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Delivery system can make RNA vaccines more powerful

Delivery system can make RNA vaccines more powerful

Vaccines made from RNA hold great potential as a way to treat cancer or prevent a variety of infectious diseases. Many biotech companies are now working on such vaccines, and a few have gone into clinical trials.

One of the challenges to creating RNA vaccines is making sure that the RNA gets into the right immune cells and produces enough of the encoded protein. Additionally, the vaccine must stimulate a strong enough response that the immune system can wipe out the relevant bacteria, viruses, or cancer cells when they are subsequently encountered.

MIT chemical engineers have now developed a new series of lipid nanoparticles to deliver such vaccines. They showed that the particles trigger efficient production of the protein encoded by the RNA, and they also behave like an “adjuvant,” further boosting the vaccine effectiveness. In a study of mice, they used this RNA vaccine to successfully inhibit the growth of melanoma tumors.

“One of the key discoveries of this paper is that you can build RNA delivery lipids that can also activate the immune system in important ways,” says Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science.

Anderson is the senior author of the study, which appears in the Sept. 30 issue of Nature Biotechnology. The lead authors of the study are former postdocs Lei Miao and Linxian Li and former research associate Yuxuan Huang. Other MIT authors include Derfogail Delcassian, Jasdave Chahal, Jinsong Han, Yunhua Shi, Kaitlyn Sadtler, Wenting Gao, Jiaqi Lin, Joshua C. Doloff, and Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute.

Vaccine boost

Most traditional vaccines are made from proteins produced by infectious microbes, or from weakened forms of the microbes themselves. In recent years, scientists have explored the idea of making vaccines using DNA that encodes microbial proteins. However, these vaccines, which have not been approved for use in humans, have so far failed to produce strong enough immune responses.

RNA is an attractive alternative to DNA in vaccines because unlike DNA, which has to reach the cell nucleus to become functional, RNA can be translated into protein as soon as it gets into the cell cytoplasm. It can also be adapted to target many different diseases.

“Another advantage of these vaccines is that we can quickly change the target disease,” he says. “We can make vaccines to different diseases very quickly just by tinkering with the RNA sequence.”

For an RNA vaccine to be effective, it needs to enter a type of immune cell called an antigen-presenting cell. These cells then produce the protein encoded by the vaccine and display it on their surfaces, attracting and activating T cells and other immune cells.

Anderson’s lab has previously developed lipid nanoparticles for delivering RNA and DNA for a variety of applications. These lipid particles form tiny droplets that protect RNA molecules and carry them to their destinations. The researchers’ usual approach is to generate libraries of hundreds or thousands of candidate particles with varying chemical features, then screen them for the ones that work the best.

“In one day, we can synthesize over 1,000 lipid materials with multiple different structures,” Miao says. “Once we had that very large library, we could screen the molecules and see which type of structures help RNA get delivered to the antigen-presenting cells.”

They discovered that nanoparticles with a certain chemical feature — a cyclic structure at one end of the particle — are able to turn on an immune signaling pathway called stimulator of interferon genes (STING). Once this pathway is activated, the cells produce interferon and other cytokines that provoke T cells to leap into action.

“Broad applications”

The researchers tested the particles in two different mouse models of melanoma. First, they used mice with tumors engineered to produce ovalbumin, a protein found in egg whites. The researchers designed an RNA vaccine to target ovalbumin, which is not normally found in tumors, and showed that the vaccine stopped tumor growth and significantly prolonged survival.

Then, the researchers created a vaccine that targets a protein naturally produced by melanoma tumors, known as Trp2. This vaccine also stimulated a strong immune response that slowed tumor growth and improved survival rates in the mice.

Anderson says he plans to pursue further development of RNA cancer vaccines as well as vaccines that target infectious diseases such as HIV, malaria, or Ebola.

“We think there could be broad applications for this,” he says. “A particularly exciting area to think about is diseases where there are currently no vaccines.”

Materials provided by Massachusetts Institute of Technology

Soybean cyst nematode and egg

Researchers discover nematode with three sexes in Mono Lake

Mono Lake in California is a hostile location for the majority of life forms similar to the Antarctic deserts or the deepest parts of the sea. Only saline shrimp and diving flies can adapt to its super-salty waters apart from bacteria and algae.
Recently, eight new species of the microscopic worm have been discovered in the lake by researchers from the California Institute of Technology and it turns out one of them is a bit different.

The team reported that Auanema sp. which is one of the newly-discovered species of nematode has three different sexes. It can also endure a dosage of arsenic 500 times more than the human limit.

Nematodes are usually classified into males and hermaphrodites but Auanema sp. also has female worms. Moreover, researchers have noticed other fascinating sex characteristics such as the arrangement of genital papillae in males of Auanema sp. in the genus. This microscopic worm also gives birth to their offspring, which is unique in the egg-laying nematode world.

Scientists think that the peculiar characteristics of the worm essential for it to remain alive in the extremely alkaline waters of Mono Lake. Thus its extreme features are not a coincidence. Pei-Yin Shih said these extremophiles can teach a lot about dealing with stress. Their study reveals the number of details left to learn about how these 1,000-celled animals have managed to survive in such conditions.

The researchers found a likewise high arsenic resistance among two sister species while comparing the strange new species of the nematode to others in the same genus. There lies another reason for this surprising tolerance because none of these creatures lived in environments with high arsenic levels.

The authors said that previous Auanema species were separated from rich soils and dung containing high phosphate concentrations. Also, it is possible that adaptation to high phosphate levels in the environment could lead to increased arsenic resistance since arsenic absorption occurs adventitiously via phosphate transporters. Nematodes might be pre-adapted to life being extremophile. Their genetic resiliency and flexibility make it easier for them to live in places like Mono Lake. Only two other species had been found which is three times saltier than sea with an alkaline pH greater than baking soda. Thus, the discovery of eight more species was not a surprise.

Nematodes are the most abundant animal on Earth thus having a high probability of even survive in Mono Lake.
Researchers from Caltech segregated nematodes from across the lake and found several niches over the period of two years in which these nematodes were prospering. They included microbe grazers, parasites, and predators.

The authors concluded that nematodes are the superior animals of Mono Lake in species richness. The phylogenetic study tells that the nematodes developed from several colonization incidents, which is remarkable, given the recent history of Mono Lake’s extreme conditions.

There are approximately 57 billion nematodes for every human on Earth so these creatures can start living in the most extreme places in no time. Tullis Onstott, geoscientist told that it’s good to find one more place with nematodes and nothing much else. These creatures might still be living in the places with absolutely nothing else.

Journal Reference: Current Biology

Researchers identify the physical effects of stress and anxiety on cells

Researchers identify the physical effects of stress and anxiety on cells

As per new research, a combination of stress and anxiety might physically change the makeup of the mitochondrial cells. In our lifetime, we often deal with events that leave a lasting impression on our minds. Major incidents such as losing a loved one, war, divorce can lead to anxiety disorders along with panic attacks. Anxiety disorder is different from normal worrying since it is prolonged and does not reduce with time. It can be bad for our emotional and physical health since it interferes with the normal daily activities making them difficult to perform. 

According to the National Institute of Mental Health, anxiety disorders are impacted by a combination of our genes and the environment resulting in an overall stressful life. It has been observed that not all people facing traumatic events develop anxiety disorder raising the question of what makes some persons respond differently than others. 

To find the answer, scientists studied mice that had displayed symptoms of depression and anxiety such as staying alone after facing highly stressful situations. Changes in the genetic activity were then tracked along with the production of protein in the area of the brain which deals with stress and anxiety. These areas are the hippocampus, prefrontal cortex, nucleus accumbens, and amygdala. The research team used the “cross-species multi-omics” technique for analyzing the genes and proteins that are associated with mitochondrial cells. They found many changes in the mitochondria of the mice’s brain cells who were exposed to stress as compared to those who were not. After that blood samples of the patients who had panic disorder were tested and scientists detected similar mitochondrial changes in them.

The researchers mentioned in PLOS Genetics that the studies revealed a regular convergence of differentially expressed pathways related to mitochondria in blood samples of patients dealing with a panic disorder after a panic attack. This method of cellular energy metabolism might be a way in which animals deal with stress. 

Mitochondria, also known as the powerhouse of cells turn the food consumed into 90 percent of the chemical energy needed for the functioning of the body along with destroying the rogue cells. Dealing with a high amount of stress can affect how the mitochondria function leading to complicated health symptoms. 

Iiris Hovatta, University of Helsinki said that right now there is very little information on the effects of chronic stress on cellular energy metabolism. So these underlying mechanisms might be essential to the prevention of diseases related to stress. Genetic studies of the persons suffering from anxiety might lead to informed treatment which is currently limited to psychotherapy and medicines. 

Journal Reference: PLOS Genetics

DNA structure

New evidence of forces responsible for separation of DNA discovered

According to a piece of new evidence, the force which holds the DNA might also be responsible for change of shape so that its repair, gene shuffling and copying can take place. The iconic double helix structure of our DNA was discovered back in 1950. It has a structure similar to that of a twisted ladder in which the nitrogen base pairs in the middle are held by the hydrogen bonds. The findings appear in the Proceedings in the National Academy of Sciences. 

These bonds are considered as a “fundamental paradigm” because of their role in holding the DNA together. However, apart from this, one important consideration is that they are water-repelling or hydrophobic. 

Replication of DNA occurs with the help of many enzymes, in which DNA molecules are essentially unzipped by enzymes by the removal of hydrogen bonds. But this might not be the only way to do it. Scientists from the Chalmers University of Technology, Sweden have tested the DNA in an increased hydrophobic environment where they found that the water-repelling force can also be used for unraveling it. It loses its structure in a water-repelling environment when a solution of polyethylene glycol is added which is a semi-hydrophobic solution. 

Bobo Feng, lead author, and the chemical engineer said that the DNA is protected by the cells and not exposed to the hydrophobic environments that might have harmful molecules. But for its use, the DNA has to be opened up. It is kept in a water solution most of the time but the environment changes to a hydrophobic one when the DNA has to be edited, copied or repaired. 

Steven Brenner, a NASA molecular biophysicist said that although this is an important discovery of a new technique of melting the DNA for its repair, it has not been covered accurately by the media. The results do not suggest that hydrogen bonds are not important for the formation of DNA while the hydrophobic forces are. This is not a new idea as models considering hydrophobic interactions in the DNA date back to the 1990s. Researchers in 1997 tested the idea that only hydrogen bonds are sufficient to keep the double helix of DNA together. It was confirmed by a later study in 2004 that hydrogen bonding was not necessary for the stability of base pairs. A 2017 study revealed that cells are not affected by the lack of complementary hydrogen bonds as the synthetic bases are translated with the help of only hydrophobic forces. 

Floyd Romesberg, lead author of the 2017 study and a biochemist said that complementary hydrogen bonds might be considered the main definitions of DNA and RNA however there are other forces that can take part in the processes of information retrieval and storage. It often occurs that the biases of the chemist separating the molecules get reflected in the analysis of the model rather than the molecules themselves. Benner feels that self-explanations can convince us to understand what is happening if the models allow us to actually make things. 

Currently, both the concepts of hydrogen-bonding and hydrophobicity help us to make advances in human medicine besides powering NASA’s search for extraterrestrial organisms. 

Feng said that it was not surprising that this behavior was not identified to date as DNA was never placed in a hydrophobic environment. 

Journal Reference:  PNAS  (Proceedings of the National Academy of Sciences of the United States of America)

Green tea could help increase the potential of antibiotics to combat infection

Green tea could help increase the potential of antibiotics to combat infection

A new study suggests that a natural antioxidant that is commonly found in green tea may help increase antibiotics potential to combat infections induced by certain strains of bacteria that are becoming more resistant to modern medicines.

The compound, epigallocatechin (EGCG), can restore the effectiveness of aztreonam. It is an antibacterial usually used to treat infections caused by Pseudomonas aeruginosa, a bacterial pathogen. P. aeruginosa delivers a variety of conditions–from ear and blood infections to skin rashes–and is considered by world leaders to be a “serious” global threat.

“The World Health Organization has identified antibiotic-resistant Pseudomonas aeruginosa as a critical threat to human health. We have shown that, in conjunction with antibiotics already in use, we can effectively eliminate such threats with the use of natural products,” said the study co-author Roberto La Ragione of the University of Surrey in a statement.

Resistance makes bacteria stronger and more troublesome to kill and has been observed in human and wildlife communities in bacteria. Approximately 51,000 infections are recorded in the US each year in individuals who had recently been to a hospital or doctor’s office, more than 6,000 (13 percent) of whom are resistant to various drugs, leading in approximately 400 fatalities each year.

To determine the impacts of EGCG when used in conjunction with aztreonam, scientists performed in vitro testing to see how both separately and when used in tandem communicated with P. aeruginosa.

When used together, the “considerably increased bacterial killing” of EGCG and aztreonam is compared to when used separately. Besides, moth larvae in vitro testing of the two verified these results, while human skin cell testing shows minimal to no toxicity.

The researchers believe that EGCG may help promote increased uptake of aztreonam by increasing permeability in the bacteria and could also interfere with a “biochemical pathway” linked to antibiotic susceptibility. Published in the Journal of Medical Microbiology, the findings could help inform how healthcare professionals combat antibiotic resistance.

Antimicrobial resistance (AMR) is a serious threat to global public health. Without effective antibiotics, the success of medical treatments will be compromised. We urgently need to develop novel antibiotics in the fight against AMR,” said study author Jonathan Betts, from the University of Surrey, in a statement. “Natural products such as EGCG, used in combination with currently licensed antibiotics, maybe a way of improving their effectiveness and clinically useful lifespan.”

green tea advantages

Image credit: Pixabay

The study authors remark that further developments of alternatives to antibiotics may be beneficial in future clinical settings.

Journal Reference: Journal of Medical Microbiology

 

Woman's blood turns blue after applying Tooth-Numbing Gel

Woman’s blood turns blue after applying Tooth-Numbing Gel

Doctors have revealed that a woman’s blood has turned blue after she had used a numbing cream to treat toothache.

The 25-year-old, from Rhode Island, US, went to A&E after suffering from fatigue, shortness of breath and skin discoloration.

She informed physicians at Miriam Hospital in Providence that after using an over-the-counter topical pain reliever with benzocaine-a local anesthetic-she had woken up feeling “weak and blue.”

She had a navy blue tinge on her skin and nails. This is often a sign that the body does not get sufficient oxygen.

In a case report released in the New England Journal of Medicine, Dr. Otis Warren, who treated the lady, said that she refused to have used the whole bottle, but it was evident to him that she had “used a whole bunch of it.” He rapidly realized that she was suffering from methemoglobinemia, which occurs when iron in the blood changes and can no longer bind to oxygen to bring it around the body.

“I’m fragile, and I’m blue,” said Otis Warren, a Miriam Hospital doctor who treated the lady and spoke to NBC News, telling her physicians. The patient reported applying “large quantities” of topical benzocaine, a numbing drug, on an aching tooth the night before, Warren and colleagues wrote in the document on the situation of the woman released in The New England Journal of Medicine on Sept. 19.

The medication can have an unusual and potentially dangerous side effect like Benzocaine can cause iron in the blood to give up electrons, change the form, and no longer bind properly to oxygen, according to NBC. The body relies on strong bonds between iron and oxygen to move the life-sustaining element through the body. Without adequate oxygen, usually red blood can turn blue, and the skin and nails soon follow.

The condition, called methemoglobinemia, necessarily stifles the body’s tissues and can cause severe damage if blood oxygen levels drop below 70%, according to Medscape.

In this case, blood drawn from the patient’s arteries appeared deep navy blue, when it should have been bright red, according to the case report. What’s more, her blood oxygen level had dipped to 67%, when it should have been hovering near 100%, NBC reported. The doctors quickly administered a medication called methylene blue, which restores iron to its proper form within the blood.

After two doses of the drug, and spending a night in the hospital, the patient’s regular coloring returned, her blood oxygen levels rose and became standard, and she went home having fully recovered.

Journal Reference: The New England Journal of Medicine

Presence of deadly brain cells hijack normal cells to grow

Presence of deadly brain cells hijack normal cells to grow

Researchers are now starting to realize why it is so difficult to prevent specific brain cancers. And here is the reason behind it.

Three claims in the Journal Nature released on Wednesday observed that these lethal tumors incorporate into the electrical network of the brain and then hijack signals from healthy nerve cells to fuel their development.

“They are like vampires,” claims Dr. Frank Winkler, a neurologist at the University of Heidelberg in Germany and author of the research, feeding on brain activity.

But the study is also striving purpose. Scientists claim the results indicate that drugs that hinder the activity of individual brain cells or interrupt relations between tumor cells and healthy cells could slow down certain brain tumors.

Two of the three research examined high-grade gliomas, including glioblastoma, cancer that murdered Sen. John McCain in 2018, including Winkler’s.

“High-grade gliomas are an intractable collection of illnesses, and we have made very little clinical progress in treating these horrible brain cancers efficiently,” says Dr. Michelle Monje, associate professor of neurology and neurology at Stanford University and writer of other research.

In 2015, when the brain cells around them became more active, Monje was part of a team that discovered high-grade gliomas to grow quicker.

Monje’s team suspected that was because active neurons produce a substance that acts as fuel for gliomas. So the team put human glioma tumors in the brains of mice that had been genetically altered so they couldn’t provide this substance.

“There wasn’t just a slowing in the tumor growth, but there was a complete stagnation,” Monje states. The study was published in 2017.

deadly brainly cells

Credits: Pixabay

In people, though, Monje was pretty sure that high-grade gliomas were somehow causing healthy brain cells to become more active and produce more fuel. And she thought the cancer cells might be doing this by forming connections with healthy neurons and hijacking the electrical signals they provide.

The new studies appear to confirm this, and even show how.

Monje’s team found that some cancer cells were forming synapses — the connections between neurons — that could be seen with an electron microscope. They also found evidence of a more primitive direct link between cancer cells and healthy brain cells.

The research is likely to have a seismic impact on brain cancer research, says Andres Barria, a neuroscientist at the University of Washington who studies synapses and inscribed an editorial accompanying the three studies.

And that discovery could lead to new and better treatments for high-grade gliomas, which now typically kill a patient within two years.

“We hope that by decreasing the electrical signals that the tumors are receiving from the normal brain, that we might be able to complement existing therapies and extend survival and improve quality of life,” Monje remarks.

Journal Reference: Nature

Research suggests, avoid making decisions on an empty stomach

Research suggests, avoid making decisions on an empty stomach

Making important decisions while on an empty stomach can lead to poor choices. We all understand that food shopping is a bad idea when hungry, but a recent study from Dundee University indicates that individuals may want to prevent making any significant choices about the future on an empty stomach.

how to make smart decisions?

The research, conducted by Dr. Benjamin Vincent from the Psychology Department of the University, discovered that hunger considerably changed people’s decision-making, making them impatient and more likely to settle for a tiny reward that comes earlier than a bigger one promised at a later date.

The study indicates that being hungry changes preferences for food-free benefits and can translate into other types of choices, such as economic or interpersonal ones.

Benjamin Vincent, who conducted the research, thinks it is essential that individuals understand that their preferences may be affected by an empty stomach, and there is also a risk that those in poverty may make choices that reinforce their condition.

Dr. Vincent added: “This is an aspect of human behavior which could potentially be exploited by marketers, so people need to know their preferences may change when hungry.

When satiated and again, when they skipped a meal, participants in an experiment designed by Dr. Vincent were asked questions about food, money, and other benefits.

While it may have been unsurprising that hungry individuals were more likely to settle for lower food incentives that came earlier, scientists discovered that being hungry changes preferences for food-free benefits.

This suggests that a reluctance to defer gratification can translate into other types of choices, such as economic and interpersonal choices. Dr. Vincent believes it is essential that people know that their preferences may be affected by hunger in ways they do not necessarily predict.

Researchers noted that if you offer people a reward now or double that reward in the future, they were usually willing to wait for 35 days to increase the award, but when hungry this plummeted to three days.

The study is published in the latest edition of the journal Psychonomic Bulletin and Review.

 

Komodo Dragons reveal the chain of bones beneath their skin

Komodo Dragons reveal the chain of bones beneath their skin

Komodo dragons are scientifically known as Varanus komodoensis. One of our planet’s most enormous, fiercest, most impressive lizards, just got that much more incredible. A fresh discovery demonstrates that these animals are covered under their scaly skin in mail-like armor made from small bones, from nose to tail tip.

 

Why would a Komodo dragon need armor, you ask? These lizards are dominant, they are quick, they are venomous, and they can bring much bigger prey down than themselves, and their species maybe millions of years ancient.

Well, according to current studies, there is likely armor to safeguard the lizards from themselves that are other dragons from Komodo.

The clue is when during their growth, these lizards develop their bone-mail. Austin and Fort Worth Zoo researchers at the University of Texas performed thorough CT scans of freshly dead Komodo dragons, an adult and a juvenile.

Researchers at The University of Texas studied the animals and found their protective armor covers them from head to tail, making them more robust in battle.

Despite being the world’s most giant lizard and the dominant predator in their natural habitat, they still need protection – but only from other Komodo dragons.

Scientists determined this after scanning the reptiles with high-powered X-rays.

Using computed tomography (CT scan) technology, scientists revealed the natural armor of the beasts to look inside and digitally reconstruct the bodies of two dead dragon samples — one adult and one child.

The adult was well-equipped with armor, but in the child, it was absent.

It is a finding that indicates that it is not until adulthood that the bony plates appear. And other dragons are the only thing that adult dragons need protection from.

Young comodo dragons are spending quite some time in forests,’ Professor Christopher Bell said.

It is a finding that indicates that it is not until adulthood that the bony plates appear. And other dragons are the only thing that adult dragons need protection from.

‘And when they’re large enough to come out of the trees, that’s when they start getting in arguments with members of their species. That would be a point when extra armor would benefit’, added Bell.

Many varieties of lizards have bones embedded in their skin known as osteoderms. Scientists had known about osteoderms present in Komodo dragons since at least the 1920s when naturalist William D. Burden noted their ubiquity as an obstruction to the mass production of dragon leather.

But since the skin is the first organ that is removed when making a skeleton, scientists do not have much information about how they are shaped or arranged inside the surface or thoughts about what they’re used for.

The researchers were able to surmount this issue by analyzing the dragons at UT’s High-Resolution X-ray Computed Tomography Facility.

Journal Reference: The Anatomical Record

 

Researchers discover one of the largest ever flying reptiles in Canada

Researchers discover one of the largest ever flying reptiles in Canada

Several million years ago, in the place we now know as Canada, there was a flying reptile of the size of an airplane. This species of pterosaur has been recently identified and it is one of the largest flying animals discovered to date. It is named Cryodrakon boreas and it had a wingspan of nearly two giraffes. The study appears in the Journal of Vertebrate Paleontology.

This enormous beast could grow till lengths of 32 feet wing tip to wing tip and it lived in the Cretaceous period nearly 77 million years ago. It existed with dinosaurs such as Panoplosaurus and Hadrosaurus. Although it appeared like a dragon, it did not belong to the family of dinosaurs. It was a member of the flying reptiles, Azhdarchid group of pterosaurs which consists of the Arambourgiania and the Montanazhdarcho. 

These pterosaurs were carnivores and they consumed small animals such as lizards, baby dinosaurs and mammals. However, the azhdarchids lived mainly inland and were terrestrial. But the paleontologists believe that they had the ability to cross oceans by flying. Due to their preference and extremely pneumatic bones, their presence in fossils is not common. 

As described in the paper, their skeleton which contained remains of the wings, neck, and ribs were found almost 30 years ago at a site named Dinosaur Park Formation in Alberta, Canada. Initially, its identity was mistaken to be the species of azhdarchid, Quetzalcoatlus which was found in Texas. But analyses conducted thereafter revealed it to be a new species and the first pterosaur to be found in Canada. Its name Cryodrakon boreas means “cold dragon of north winds”. 

The main skeleton belonged to a younger individual whose wingspan is estimated to be nearly 16 feet. On the other hand, a neckbone from an adult suggests the wingspan might be till 32 feet thus making it to the comparison of the biggest group of pterosaurs such as Quetzalcoatlus. Quetzalcoatlus weighed nearly 250 kilograms with a wingspan of nearly 35 feet. 

Researchers think that Cryodrakon might have possessed the same structure and size of Quetzalcoatlus with similar flight muscle fractions and flight performance. Cryodrakon is believed to be heavier with a slightly more robust neck than Quetzalcoatlus. 

David Hone, the study’s lead author from Queen Mary University, London said that identifying Cryodrakon as a distinct species with respect to Quetzalcoatlus is significant for the study of the evolution of predatory pterosaurs in North America. 

Journal Reference:  Journal of Vertebrate Paleontology.