UCI, Swiss researchers eliminate brain tumors without damaging cognition.
Treating cancer without debilitating side effects has long been the holy grail of oncologists, and researchers at the University of California, Irvine and Switzerland’s Lausanne University Hospital may have found it.
Charles Limoli, professor of radiation oncology at UCI, and Marie-Catherine Vozenin, associate professor of radiation oncology at the Swiss facility, used an ultra-high dose rate of radiation therapy to eliminate brain tumors in mice, bypassing key side effects usually caused by cranial irradiation. Their findings are published in Clinical Cancer Research.
“It’s not unreasonable to expect that in 10 years, this may become a widespread option for radiotherapy patients worldwide,” Limoli said.
Traditional radiation therapy exposes a tumor and nearby normal tissue to radiation for several minutes at a time, but Flash radiation therapy (Flash-RT) allows delivery of the same dose in only tenths of seconds. The speed eliminates many of the toxicities that normally plague cancer survivors long after radiation treatments, significantly decreasing side effects such as inflammation and impairments to cognition.
As in traditional radiation therapy, the researchers fractionated the dose – divided the total over several sessions. Using Flash-RT, they found that the same total dose of radiation delivered at quicker dose rates removed brain tumors just as effectively as the traditional method.
“This is very important, since fractionation is the standard in the clinic and the easiest way to transfer Flash-RT at the clinical level,” said principal investigator Vozenin, an adjunct professor at UCI.
Though this work focused on the brain, Flash-RT has also been used to treat lung, skin and intestinal cancers, while still preventing many radiation-induced complications. These additional studies have been successful across several types of animals, including fish, mice, pigs, cats and one human subject.
“It seems that this treatment is going to be universally beneficial for most cancer types,” Limoli said.
Now that researchers have verified that the method works, groups around the world are developing machines that would make Flash technology available in clinics. One device is awaiting approval in the U.S. and Europe, and Vozenin plans to use it in two clinical trials at the Lausanne University Hospital early next year.
Meanwhile, she and Limoli are investigating the mechanisms behind Flash-RT’s beneficial effects to better understand how the technology works.
Said Limoli: “In the last 30 or 40 years, I’d say, there’s been nothing in the field of radiation sciences as exciting as this.”
References: Pierre Montay-Gruel, Munjal M Acharya, Partrik Gonçalves Jorge, Benoit Petit, Ioannis G Petridis, Philippe Fuchs, Ron Leavitt, Kristoffer Petersson, Maude Gondre, Jonathan Ollivier, Raphael Moeckli, François Bochud, Claude Bailat, Jean Bourhis, Jean-François Germond, Charles L Limoli and Marie-Catherine Vozenin, “Hypo-fractionated FLASH-RT as an effective treatment against glioblastoma that reduces neurocognitive side effects in mice”, Clin Cancer Res October 15 2020 DOI: 10.1158/1078-0432.CCR-20-0894 link: https://clincancerres.aacrjournals.org/content/early/2020/10/15/1078-0432.CCR-20-0894.article-info
Two fossils from a group of extinct seabirds represent the largest individuals ever found.
Fossils recovered from Antarctica in the 1980s represent the oldest giant members of an extinct group of birds that patrolled the southern oceans with wingspans of up to 21 feet that would dwarf the 11½-foot wingspan of today’s largest bird, the wandering albatross.
Called pelagornithids, the birds filled a niche much like that of today’s albatrosses and traveled widely over Earth’s oceans for at least 60 million years. Though a much smaller pelagornithid fossil dates from 62 million years ago, one of the newly described fossils — a 50 million-year-old portion of a bird’s foot — shows that the larger pelagornithids arose just after life rebounded from the mass extinction 65 million years ago, when the relatives of birds, the dinosaurs, went extinct. A second pelagornithid fossil, part of a jaw bone, dates from about 40 million years ago.
“Our fossil discovery, with its estimate of a 5-to-6-meter wingspan — nearly 20 feet — shows that birds evolved to a truly gigantic size relatively quickly after the extinction of the dinosaurs and ruled over the oceans for millions of years,” said Peter Kloess, a graduate student at the University of California, Berkeley.
The last known pelagornithid is from 2.5 million years ago, a time of changing climate as Earth cooled, and the ice ages began.
Kloess is the lead author of a paper describing the fossil that appears this week in the open access journal Scientific Reports. His co-authors are Ashley Poust of the San Diego Natural History Museum and Thomas Stidham of the Institute of Vertebrate Paleontology and Paleoanthropology at the Chinese Academy of Sciences in Beijing. Both Poust and Stidham received their Ph.Ds from UC Berkeley.
Birds with pseudoteeth
Pelagornithids are known as ‘bony-toothed’ birds because of the bony projections, or struts, on their jaws that resemble sharp-pointed teeth, though they are not true teeth, like those of humans and other mammals. The bony protrusions were covered by a horny material, keratin, which is like our fingernails. Called pseudoteeth, the struts helped the birds snag squid and fish from the sea as they soared for perhaps weeks at a time over much of Earth’s oceans.
Large flying animals have periodically appeared on Earth, starting with the pterosaurs that flapped their leathery wings during the dinosaur era and reached wingspans of 33 feet. The pelagornithids came along to claim the wingspan record in the Cenozoic, after the mass extinction, and lived until about 2.5 million years ago. Around that same time, teratorns, now extinct, ruled the skies.
The birds, related to vultures, “evolved wingspans close to what we see in these bony-toothed birds (pelagornithids),” said Poust. “However, in terms of time, teratorns come in second place with their giant size, having evolved 40 million years after these pelagornithids lived. The extreme, giant size of these extinct birds is unsurpassed in ocean habitats,””
The fossils that the paleontologists describe are among many collected in the mid-1980s from Seymour Island, off the northernmost tip of the Antarctic Peninsula, by teams led by UC Riverside paleontologists. These finds were subsequently moved to the UC Museum of Paleontology at UC Berkeley.
Kloess stumbled across the specimens while poking around the collections as a newly arrived graduate student in 2015. He had obtained his master’s degree from Cal State-Fullerton with a thesis on coastal marine birds of the Miocene era, between 17 million and 5 million years ago, that was based on specimens he found in museum collections, including those in the UCMP.
“I love going to collections and just finding treasures there,” he said. “Somebody has called me a museum rat, and I take that as a badge of honor. I love scurrying around, finding things that people overlook.”
Reviewing the original notes by former UC Riverside student Judd Case, now a professor at Eastern Washington University near Spokane, Kloess realized that the fossil foot bone — a so-called tarsometatarsus — came from an older geological formation than originally thought. That meant that the fossil was about 50 million years old instead of 40 million years old. It is the largest specimen known for the entire extinct group of pelagornithids.
The other rediscovered fossil, the middle portion of the lower jaw, has parts of its pseudoteeth preserved; they would have been up to 3 cm (1 inch) tall when the bird was alive. The approximately 12-cm (5-inch-) long preserved section of jaw came from a very large skull that would have been up to 60 cm (2 feet) long. Using measurements of the size and spacing of those teeth and analytical comparisons to other fossils of pelagornithids, the authors are able to show that this fragment came from an individual bird as big, if not bigger, than the largest known skeletons of the bony-toothed bird group.
A warm Antarctica was a bird playground
Fifty million years ago, Antarctica had a much warmer climate during the time known as the Eocene and was not the forbidding, icy continent we know today, Stidham noted. Alongside extinct land mammals, like marsupials and distant relatives of sloths and anteaters, a diversity of Antarctic birds occupied the land, sea and air.
The southern oceans were the playground for early penguin species, as well as extinct relatives of living ducks, ostriches, petrels and other bird groups, many of which lived on the islands of the Antarctic Peninsula. The new research documents that these extinct, predatory, large- and giant-sized bony-toothed birds were part of the Antarctic ecosystem for over 10 million years, flying side-by-side over the heads of swimming penguins.
“In a lifestyle likely similar to living albatrosses, the giant extinct pelagornithids, with their very long-pointed wings, would have flown widely over the ancient open seas, which had yet to be dominated by whales and seals, in search of squid, fish and other seafood to catch with their beaks lined with sharp pseudoteeth,” said Stidham. “The big ones are nearly twice the size of albatrosses, and these bony-toothed birds would have been formidable predators that evolved to be at the top of their ecosystem.”
Museum collections like those in the UCMP, and the people like Kloess, Poust and Stidham to mine them, are key to reconstructing these ancient habitats.
“Collections are vastly important, so making discoveries like this pelagornithid wouldn’t have happened if we didn’t have these specimens in the public trust, whether at UC Riverside or now at Berkeley,” Kloess said. “The fact that they exist for researchers to look at and study has incredible value.”
Fluorine-18-labeled fluciclovine PET/MRI demonstrates utility in the initial staging of high-risk prostate cancer, as well as for evaluating the response to androgen deprivation therapy.
According to an open-access article in ARRS’ American Journal of Roentgenology (AJR), fluorine-18-labeled fluciclovine PET/MRI demonstrated utility in the initial staging of high-risk prostate cancer, as well as for evaluating the response to androgen deprivation therapy (ADT).
Between January 2018 and February 2019, 14 men with newly diagnosed high-risk prostate cancer and negative or equivocal conventional staging imaging were enrolled in this prospective pilot study (ClinicalTrials.gov registration number NCT03264456). “All patients underwent pretreatment 18F-fluciclovine PET/MRI including multiparametric prostate MRI; twelve underwent 18F-fluciclovine PET/MRI after surgery or between ADT and radiotherapy,” explained lead investigator Samuel Joseph Galgano from the University of Alabama at Birmingham’s multidepartment team.
For all 14 patients, the biopsy-proven lesion in the prostate gland was accurately identified on both MRI and 18F-fluciclovine PET/MRI, and the activity noted on PET/MRI correlated with both the MRI-defined intraprostatic lesions and biopsy-proven prostate cancer. Suspected pelvic regional nodal metastases were detected in 3 patients on MRI vs 7 patients on PET/MRI. Of the three patients with suspected nodal metastases on MRI, 18F-fluciclovine PET/MRI was concordant for lymph node metastases and demonstrated additional suspected lymph node metastases not detected on MRI alone.
Ten of the 14 patients underwent ADT prior to radiation therapy. The primary intraprostatic lesion was accurately identified in all 10 patients, 7 of whom demonstrated suspicious lymph nodes on the pretreatment PET/MRI. Following ADT, all 10 patients demonstrated a decrease in tracer activity either with the primary intraprostatic lesion, all suspicious lymph nodes detected on the pretreatment 18F-fluciclovine PET/MRI, or both.
“Given the FDA approval and widespread availability of 18F-fluciclovine,” the authors of this AJR article concluded, “the findings could have impact in the immediate future in guiding initial management of patients with prostate cancer.”
Butterflies have long captured our attention due to their amazing color diversity. But why are they so colorful? A new publication led by researchers from Sweden and Germany suggests that female influence butterfly color diversity by mating with colorful males.
In many species, especially birds and butterflies, males are typically more colorful than females, a phenomenon known as dichromatism. In many dichromatic species, the more conspicuous sex is more vulnerable to predation. Certainly, the male peacock is a much easier target than the more camouflaged hen. Explaining why one member of a species would place itself in more danger was a challenge to Charles Darwin’s early views on evolution by natural selection, as Darwin envisioned natural selection acting to reduce such risks.
Examples of dichromatism in fact were one of the issues that lead him to develop his theory of sexual selection, where elaborate male traits could evolve through female preference for conspicuous males, even in the face of the increased dangers such males would encounter.
Today, many naturalists and biologists alike generally ascribe the exaggerated coloration of males as being due to sexual selection. However, when we see a species in which males are more colorful than females, sexual selection is not necessarily the only answer. An alternative route to dichromatism might begin with males and females both being very colorful, followed by natural selection acting upon females to make them less conspicuous, perhaps due to the cost of being easier prey. Stated another way, perhaps females become less colorful so they are better camouflaged and therefore preyed upon less. The argument that natural selection could give rise to dichromatism was posited by Darwin’s contemporary, Alfred Russel Wallace. Darwin and Wallace in fact argued for decades about the origins of dichromatism in birds and butterflies.
The reason for this long debate between Darwin and Wallace arises because, without knowing how males and females looked in evolutionary past, either sexual selection or natural selection could give rise to dichromatism. Since they had no way of formally assessing what species used to look like, their argument had few routes for resolution.
This is where researchers from Sweden (Stockholm University and Lund University) and Germany (University of Marburg) have recently made progress, by developing statistical means for inferring the ancestral color states of males and females over evolutionary time.
To do this, they first reconstructed the evolutionary relationships among European butterflies and put this into a time calibrated framework. Then they scanned scientific drawings of all these male and female butterfly species, and used that color information in its evolutionary context to estimate the direction of butterfly color evolution for each sex, and in relation to the amounts of dichromatism per species. “Tracking evolutionary colour vectors through time made it possible to quantify both the male and female contribution to dichromatism”, says Dr. Dirk Zeuss from the University of Marburg, who is coauthor of the new study.
“We find that the rates of color evolution in males are faster than in females”, says Dr. Wouter van der Bijl, the lead author of the study. While this finding itself suggested that males might be the target of sexual selection, further analysis was needed to rule out alternative explanations. For example, male color could be evolving rapidly when species are already dichromatic, but not when males and females start to first diverge from each other in color. By modelling both the changes in dichromatism and the changes in male and female color over evolutionary time, the researchers could calculate that changes in male color are twice as important to the evolution of dichromatism than changes in female color.
This finding suggests that Darwin was right, as it is consistent with female preference and thus sexual selection for colorful males being the driving force in color evolution. Thus, the researchers provided some resolution to the 150-year-old argument between Darwin and Wallace about the origins of dichromatism in butterflies, finding that Darwin’s, but not Wallace’s, model of dichromatism evolution explains the patterns better.
References: van der Bijl, W., Zeuss, D., Chazot, N., Tunström, K., Wahlberg, N., Wiklund, C., Fitzpatrick, J.L. and Wheat, C.W. (2020), Butterfly dichromatism primarily evolved via Darwin’s, not Wallace’s, model. Evolution Letters. doi:10.1002/evl3.199 link: https://onlinelibrary.wiley.com/doi/full/10.1002/evl3.199
It is common that neurons transmit information to another group of neurons by increasing or decreasing their activity, i.e. “firing rate changes”. In addition to firing rate changes, synchronized activity of a certain group of neurons, i.e. “correlated activity”, has been suggested to play an important role in conveying information. This study revealed that, in the basal ganglia, information for the movement control is conveyed primarily by firing rate changes and correlated activity play only minor role in healthy conditions (Figure).
The research team consists of Dr. Woranan Wongmassang, Professor Atsushi Nambu, and their colleagues recorded neuronal activity of multiple neurons simultaneously in the basal ganglia while monkeys performed a motor task that required their arm movements. They found that most neurons located in the arm regions of the basal ganglia showed firing rate changes in relation to arm movements. On the other hand, the percentage of neurons that showed correlated activity during the task was very small.
Professor Nambu claims, “Unlike in healthy conditions, a large proportion of neurons in the basal ganglia show strong synchronized activity in Parkinson’s disease. So, it is possible that symptoms could be improved by decreasing abnormally increased correlated activity in the basal ganglia. The findings provide important clues to develop effective treatment for Parkinson’s disease.”
Big tidal ranges some 400 million years ago may have initiated the evolution of bony fish and land vertebrates. This theory is now supported by researchers in the UK and at Uppsala University who, for the first time, have used established mathematical models to simulate tides on Earth during this period. The study has been published in Proceedings of the Royal Society A.
“During long periods of the Earth’s history, we’ve had small tidal ranges. But in the Late Silurian and Early Devonian, they seem to have been large in some parts of the world. These results appear highly robust, because even if we changed model variables such as ocean depth, we got the same patterns,” says Per Ahlberg, professor of evolutionary organismal biology at Uppsala University.
Between 420 and 380 million years ago (Ma) – that is, during the end of one geological period, the Silurian, and beginning of the next, the Devonian – Earth was a completely different world from now. Instead of today’s well-known continents there were other land masses, clustered in the Southern Hemisphere. Stretching across the South Pole was the huge continent of Gondwana. North of it was another big one known as Laurussia, and squeezed between the two were a few small continents. Other salient differences compared with now were that Earth’s day lasted only 21 hours, since our planet revolved faster on its own axis, and the Moon looked much larger because its orbit was closer to Earth.
Life on land had gradually begun to get established. But the vertebrates, then consisting only of various kinds of fish, were still to be found only in the oceans. Then, during the Devonian, immense diversification of fish took place. One group to emerge was the bony fish, which make up more than 95 per cent of all fish today but were also the ancestors of terrestrial vertebrates. The earliest bony fish were the first animals to evolve lungs. What set off the evolution of bony fish, and how some of them started to adapt to a life on land, has not been clarified. One theory is that it happened in tidal environments where, in some periods, fish had been isolated in pools as a result of particularly large tides. This challenging habitat may have driven the evolution of lungs and, later on, the transformation of fins into front and hind legs.
To test this tidal theory, researchers at Uppsala University, in collaboration with colleagues from the Universities of Oxford and (in Wales) Bangor, used an established mathematical model of the tidal system for the first time to simulate, in detail, the tides in the Late Silurian and Early Devonian. Data on the positions of the continents, the distance of the Moon, the duration of Earth’s day, our planet’s gravity and the physical properties of seawater were fed into the model. These simulations showed unequivocally that the period, just like that of the present day, was one when large tides occurred in some places. The small continent of South China on the Equator showed a difference of more than four metres in sea level between high and low tide. The existence of tides at the time has previously been verified through studies of geological strata, but determining the extent of the difference between low and high tide has not been feasible. To researchers this news has been interesting, since fossil finds indicate that it was specifically around South China that bony fish originated.
“Our results open the door to further and even more detailed tidal analyses of key episodes in Earth’s past. The method can be used to explore the possible role of tides in other evolutionary processes of vertebrate development. And perhaps, conversely, whether tides, with their influence on ocean dynamics, played a part in the big marine extinctions that have taken place again and again in Earth’s history,” Ahlberg says.
References: H.M. Byrne et al. (2020), A key environmental driver of osteichthyan evolution and the fish-tetrapod transition?, Proceedings of the Royal Society A. DOI: 10.1098/rspa.2020.0355link: http://dx.doi.org/10.1098/rspa.2020.0355
The UNC School of Medicine lab of Qi Zhang, PhD, used nuclear magnetic resonance imagine to discover an RNA-centric mechanism for regulating the creation of a microRNA in response to environmental stimuli.
MicroRNAs (miRNAs) are evolutionarily conserved small noncoding RNAs – bits of genetic code that serve as critical gene regulators in many aspects of biological processes important for human health. Due to their essential roles in gene regulation, miRNAs are tightly regulated, and abnormal miRNA expressions have been linked to cancer, neurological disorders, cardiovascular diseases, and other diseases.
Understanding how miRNAs are regulated has been the focus of intense recent study. Over the years, scientists have discovered multiple protein regulators of miRNA biogenesis cellular pathways, and it is often perceived that these protein factors act on largely passive miRNA processing intermediates to direct their maturation. Now, the lab of Qi Zhang, PhD, associate professor in the UNC Department of Biochemistry and Biophysics, discovered a new RNA-centric mechanism by which miRNA processing intermediates can play direct, active roles in regulating miRNA biogenesis.
These findings, published in the journal Nature Chemical Biology, unveil that a ‘hidden’ layer of regulation by which the intrinsic dynamic ensemble of miRNA processing intermediates can direct the outcome of important biological processes in response to environmental and cellular stimuli in the absence of protein factors. If these processes go awry, then disease could result. Understanding the roles of miRNAs in disease is a needed step in finding new routes to better therapeutics.
MicorRNA-21 (miR-21) is involved in the creation, progression, metastasis of cancerous tumors, and it is involved in cell survival. When Zhang’s lab studied miR-21 using NMR relaxation dispersion – an advanced imaging technique capable of detecting sparsely populated transient states that often evade conventional detection techniques – they found the precursor of miR-21 exists as an ensemble of dynamic conformational states, which is surprisingly sensitive to the acidity of the environment.
They discovered that, across physiological conditions, about 1 – 15% of the miR-21 precursor carries one additional proton, the smallest chemical modification known as protonation. With a lifetime of approximately 0.8 milliseconds, this protonated state sequesters a key residue into a new structure that substantially enhances the efficiency of processing the precursor into mature miR-21.
With these powerful “imaging” techniques, scientists can now unveil transient RNA states as the ‘hidden’ layers of regulation, including a fleeting riboswitch state important in controlling gene transcription – a state the Zhang laboratory discovered in 2017.
“We think these techniques add more promise for new strategies to create RNA-targeted therapeutics,” said Zhang, a member of the UNC Lineberger Comprehensive Cancer Center. “And that is our goal; we need better targeted therapies for many diseases including cancers.”
Scientists have long believed that the brain protects itself from an aggressive immune response to keep down inflammation. However, that evolutionary control may work against it when a cancer cell attempts to spread to the brain, researchers at the University of Notre Dame have discovered.
In newly published research in the journal Cell, researchers showed that one type of cell important for immunity, called a myeloid cell, can suppress the immune response — which has the effect of allowing breast cancer cells to metastasize to the brain to form secondary tumor cells there.
“We wanted to understand how the brain immune environment responds to the tumor, and there are so many different cells, and so many changes,” said Siyuan Zhang, the Dee Associate Professor in the Department of Biological Sciences, a researcher for Harper Cancer Research Institute and a co-author on the paper. “The traditional belief was that the process described in this paper would be anti-tumor, but in our case, after a lot of experimenting, we discovered it is a proponent of metastasis.”
Through single-cell sequencing — not powerful enough even a few years ago for this type of work — and an imaging technique, the researchers discovered that a myeloid cell type called microglia promoted the outgrowth of breast cancer that has spread to the brain by the expression of several proteins. The microglia release one protein — an immune cell-attracting protein called CXCL10 — to recruit more microglia to the metastasis. All these microglia express a protein named VISTA, which serves as protection against brain inflammation. But when faced with a cancer cell, this two-part process suppressed important T-cells. T-cells, which heighten the body’s immune response, would usually prevent the spread of cancer throughout the body.
The activation of the VISTA checkpoint had not previously been known as a potential promoter of brain metastasis, said the paper’s lead author, Ian Guldner, a graduate student in Zhang’s lab. In addition to using a mouse model for the research, the team used data mining techniques to validate how humans’ brains would respond.
Clinically, the discovery is relevant, because antibodies have been developed that blocked VISTA in humans, Guldner said. However, significant additional work needs to be performed to ensure the safe and effective use of VISTA-blocking antibodies in people with brain metastases.
Learning about the structures within cells in the brain will help researchers not only understand cancer, but also degenerative diseases such as Parkinson’s, multiple sclerosis and Alzheimer’s, Zhang said.
“The brain immune system is a very active field, since brain cells are dysregulated during the aging process,” Zhang said. “There is so much to learn.”
A joint research group led by Prof. Jens Eisert of Freie Universität Berlin and Helmholtz-Zentrum Berlin (HZB) has shown a way to simulate the quantum physical properties of complex solid state systems. This is done with the help of complex solid state systems that can be studied experimentally. The study was published in the renowned journal Proceedings of the National Academy of Sciences of the United States of America (PNAS).
“The real goal is a robust quantum computer that generates stable results even when errors occur and corrects these errors,” explains Jens Eisert, professor at Freie Universität Berlin and head of a joint research group at HZB. So far, the development of robust quantum computers is still a long way off, because quantum bits react extremely sensitively to the smallest fluctuations in environmental parameters.
But now a new approach could promise success: two postdocs from the group around Jens Eisert, Maria Laura Baez and Marek Gluza have taken up an idea of Richard Feynman, a brilliant US-American physicist of the post-war period. Feynman had proposed to use real systems of atoms with their quantum physical properties to simulate other quantum systems. These quantum systems can consist of atoms strung together like pearls in a string with special spin properties, but could also be ion traps, Rydberg atoms, superconducting Qbits or atoms in optical lattices. What they have in common is that they can be created and controlled in the laboratory. Their quantum physical properties could be used to predict the behaviour of other quantum systems. But which quantum systems would be good candidates? Is there a way to find out in advance?
Eisert’s team has now investigated this question using a combination of mathematical and numerical methods. In fact, the group showed that the so-called dynamic structure factor of such systems is a possible tool to make statements about other quantum systems. This factor indirectly maps how spins or other quantum quantities behave over time, it is calculated by a Fourier transformation.
“This work builds a bridge between two worlds,” explains Jens Eisert. “On the one hand, there is the Condensed Matter Community, which studies quantum systems and gains new insights from them – and on the other hand there is Quantum Informatics – which deals with quantum information. We believe that great progress will be possible if we bring the two worlds together,” says the scientist.
References: Maria Laura Baez, Marcel Goihl, Jonas Haferkamp, Juani Bermejo-Vega, Marek Gluza, Jens Eisert, “Dynamical structure factors of dynamical quantum simulators”, PNAS 2020. DOI: 10.1073/pnas.2006103117 http://dx.doi.org/10.1073/pnas.2006103117