert, instructor of immunology at Baylor and first author of this work. "Although further research is needed, we anticipate that this novel mechanism has potential important clinical applications."

Research has shown that naturally developed cell-mediated immunity against viral infections tends to confer protection that lasts longer than antibody-mediate immunity, which is induced by some vaccines. The authors propose that this novel mechanism that steers the immune response toward the cellular type offers a valuable opportunity to design vaccines that may induce more effective and durable cell-based immunity against current and future viral diseases as well as against cancers. Importantly, the Decker group is implementing this strategy in clinical trials, including a study for intent to treat pancreatic cancer (NCT04157127) due to open in June 2020 at Baylor St. Luke's Medical Center.

Suicide is the second leading cause of death for persons ages 10-24. And according to the Centers for Disease Control and Prevention (CDC), youth suicide rates have nearly tripled from 2007 to 2017. Understanding risk factors in younger children can increase the likelihood of a child receiving behavioral health services in a timely fashion and can contribute to the development of interventions dedicated to preventing a first suicide attempt in at-risk youth.

A parental history of suicidal behavior has been shown to increase the odds of a youth suicide attempt 4-6 times, even after controlling for mental health disorders in youth associated with suicidal behavior (e.g., major depressive disorder). Additionally, emotional regulation, or how children understand, respond to and control their emotions, is strongly associated with various risk factors for youth suicide attempts. Research examining the intersection of these two risk factors, however, is limited.

In a recent study, researchers at Nationwide Children's Hospital examined the intersection of these two risk factors, parental history of suicidal behavior and emotion regulation, in children 6-9 years of age. The study, published in Child Psychiatry & Human Development, suggests youth with a parental history of a suicide attempt experienced more stressful life events and more emotion dysregulation compared to youth without a parental history of suicidal behavior. These risks have been associated with suicidal behavior in adolescents and adults.

"The epidemiology of suicide has changed over time and rates are increasing," said Arielle Sheftall, PhD, principal investigator with the Center for Suicide Prevention and Research in the Abigail Wexner Research Institute at Nationwide Children's and first author of the paper. "Studies like this allow us to start identifying some of the factors that might be associated with these changes in the rate of youth suicide and suicidal behavior. By identifying the areas of risk, we're able to create and test interventions - with the goal of reducing suicide deaths among the most vulnerable."

During the study, mothers and their children were asked to report on lifetime and past-month suicidal ideation and attempts, significant events that took place in the child's life in the past year, and their child's emotion regulation skills. The study examined 21 children, ages 6-9 years old, with and without a parental history of suicidal behavior across three appointments, with 100% of participants retained for a 6-month phone interview and 90.5% for a 1-year follow-up appointment.

Results from this study suggest early intervention in childhood to provide emotion regulation strategies and increase resiliency in at-risk youth may decrease the likelihood of the development of risk factors associated with future suicidal behaviors. Future research incorporating both mothers and fathers and observational measures of emotional regulation, rather than self-report measures, will be valuable in examining these findings further.

"Our study highlights young children with a parental history may benefit from interventions that build upon emotion regulation skills and strategies," said Dr. Sheftall. "Providing these skills early in childhood, even in children at high risk for future suicidal behavior could make a big difference and save a child's life."

"Something else that is vital in fighting against youth suicide and suicidal behavior is knowing the warning signs," explained Dr. Sheftall. "Our past research indicates factors prior to suicide death in children differ compared to adolescents who died by suicide, and the warning signs in young children are also somewhat different. If a child is making suicidal statements, has been unhappy for an extended period, is withdrawing from friends or school activities, is giving away their possessions to others, or being increasingly aggressive or irritable, these are clear signs that something is wrong, a conversation is needed, and seeking out mental health care, especially if suicidal statements are being made, is necessary."

"Finally, there is hope," said Dr. Sheftall. "If a child gets the help they need, learns the skills necessary to combat the suicidal thoughts they are experiencing, and knows there is someone available to help them through the tough times, children can bounce back and get better. Having suicidal thoughts is very common, but there are ways to fight against them, and building youth up and supporting them is one of the ways we can all do so."

The discovery of large well-preserved footprints belonging to an ancestor of modern-day crocodiles from the Lower Cretaceous Jinju Formation of South Korea is reported this week in Scientific Reports. The study suggests that footprints found previously, thought to have been made by giant pterosaurs walking on two legs, may have instead been made by ancient crocodile relatives.

Kyung Soo Kim, Martin G. Lockley and colleagues discovered multiple sets of footprints during excavation at the Sacheon Jahye-ri site, near Sacheon City, South Korea. The tracks - which the authors name Batrachopus grandis - belong to a new species of crocodylomorph, which are ancestors to modern-day crocodiles, fish-eating crocodiles and alligators. The tracks are more than twice as large as previously found batrachopodid tracks and include footprint lengths of 18-24cm, indicating a body length of up to three metres. The narrow trackways were made entirely by the back limbs, with clear heel to toe impressions and skin traces in some areas. There is no definitive evidence, either from back footprints covering those made by the front feet or poor track conservation, to suggest the trackways were made by a four-legged crocodylomorph, indicating that B. grandis represents animals that walked on two legs. This is a gait not previously seen from trackway specimens belonging to this family.

The findings suggest that tracks found at younger sites, originally believed to have been made by giant pterosaurs able to walk on two legs to protect their wings when on land, may instead belong to crocodylomorphs. This supports the general consensus of those studying trace fossils that pterosaurs walked using all four limbs and highlights the need for re-examination of other morphologically similar specimens from this period in history.

More than 120,000 novel human genetic variations that affect large regions of DNA have been discovered, some of which are linked to immune response, disease susceptibility or digestion. Scientists at the Wellcome Sanger Institute identified these changes affecting multiple bases of DNA, known as structural variations, in a study of the most diverse worldwide populations examined to date. This included variations in medically-important genes in populations from Papua New Guinea that were inherited from Denisovan ancestors.

The resource, published today in Cell (11 June), adds new regions of sequence to the human reference genome, the world standard for all of human genetics, which is nevertheless incomplete. These previously-unknown variations in medically-important genes, which could affect the efficacy of medical treatments in certain populations, will be a valuable resource for the field of precision medicine around the globe.

Structural variations are genetic changes that can encompass anything from a few to millions of base pairs of DNA and are therefore particularly likely to affect how genes function. Some genes, such as those that influence immune response, are considered to be 'medically important'. DNA changes affecting how these genes function can lead to health problems or increased resistance or susceptibility to particular diseases.

Up until now, most large-scale genetic studies have generally focused on changes affecting single base pairs of DNA.

Scientists at the Wellcome Sanger Institute had previously led the sequencing of 911 genomes from 54 geographically, linguistically and culturally diverse populations from across the globe, and have now searched for structural variations* in these sequences.

The sequences were compared to the human reference genome to create a catalogue of structural variations, over three quarters of which were previously unknown. The team then investigated how common these structural variations are in each of the 54 populations, and which of them were inherited from Neanderthal or Denisovan ancestors.

Among the 126,018 structural variations discovered were medically-important variations inherited from Denisovan ancestors in Oceanian populations from Papua New Guinea and nearby, including a high-frequency deletion in the AQR gene that plays a role in detection of viruses and regulation of antiviral immune response.

Mohamed Almarri, first author of the study and PhD student at the Wellcome Sanger Institute, said: "By analysing the genomes of understudied populations we've been able to find high-frequency structural variations not uncovered by previous large-scale sequencing projects. Several of these are in medically-important genes that tell us how a population has evolved to resist a certain disease or why they might be susceptible to others. This is vital knowledge and will help to ensure that treatments can be tailored to each specific population."

Other notable structural variations were uncovered by the study that, together with existing knowledge of human evolution and the role of specific genes, shine a light on how individual populations have evolved.

The Karitiana people, who reside in modern-day Brazil, were found to carry a variation in the MGAM gene that affects starch digestion. The Karitiana diet is derived from fishing, hunting and farming, so a decrease in starch digestion is probably disadvantageous and therefore surprising. It is thought that bad luck may have concentrated this variation in the small population that survived a population crash within the last 5,000 years.

The team also discovered novel 'runaway duplications', where populations have evolved to carry multiple copies of genes. For example, all of the African populations included in the study carried multiple copies of the HPR gene, which is associated with resistance to sleeping sickness**. The highest numbers of copies (up to nine) were carried by Central and West African populations, where the disease is most prevalent.

Dr Ed Hollox, an expert in the field from the University of Leicester, said: "This is a very valuable study showing the importance of structural variation of the human genome in the genetic diversity of humans around the world. The work supports the concept that some human adaptations to different environments are due to the loss or gain of whole genes, or parts of genes. Structural variation can be challenging to find, and this study also provides a well-founded structural variation reference set which will serve as an important springboard for future studies."

The study adds almost two million newly-identified base pairs to the human reference genome sequence. Because the human reference genome was assembled from a small number of people, regions of DNA that were not present in these individuals are missing from the reference sequence.

The team recreated 25 diverse human genomes from scratch using a recent technological innovation called de novo genome assembly. By directly comparing these assembled genomes to the reference, the researchers were able to identify missing sequences present in multiple populations. This illustrates the limitation of a single human reference and the need for high-quality reference genomes from diverse populations.

Dr Yali Xue, recently retired from the Wellcome Sanger Institute, said: "Structural variants are complicated yet very important functionally, evolutionarily and medically. The discovery of these new structural variations provides one of the richest resources of this kind of variation so far, which not only offers unique insights into population histories and improves the currently used human reference genome, but will also substantially benefit future medical studies."

Trinidadian guppies behave like matadors, focusing a predator's point of attack before dodging away at the last moment, new research shows.

The tiny fish (10-40mm) draw attention by turning their irises black, which makes their eyes very conspicuous.

This encourages pike cichlids - a large fish that is the guppies' main predator - to charge at their head rather than their body.

The international study, led by the University of Exeter, found guppies then use their lightning reflexes to whip their head out of the way, causing the predators to miss, before swimming away.

Many fish, including guppies, often approach their predators to find out if they are hungry and thus a current threat.

"We noticed that guppies would approach a cichlid at an angle, quickly darkening their eyes to jet-black, and then waiting to see if it would attack," said lead author Dr Robert Heathcote, who undertook the experimental work at Exeter and is now at the University of Bristol.

"Cichlids are ambush predators, lying in wait like a coiled spring before launching themselves at their prey.

"The guppies actually use their eyes to get the predator's attention, causing them to lunge at a guppy's head rather than its body.

"Whilst it seems completely counterintuitive to make a predator attack your head, this strategy works incredibly well because guppies wait until the predator commits to its attack before pivoting out of the way.

"The speed of the whole interaction is extraordinary - at around three hundredths of a second - so was only observable using a high-speed camera."

Many animals are known to use "conspicuous colouration" for purposes such as communication, attracting mates, startling predators and advertising toxicity.

This paper demonstrates a previously unknown divertive strategy - but the researchers think it may be used by other species too.

"We don't know for sure, but it seems highly likely that other animals also use a 'matador' strategy like the one we have identified in guppies," said Professor Darren Croft, of the University of Exeter.

"Eyes are one of the most easily recognised structures in the natural world and many species go to great lengths to conceal and camouflage their eyes to avoid unwanted attention from predators.

"Some species, however, have noticeable or prominent eyes and, for the most part, it has remained a mystery as to why this would be.

"Our latest research gives new insight into why 'conspicuous' and colourful eyes have evolved."

The study was conducted in several stages:

Guppies were observed approaching pike cichlids, often turning their irises black.

The attack strategy of cichlids was tested by placing them in tanks with realistic robotic guppies. When robotic guppies had black eyes, cichlids tended to strike towards the head rather than towards the centre of the body.

By placing guppies and cichlids in a tank (with a transparent screen to prevent the guppies being eaten) and filming with high-speed cameras, researchers observed the success rates of cichlid attacks. Guppies that turned their eyes black were 38% more successful at escaping than guppies with normal eye colouration.

Findings were then confirmed using footage of a previous study in which cichlids were filmed hunting real guppies.

"This project presented a wonderful range of technological challenges, including the creation of robotic guppies matched to the colour vision of pike cichlids, and high-speed computer tracking of guppies as they escaped," said Dr Jolyon Troscianko, of the University of Exeter.

"These advances allowed us to work out whether an attack would have been successful without needing to run life-and-death experiments with fish."

One surprising finding was that larger guppies were better than smaller ones at escaping using this method.

"As animals become larger, they generally become less agile. If larger prey don't have weapons or other ways of defending themselves, this can result in them being easier for predators to catch," said Dr Heathcote.

"By turning their eyes black, larger guppies actually reverse this phenomenon.

"Bigger guppies with black eyes are better at diverting and escaping predator attacks.

"Since bigger animals produce more or larger offspring, it would be really exciting to find out if the animals that use these kinds of strategies have evolved to become larger."

Professor Indar Ramnarine, of the University of the West Indies, St Augustine Campus, said: "We first discovered this particular behaviour in guppies several years ago and wondered what was the significance of this. Now we know."

Previous research has shown that guppies also turn their eyes black to display aggression towards each other.

Dr Safi K. Darden, of the University of Exeter, said: "We knew that changing iris colour was somehow involved in interactions with with other guppies, but when we saw that guppies performing predator inspections were also changing the colour of their irises, we figured that something really interesting must be going on.

"It is thrilling to have had such a skilled team with diverse expertise come together to be able to investigate this behaviour in such detail."

What The Viewpoint Says: Possible outcomes of the COVID-19 pandemic on low- and middle-income countries are described.

Authors: Daniel Vigo, M.D., Lic. Psych., Dr.P.H., of the University of British Columbia in Vancouver, Canada, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamapsychiatry.2020.2174)

Editor's Note: Please see the articles for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

What The Study Did: This study combined the results of 15 observational studies with 9,500 patients who underwent radical hysterectomy for early-stage cervical cancer to compare the risk of cancer recurrence and death associated with receiving minimally invasive versus open radical hysterectomy.

Authors: Alexander Melamed, M.D., M.P.H., of the Columbia University Vagelos College of Physicians and Surgeons in New York, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/ 

(doi:10.1001/jamaoncol.2020.1694)

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An international research team has been stunned to discover that some species of ancient crocodiles walked on their two hind legs like dinosaurs and measured over three metres in length.

University of Queensland palaeontologist Dr Anthony Romilio said the researchers first thought the similar-shaped fossilised footprints were from another ancient animal known as the pterosaurs.

"At one site, the footprints were initially thought to be made by a giant bipedal pterosaur walking on the mudflat, we now understand that these were bipedal crocodile prints," Dr Romilio said.

"The footprints measure around 24 centimetres, suggesting the track-makers had legs about the same height as human adult legs.

"These were long animals that we estimate were over three metres in length.

"And while footprints were everywhere on the site, there were no handprints."

The research team, led by Professor Kyung Soo Kim from Chinju National University of Education, soon found clues as to why there were no handprints.

"Typical crocodiles walk in a squat stance and create trackways that are wide," Professor Kim said.

"Oddly, our trackways are very narrow looking - more like a crocodile balancing on a tight-rope.

"When combined with the lack of any tail-drag marks, it became clear that these creatures were moving bipedally.

"They were moving in the same way as many dinosaurs, but the footprints were not made by dinosaurs.

"Dinosaurs and their bird descendants walk on their toes.

"Crocodiles walk on the flat of their feet leaving clear heel impressions, like humans do."

The footprints dated between 110-120 million years ago and were discovered after analysing animal track sites in what is now known as South Korea.

Researchers initially questioned the absence of hand impressions from the trackways, given that today's typical crocodiles are 'four-legged' or quadrupedal.

"Fossil crocodile tracks are quite rare in Asia, so finding an abundance of nearly one hundred footprints was extraordinary," Dr Romilio said.

"As an animal walks, the hind feet have the potential of stepping into the impression made by the hand and 'over-printing' it, but we find no evidence of this at these Korean sites.

"It isn't due to poor preservation either, because these fossils are spectacular, they even have the fine details of the toe-pads and scales on their soles preserved."

What The Study Did: The association between climate and the spread of COVID-19 is examined in this observational study.

Authors: Mohammad M. Sajadi, M.D., of the University of Maryland School of Medicine in Baltimore, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2020.11834)

Editor's Note: The article includes funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

What The Study Did: How commonly reported gastrointestinal symptoms were in patients with COVID-19 and viral RNA shedding was detected in these patients' stool are examined in this systematic review and meta-analysis.

Authors: Sravanthi Parasa, M.D., of Swedish Medical Center in Seattle, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2020.11335)

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A new study released today in Scientific Reports announced the surprising discovery of abundant, well-preserved 110-120-million-year-old footprints, belonging to a large bipedal ancestor of modern-day crocodiles from the Lower Cretaceous Jinju Formation of South Korea. The team of palaeontologist trackers that made the discovery includes researchers from Korea, Australia, and University of Colorado Denver professor, Martin Lockley.

While palaeontologists knew that some crocodiles from the "age of dinosaurs" were more adapted to life on land than their modern relatives, these were small animals about one meter long with footprints showing they walked on all fours.

"It shocked us to learn that the trackways represent bipedal animals 3-4 meters long," said team leader Professor Kyung Soo Kim, Chinju National University of Education.

The team named the 18-24 cm-long tracks Batrachopus grandis emphasizing the large size in comparison with much older and smaller 2-3 long cm tracks of the Batrachopus type, commonly found in the Jurassic of North America.

"Nobody expected such large bipedal crocs," said Martin Lockley, a University of Colorado professor who has been studying fossil footprints in Korea for 30 years. "The Jinju Formation is so rich in tracks; you can read the entire ecology."

The discovery of well-preserved tracks is important to palaeontologist trackers because they show details of skin impressions as clear as if made yesterday. Tracks also read the pattern of pads, showing foot bone structure and the tell-tale narrowness of trackways which show a bipedal gait, different from the sprawling posture of modern crocodiles. There has even been evidence from parallel trackways that show they may have travelled in social groups, just like their dinosaur cousins.

Among with the remains of some of the oldest terrestrially adapted crocodiles, are large Triassic species, more than 200 million years old, that some palaeontologists think may have been bipedal, based on anatomy.

"The Korean trackways prove this hypothesis, at least for the Cretaceous Period," said co-author of the study, Anthony Romilio. "It also proves this adaptation was effective for millions of years, even with big fierce dinosaurs running around."

The new study has also solved a tracking mystery dating back to 2012, when some poorly preserved tracks of a bipedal animal were first found in another South Korean rock unit, described as "enigmatic." There was debate over whether the giant pterosaurs were bipeds, quadrupeds or possibly even pterosaurian or human.

We move our eyes several times per second. These fast eye movements, called saccades, create large image shifts on the retina - making our visual system work hard to maintain a stable perceptual world. Remapping the retinal image compensates for this; however, errors in actual eye movements cause image shifts, even with remapping.

To do this, our eyes reduce sensitivity to the displacement of visual stimuli during saccades using a process called Saccadic Suppression of Displacement (SSD). However, SSD remains a mystery to researchers. A research team at Tohoku University's Research Institute of Electrical Communication, led by Professor Satoshi Shiori, investigated the mechanisms underlying SSD.

In their psychophysical experiment (Figure 2), an observer first stared at a fixation point for a random duration between 500 and 1300ms. After the fixation point disappeared, the observer had to shift their eyes to a target disc at the other side of the monitor. The target disc moved its location slightly during the observer's saccadic eye movement (about 500 ms), and the observer was asked to judge the direction of target disc displacement (either left or right). Researchers varied the target disc contrasts, before and after saccadic movements separately, to manipulate the retinal input strength. Furthermore, they analyzed the observer's accuracy to detect displacement at each contrast level.

Interestingly, the results show two distinct contrast effects which informed us about the involvement of two visual pathways. Higher contrast in pre-saccadic stimuli enhanced observers' sensitivity to detect visual motion, which is the typical contrast effect on vision. However, an opposite contrast effect was discovered for post-saccadic visual stimuli: higher contrast led to lower detection sensitivity. The research group explains the results successfully with a model which includes two major pathways of early vision: parvo-pathway and magno-pathway. In this model, the signals in the magno-pathway are responsible for detecting displacements while the signals in the parvo-pathway suppress erroneous motion information across saccades. SSD occurs when parvo-pathway signals suppress magno-pathway signals immediately after a saccade.

The understanding the mysterious phenomenon, visual stability across saccades, would help future AI/robots to perceive the world as we do.