Culture

New imaging system and artificial intelligence algorithm accurately identify brain tumors

image: Stimulated Raman histologic images of diffuse astrocytoma (left) and meningioma (right).

Image: 
Daniel Orringer, NYU Langone Health

A novel method of combining advanced optical imaging with an artificial intelligence algorithm produces accurate, real-time intraoperative diagnosis of brain tumors, a new study finds.

Published in Nature Medicine on January 6, the study examined the diagnostic accuracy of brain tumor image classification through machine learning, compared with the accuracy of pathologist interpretation of conventional histologic images. The results for both methods were comparable: the AI-based diagnosis was 94.6% accurate, compared with 93.9% for the pathologist-based interpretation.

The imaging technique, stimulated Raman histology (SRH), reveals tumor infiltration in human tissue by collecting scattered laser light, illuminating essential features not typically seen in standard histologic images.

The microscopic images are then processed and analyzed with artificial intelligence, and in under two and a half minutes, surgeons are able to see a predicted brain tumor diagnosis. Using the same technology, after the resection, they are able to accurately detect and remove otherwise undetectable tumor.

"As surgeons, we're limited to acting on what we can see; this technology allows us to see what would otherwise be invisible, to improve speed and accuracy in the OR, and reduce the risk of misdiagnosis," says senior author Daniel A. Orringer, MD, associate professor of Neurosurgery at NYU Grossman School of Medicine, who helped develop SRH and co-led the study with colleagues at the University of Michigan. "With this imaging technology, cancer operations are safer and more effective than ever before."

How the Study Was Conducted

To build the artificial intelligence tool used in the study, researchers trained a deep convolutional neural network (CNN) with more than 2.5 million samples from 415 patients to classify tissue into 13 histologic categories that represent the most common brain tumors, including malignant glioma, lymphoma, metastatic tumors, and meningioma.

In order to validate the CNN, researchers enrolled 278 patients undergoing brain tumor resection or epilepsy surgery at three university medical centers in the prospective clinical trial. Brain tumor specimens were biopsied from patients, split intraoperatively into sister specimens, and randomly assigned to the control or experimental arm.

Specimens routed through the control arm--the current standard practice--were transported to a pathology laboratory and went through specimen processing, slide preparation by technicians, and interpretation by pathologists, a process which takes 20-30 minutes. The experimental arm was performed intraoperatively, from image acquisition and processing to diagnostic prediction via CNN.

Notably, the diagnostic errors in the experimental group were unique from the errors in the control group, suggesting that a pathologist using the novel technique could achieve close to 100% accuracy. The system's precise diagnostic capacity could also be beneficial to centers that lack access to expert neuropathologists.

"SRH will revolutionize the field of neuropathology by improving decision-making during surgery and providing expert-level assessment in the hospitals where trained neuropathologists are not available," says Matija Snuderl, MD, associate professor in the Department of Pathology at NYU Grossman School of Medicine and a co-author of the study.

NYU Langone's Brain and Spine Tumor Center Offers Cutting-Edge Treatment

Dr. Orringer joined NYU Langone in August 2019, bringing with him the SRH technology he helped to develop. NYU Langone's Brain and Spine Tumor Center is the first to offer this technique, using Invenio's NIO Laser Imaging System, in the Northeast.

The newest addition to the center's comprehensive suite of neurosurgical imaging technologies, SRH works in concert with intraoperative MRI and fluorescence-guided surgery to provide high-resolution precision guidance for NYU Langone's world-class neurosurgeons.

"NYU Langone's Department of Neurosurgery has long been a leader in bringing the most advanced treatment options to our patients," says John G. Golfinos, MD, Joseph P. Ransohoff Professor of neurology and chair of the Department of Neurosurgery. "With the addition of Dr. Orringer's expertise and this game-changing technology, we're now even better equipped to provide safe surgeries and quality outcomes for the most complex brain tumor cases."

The implementation of this new system is the most recent of NYU Langone's efforts to integrate artificial intelligence in clinical practice to improve diagnostics of cancer. Researchers and clinicians at NYU Langone's Perlmutter Cancer Center have made recent strides in lung cancer, breast cancer, and brain tumor.

Credit: 
NYU Langone Health / NYU Grossman School of Medicine

Over-hunting walruses contributed to the collapse of Norse Greenland, study suggests

image: Church ruins from Norse Greenland's Eastern Settlement.

Image: 
James H. Barrett

The mysterious disappearance of Greenland's Norse colonies sometime in the 15th century may have been down to the overexploitation of walrus populations for their tusks, according to a study of medieval artefacts from across Europe.

Founded by Erik the Red around 985AD after his exile from Iceland (or so the Sagas tell us), Norse communities in Greenland thrived for centuries - even gaining a bishop - before vanishing in the 1400s, leaving only ruins.

Latest research from the universities of Cambridge, Oslo and Trondheim has found that, for hundreds of years, almost all ivory traded across Europe came from walruses hunted in seas only accessible via Norse settlements in south-western Greenland.

Walrus ivory was a valuable medieval commodity, used to carve luxury items such as ornate crucifixes or pieces for games like chess and Viking favourite hnefatafl. The famous Lewis chessmen are made of walrus tusk.

However, the study also indicates that, as time wore on, the ivory came from smaller animals, often female; with genetic and archaeological evidence suggesting they were sourced from ever farther north - meaning longer and more treacherous hunting voyages for less reward.

Increasingly globalised trade saw elephant ivory flood European markets in the 13th century, and fashions changed. There is little evidence of walrus ivory imports to mainland Europe after 1400.

Dr James H. Barrett, from the University of Cambridge's Department of Archaeology, argues that the Norse abandonment of Greenland may have been precipitated by a "perfect storm" of depleted resources and volatile prices, exacerbated by climate change.

"Norse Greenlanders needed to trade with Europe for iron and timber, and had mainly walrus products to export in exchange," said Barrett, lead author of the study published in Quaternary Science Reviews.

"We suspect that decreasing values of walrus ivory in Europe meant more and more tusks were harvested to keep the Greenland colonies economically viable."

"Mass hunting can end the use of traditional haul-out sites by walruses. Our findings suggest that Norse hunters were forced to venture deeper into the Arctic Circle for increasingly meagre ivory harvests. This would have exacerbated the decline of walrus populations, and consequently those sustained by the walrus trade."

Other theories for collapse of the colonies have included climate change - the "Little Ice Age", a sustained period of lower temperatures, began in the 14th century - as well as unsustainable farming methods and even the Black Death.

"An overreliance on walrus ivory was not the only factor in Norse Greenland's demise. However, if both the population and price of walrus started to tumble, it must have badly undermined the resilience of the settlements," says co-author Bastiaan Star of the University of Oslo. "Our study suggests the writing was on the wall."

Analysis using carved artefacts would risk damage, so researchers examined pieces of "rostrum": the walrus skull and snout to which tusks remained attached during shipment, creating a protective "package" that got broken up in the ivory workshops of medieval trading centres such as Dublin, Trondheim and Bergen.

In total, the team studied 67 rostra taken from sites across Europe, dating between the 11th and 15th century. Ancient DNA (25 samples) and stable isotopes (31 samples) extracted from samples of bone, as well as tusk socket size, provided clues to the animals' sex and origins.

The stable isotope analysis was conducted by Cambridge's Dorothy Garrod Laboratory for Isotopic Analysis, and the DNA analysis by Oslo's Department of Biosciences.

The researchers also studied traces of "manufacturing techniques" - changing styles of butchery and skull preparation - to help place the walrus remains in history.

While impossible to determine exact provenance, the researchers detected a shift in European walrus finds around the 13th century to walruses from an evolutionary branch most prevalent in the waters around Baffin Bay.

These animals must have been hunted by sailing northwest up the Greenland coast, and more recent specimens were smaller and often female. "If the original hunting grounds of the Greenland Norse, around Disko Bay, were overexploited, they may have journeyed as far north as Smith Sound to find sufficient herds of walrus," said Barrett.

Norse artefacts have previously been found among the remains of 13th and 14th century Inuit settlements in this most northern of regions. One former Inuit camp on an islet off Ellesmere Island contained the rivets of a Norse boat - quite possibly a hunting trip that never returned.

"Ancestors of the Inuit occupied northern Greenland during the time of the Norse colonies. They probably encountered and traded with the Norse," said Barrett. "That pieces of a Norse boat were found so far north hints of the risks these hunters might have ended up taking in their quest for ivory."

Barrett points out that the Inuit of the region favoured female walruses when hunting, so the prevalence of females in Greenland's later exports could imply a growing Norse reliance on Inuit supply.

He says that hunting season for the Norse would have been short, as seas were choked with ice for much of the year. "The brief window of summer would have barely been sufficient for rowing the many hundreds of miles north and back."

The legend of Erik the Red itself may mask what Barrett calls "ecological globalisation": the chasing of natural resources as supply dwindles. Recent research revealed that Greenland might have been settled only after Icelandic walruses were hunted to exhaustion.

Ultimately, having been highly prized for centuries, the marbled appearance of walrus ivory fell out of favour as West African trade routes opened up, and the homogenous finish of elephant ivory became de rigueur in the 13th century.

One account suggest that in the 1120s, Norse Greenlanders used walrus ivory to secure their own bishopric from the King of Norway. By 1282, however, the Pope requests his Greenland tithes be converted from walrus tusk into silver or gold.

"Despite a significant drop in value, the rostra evidence implies that exploitation of walruses may have even increased during the thirteen and fourteenth centuries," said Barrett.

"As the Greenlanders chased depleted walrus populations ever northwards for less and less return in trade, there must have come a point where it was unsustainable. We believe this 'resource curse' undermined the resilience of the Greenland colonies."

Credit: 
University of Cambridge

2017 San Diego wildfire increased pediatric ER visits for breathing problems

image: Following a 2017 San Diego wildfire, increased number of children visited the ER with respiratory problems, including asthma.

Image: 
ATS

Jan. 6, 2020--A small wildfire in San Diego County in 2017 resulted in a big uptick in children visiting the emergency room for breathing problems, according to new research published online in the Annals of the American Thoracic Society.

In "Increase in Pediatric Respiratory Visits Associated with Santa Ana Wind-driven Wildfire Smoke and PM2.5 levels in San Diego County," Sydney Leibel, MD, MPH, and co-authors report that the Lilac Fire, which burned from Dec. 7-16, resulted in 16 more visits each day to the ER by children under the age of 19 for breathing complaints. The complaints included difficulty breathing, respiratory distress, wheezing and asthma.

Before it was extinguished, the Lilac Fire burned 4,100 acres. In 2017, wildfires burned more than 1.5 million acres across California, according to the state's Department of Forestry & Fire Protection.

"We conducted this study because wildfires are becoming increasingly common in California," said Dr. Leibel, a pediatric allergist/immunologist at Rady Children's Hospital in San Diego and an assistant professor of pediatrics at UC San Diego School of Medicine. "While there is significant data on the respiratory effects of theses wildfires in adults, we wanted to investigate the health effects of wildfire smoke in the vulnerable pediatric population."

In collaboration with the Scripps Institute of Oceanography, the authors also demonstrated how the regional phenomenon known as the Santa Ana Winds have increased the health impacts of these fires in the county.

The researchers also found that children under the age of 12 were more likely to develop breathing problems leading to an ER visit than older children. The authors report that they found a similar pattern of increased visits for respiratory complaints to the county's urgent care centers during the wildfire, especially by younger children.

To account for seasonal changes in ER and urgent care visits, the researchers analyzed health electronic medical records from 2011-17. They also analyzed levels of fine particle pollution, known scientifically as PM2.5. over the same time period. The researchers estimated that there was a five-fold increase in these tiny particles during the wildfire.

The authors said that the five zip codes with the largest changes in ER and urgent care visits for pediatric respiratory problems were located downwind of the wildfire, which was driven by the Santa Ana Winds blowing from northeast towards the county's more populated coastal communities.

Given predicted changes in climate and population growth, the authors write that the impact of wildfires in the county is likely to grow in the coming decades.

"Our findings suggest that public health efforts focused on protecting young children with early warning systems and mitigation efforts downwind of Santa Ana Wind-driven wildfires may decrease the impact of these destructive wildfires in the future," Dr. Leibel said.

Credit: 
American Thoracic Society

Researchers create nanoscale sensors to better see how high pressure affects materials

image: Krishan Kumar Pandey, Valery Levitas and Mehdi Kamrani, left to right, study materials subject to high pressures in Levitas' Iowa State University laboratory.

Image: 
Photo by Christopher Gannon/Iowa State University

AMES, Iowa - Researchers have developed new nanoscale technology to image and measure more of the stresses and strains on materials under high pressures.

As the researchers reported in the journal Science, that matters because, "Pressure alters the physical, chemical and electronic properties of matter."

Understanding those changes could lead to new materials or new phases of matter for use in all kinds of technologies and applications, said Valery Levitas, a paper co-author and Anson Marston Distinguished Professor in Engineering at Iowa State University, the Vance Coffman Faculty Chair and professor in aerospace engineering.

Levitas - whose lab specializes in experimental testing and computational modeling of high-pressure sciences - said the new sensing technology could also advance high-pressure studies in chemistry, mechanics, geology and planetary science.

Development and demonstration of the technology is described in a paper, "Imaging stress and magnetism at high pressures using a nanoscale quantum sensor," just published by Science. The lead author is Norman Yao, an assistant professor of physics at the University of California, Berkeley. Iowa State's Mehdi Kamrani, a doctoral student in aerospace engineering, is also a co-author.

The paper describes how the researchers fit a series of nanoscale sensors - they call them nitrogen-vacancy color centers - into diamonds used to exert high pressures on tiny material samples. Typically, those "diamond anvil" experiments with materials squeezed between two diamonds have allowed researchers to measure pressure and changes in volume.

The new system allows researchers to image, measure and calculate six different stresses - a much more comprehensive and realistic measure of the effects of high pressure on materials. The new tests also allow researchers to measure changes in a material's magnetism.

"This has been one of the key problems in high-pressure science," Levitas said. "We need to measure all six of these stresses across a diamond and sample. But it's hard to measure all of them under high pressure."

Levitas' lab has done unique experiments by putting materials under high pressure and then giving them a twist, allowing researchers to drastically reduce phase transformation pressure and search for new phases of matter, which may have technological applications.

The lab also does multiscale computer modeling for high-pressure diamond anvil experiments - Levitas says it's the only lab in the world doing such simulations. He said that experience with high-pressure simulations was why he was invited to collaborate with Yao's sensor project. Simulations made it possible to reconstruct fields of all six stresses in the entire diamond anvil, where they could not be measured, as well as verify experimental results. Levitas plans to use this sensor in his lab.

The sensor enables "pursuit of two complementary objectives in high-pressure science: understanding the strength and failure of materials under pressure (e.g., the brittle-ductile transition) and discovering and characterizing exotic phases of matter (e.g., pressure-stabilized high-temperature superconductors)," the researchers wrote in their paper.

The nitrogen-vacancy sensing technology described in the paper has also been used to measure other material properties - for example, electric and thermal characteristics. The researchers wrote it "can now straightforwardly be extended to high-pressure environments, opening up a large range of experiments for quantitatively characterizing materials at such extreme conditions."

Credit: 
Iowa State University

Laser pulse creates frequency doubling in amorphous dielectric material

image: A red laser creates nonlinear effects with tiny triangles of gold. The blue beam shows the frequency-doubled light and the green beam controls the hot-electron migration.

Image: 
Rob Felt, Georgia Tech

Researchers have demonstrated a new all-optical technique for creating robust second-order nonlinear effects in materials that don't normally support them. Using a laser pulse fired at an array of gold triangles on a titanium dioxide (TiO2) slab, the researchers created excited electrons that briefly doubled the frequency of a beam from a second laser as it bounced off the amorphous TiO2 slab.

By widening the range of optical materials useful for micro- and nanoscale optoelectronic applications, the work could give optical engineers new options for creating second-order nonlinear effects, which are important in such areas as optical computers, high-speed data processors and bioimaging safe for use in the human body.

"Now that we can optically break the crystalline symmetry of traditionally linear materials such as amorphous titanium dioxide, a much wider range of optical materials can be adopted in the mainstream of micro- and nanotechnology applications such as high-speed optical data processors," said Wenshan Cai, a professor in the School of Electrical and Computer Engineering at the Georgia Institute of Technology.

The proof-of-concept findings were reported January 2 in the journal Physical Review Letters. The research received support from the Office of Naval Research, the National Science Foundation, and the U.S. Department of Energy Office of Science.

A majority of optical materials tend to have a symmetric crystal structure that limits their ability to create second-order nonlinear effects such as frequency doubling that have important technological applications. Until now, this symmetry could only be interrupted by applying electrical signals or mechanical strain to the crystal.

In the laboratory, Cai and collaborators Mohammad Taghinejad, Zihao Xu, Kyu-Tae Lee and Tianquan Lian created an array of tiny plasmonic gold triangles on the surface of a centrosymmetric TiO2 slab. They then illuminated the TiO2/gold structure with a pulse of red laser light, which acted as an optical switch for breaking the crystal symmetry of the material. The amorphous TiO2 slab would not naturally support strong second-order nonlinear effects.

"The optical switch excites high-energy electrons inside the gold triangles, and some of the electrons migrate to the titanium dioxide from the triangles' tips," Cai explained. "Since the migration of electrons to the TiO2 slab primarily happens at the tips of triangles, the electron migration is spatially an asymmetric process, fleetingly breaking the titanium dioxide crystal symmetry in an optical fashion."

The induced symmetry breaking effect is observed almost instantaneously after the red laser pulse is triggered, doubling the frequency of a second laser that is then bounced off the titanium dioxide containing the excited electrons. The lifetime of the induced second-order nonlinearity generally depends on how fast electrons can migrate back from the titanium dioxide to the gold triangles after the disappearance of the pulse. In the case study reported by the researchers, the induced nonlinear effect lasted for a few picoseconds, which the researchers say is enough for most applications where short pulses are used. A stable continuous wave laser can make this effect last for as long as the laser is on.

"The strength of the induced nonlinear response strongly depends on the number of electrons that can migrate from gold triangles to the titanium dioxide slab," Cai added. "We can control the number of migrated electrons through the intensity of the red laser light. Increasing the intensity of the optical switch generates more electrons inside the gold triangles, and therefore sends more electrons into the TiO2 slab."

Additional research will be needed to build on the proof of concept, which showed for the first time that the crystal symmetry of centrosymmetric materials can be broken by optical means, via asymmetric electron migrations.

"To approach the practical criteria detailed on the essence of our technique, we still need to develop guidelines that tell us what combination of metal/semiconductor material platform should be used, what shape and dimension would maximize the strength of the induced second-order nonlinear effect, and what range of laser wavelength should be used for the switching light," Cai noted.

Frequency doubling is just one potential application for the technique, he said.

"We believe that our findings not only provide varieties of opportunities in the field of nonlinear nanophotonics, but also will play a major role in the field of quantum electron tunneling," Cai added. "Indeed, built upon the accumulated knowledge in this field, our group is devising new paradigms to employ the introduced symmetry breaking technique as an optical probe for monitoring the quantum tunneling of electrons in hybrid material platforms. Nowadays, achieving this challenging goal is only possible with scanning tunneling microscopy (STM) techniques, which are very slow and show low yield and sensitivity."

Credit: 
Georgia Institute of Technology

Sleep difficulties in children with Autism caused by shallower brain waves

BEER-SHEVA, Israel, January 6, 2020 -- Children with autism have more significant sleep difficulties caused by shallower brain waves than typically developing children, according to researchers at Ben-Gurion University of the Negev (BGU). The study was reported in Sleep, the premier journal in the field.

"For the first time, we found that children with more serious sleep issues showed brain activity that indicated more shallow and superficial sleep," says BGU Prof. Ilan Dinstein," head of the National Autism Research Center of Israel and a member of BGU's Department of Psychology.

"We also found a clear relationship between the severity of sleep disturbances as reported by the parents and the reduction in sleep depth. It appears that children with autism, and especially those whose parents reported serious sleep issues, do not tire themselves out enough during the day, do not develop enough pressure to sleep and do not sleep as deeply."

Previous studies have shown that 40% to 80% of children on the autism spectrum have some form of sleep disturbances - trouble falling asleep, frequently awakening during the night and rising early - which create severe challenges for the children and their families. Determining the causes that create these sleep disturbances is a first critical step in finding out how to mitigate them.

The research team, led by Prof. Dinstein, examined the brain activity of 29 children with autism and 23 children without. Their brain activity was recorded as they slept during an entire night in the Sleep Lab at Soroka University Medical Center, managed by Prof. Ariel Tarasiuk.

Normal sleep starts with periods of deep sleep that are characterized by high amplitude slow brain waves. However, the recordings revealed that the brain waves of children with autism are, on average, 25% weaker (shallower) than those of typically developing children, indicating that they have trouble entering deep sleep -- the most critical aspect of achieving a restful and rejuvenating sleep experience.

Now that the team has identified the potential physiology underlying these sleep difficulties, BGU researchers are planning follow-up studies to determine how to generate deeper sleep and larger brain waves. This could include increasing daytime physical activity, behavioral therapies and pharmacological alternatives, such as medical cannabis.

Credit: 
American Associates, Ben-Gurion University of the Negev

Dogs and wolves are both good at cooperating

video: The test apparatus involved a barrier separating the participants from a food reward, with two openings on opposite ends that were controlled by a researcher. When the first animal approached an opening, the door before it would shut while the opposite door remained open, allowing the partner to enter first and access the food. The door then remained open, so that other animal could then enter. Thus the animals had to cooperate in two ways - first by positioning themselves on opposite ends of the barrier and then by timing and coordinating their approaches towards the barrier.

Image: 
Katharina Stenglein

A team of researchers have found that dogs and wolves are equally good at cooperating with partners to obtain a reward. When tested in same-species pairs, dogs and wolves proved equally successful and efficient at solving a given problem. This finding suggests that basic cooperation abilities were present in a common ancestor of dogs and wolves, and have not been lost in the domestication process.

It is estimated that dogs were domesticated as much as 30,000 - 40,000 years ago, and over that span of time they have undergone many changes from their wild counterparts, wolves. In a study published in the Journal of Comparative Psychology, researchers tested dogs and wolves for the ability to coordinate their actions with a partner of the same species to obtain rewards. The wolves in the study were from Tierpark Petersberg and Wolfcenter Dörverden. The researchers from the Max Planck Institute for the Science of Human History, the Max Planck Institute for Evolutionary Anthropology, and colleagues, found that dogs and wolves performed equally well on the task, suggesting that this ability was present prior to dogs' domestication in a common ancestor. The researchers hypothesize that, since dogs have been specifically selected for their ability and willingness to cooperate with humans, they might have an even higher success rate when humans are the cooperation partner.

The Test Scenario: Hunting large prey

To test cooperation ability, the researchers created a test scenario that was designed to mimic a hunting situation, one in which multiple animals were trying to take down a larger herbivore, such as an elk or other horned prey. The concept was that, in the wild, one of the animals would need to draw the attention - and the dangerous horns - of the potential prey, so that the other could attack from the rear and bring the prey down. Thus the animal that took the most risk in the hunt also had to trust that it would be given a share of the reward in the end. The test apparatus involved a barrier separating the participants from a food reward, with two openings on opposite ends that were controlled by a researcher. When the first animal approached an opening, the door before it would shut while the opposite door remained open, allowing the partner to enter first and access the food. The door then remained open, so that other animal could then enter. Thus the animals had to cooperate in two ways - first by positioning themselves on opposite ends of the barrier and then by timing and coordinating their approaches towards the barrier.

The researchers found that the dogs and wolves were equally successful, succeeding in about three out of four trials on average. "Dogs were not outperformed by wolves in coordinating their actions, in the frequency of success or in how long the task took," explains Juliane Bräuer of the Max Planck Institute for the Science of Human History, lead author of the study and head of the DogStudies group at the institute. "This is somewhat surprising, as it contradicts recent findings by other researchers related to more complex cooperation tasks performed by dogs and wolves." The researchers hypothesize that this could be due to the simple nature of the task in the present study, which might require only basic cooperation skills.

Food sharing depends on the dynamics of the pair, not on species

After solving the test, the pairs generally shared the food reward, but sharing was more likely when the dominant member of the pair was the second to arrive at the reward. "The probability of co-feeding during successful trials was higher when dominants 'took the risk,' so to speak, in moving first and drawing the closed door, because their higher rank gave them a higher chance to nonetheless get their share even if they accessed the food reward a few seconds after the subordinate," explains Bräuer. So while the researchers set out to test cooperation, it turned out that competition within the pair was also a factor.

Interestingly, however, dogs and wolves seemed to differ in which animal in the pair was willing to move first, drawing the closed door and thus being second to the food. Dominant wolves seemed to be more willing to take on this task in general than dominant dogs, and did so more frequently the more times the pair shared food. Dominant dogs, on the other hand, apparently seem to prefer to wait for their partner to draw the closed door. As would be expected, the more times dogs shared food, the more likely the subordinate member of the pair was to move first and draw the closed door.

More complex cooperation remains to be investigated

The researchers point out that, although the kind of coordination shown in the present study may rely on more simple mechanisms than full, conscious cooperation, it can still inform us about how cooperative behavior might have changed - or not - during the domestication process. "Our results suggest that the abilities needed to coordinate actions were already present in the dog-wolf ancestor," notes Bräuer. "In future studies, it would be interesting to focus on the question of how exactly factors like social dynamics, living conditions, the type of task and maybe also breed differences influence the cooperative behavior of dogs and wolves."

Credit: 
Max Planck Institute of Geoanthropology

Antibodies gather and form a circle for defensive attack

video: The antibodies assembled into a hexameric ring (white circle) transiently interact with the complement component C1q (white arrow) on the membrane containing GM1 as antigen.

Image: 
Supplementary Movie S7 with indicators

Antibodies are key players in our immune system. These antibodies recognize antigens displayed on foreign cell membranes and thereby recruit attacking forces, called complements. This mechanism is detrimental to our own immune system at times when our own cells exhibit some molecules that resemble infectious bacterial ones. Guillain-Barré syndrome is a postinfectious autoimmune disorder which is characterized by antibodies misdirected against GM1, self-molecule found in our neuronal cells. Although molecular mimicry between GM1 and the infectious bacterial lipo-oligosaccharide has been proven, the detailed mechanisms linking autoantigen recognition and complement activation remain unexplored.

The collaborative groups, including researchers at Exploratory Research Center on Life and Living Systems (ExCELLS) and Institute for Molecular Science (IMS) of National Institutes of Natural Sciences and Graduate School of Pharmaceutical Sciences of Nagoya City University investigated this mechanism utilizing high-speed atomic force microscopy. They successfully visualized the dynamic process by which the autoantibodies that are bound to GM1 contained in membranes spontaneously assemble to form a hexameric ring structure on the membrane. They also revealed that the assembled antibodies serve as a landing place for the first charge commander C1q on the membrane, which is the initial step of complement-mediated cell lysis. The groups' findings will provide deep insights into the molecular mechanisms behind Guillain-Barré syndrome and offer clues for controlling antibody assembly and consequent complement activation.

Credit: 
National Institutes of Natural Sciences

The turbulent life of two supermassive black holes caught in a galaxy crash

video: An international team of astronomers used ALMA to create the most detailed image yet of the gas surrounding two supermassive black holes in a merging galaxy.

Image: 
ALMA (ESO/NAOJ/NRAO), E. Treister; NRAO/AUI/NSF, S. Dagnello; NASA/ESA Hubble

An international team of astronomers used the Atacama Large Millimeter/submillimeter Array (ALMA) to create the most detailed image yet of the gas surrounding two supermassive black holes in a merging galaxy.

400 million light-years away from Earth, in the constellation of Ophiuchus, two galaxies are crashing into each other and forming a galaxy we know as NGC 6240. This peculiarly-shaped galaxy has been observed many times before, as it is relatively close by. But NGC 6240 is complex and chaotic. The collision between the two galaxies is still ongoing, bringing along in the crash two growing supermassive black holes that will likely merge as one larger black hole.

To understand what is happening within NGC 6240, astronomers want to observe the dust and gas surrounding the black holes in detail, but previous images have not been sharp enough to do that. New ALMA observations have increased the resolution of the images by a factor of ten - showing for the first time the structure of the cold gas in the galaxy, even within the sphere of influence of the black holes.

"The key to understanding this galaxy system is molecular gas," explained Ezequiel Treister of the Pontificia Universidad Católica in Santiago, Chile. "This gas is the fuel that is needed to form stars, but it also feeds the supermassive black holes, which allows them to grow."

Most of the gas is located in a region between the two black holes. Less detailed observations taken previously suggested that this gas might be a rotating disk. "We don't find any evidence for that," said Treister. "Instead, we see a chaotic stream of gas with filaments and bubbles between the black holes. Some of this gas is ejected outwards with speeds up to 500 kilometers per second. We don't know yet what causes these outflows."

Another reason to observe the gas in such detail is that it helps to determine the mass of the black holes. "Previous models, based on surrounding stars, indicated that the black holes were much more massive than we expected, around a billion times the mass of our Sun," said Anne Medling of the University of Toledo in Ohio. "But these new ALMA images for the first time showed us how much gas is caught up inside the black holes' sphere of influence. This mass is significant, and therefore we now estimate the black hole masses to be lower: around a few hundred million times the mass of our Sun. Based on this, we think that most previous black hole measurements in systems like this could be off by 5-90 percent."

The gas also turned out to be even closer to the black holes than the astronomers had expected. "It is located in a very extreme environment," explained Medling. "We think that it will eventually fall into the black hole, or it will be ejected at high speeds."

The astronomers don't find evidence for a third black hole in the galaxy, which another team recently claimed to have discovered. "We don't see molecular gas associated with this claimed third nucleus," said Treister. "It could be a local star cluster instead of a black hole, but we need to study it much more to say anything about it with certainty."

ALMA's high sensitivity and resolution are crucial to learn more about supermassive black holes and the role of gas in interacting galaxies. "This galaxy is so complex, that we could never know what is going on inside it without these detailed radio images," said Loreto Barcos-Muñoz of the National Radio Astronomy Observatory in Charlottesville, Virginia. "We now have a better idea of the 3D-structure of the galaxy, which gives us the opportunity to understand how galaxies evolve during the latest stages of an ongoing merger. In a few hundred million years, this galaxy will look completely different."

Credit: 
National Radio Astronomy Observatory

LD Motif Finder locates ancient hidden protein patterns

image: The researchers used AI methods to predict the interaction (shown by the dashed lines) of short, linear protein segments (green stick model) with their target proteins (molecular representation on the left). Predictions were experimentally confirmed as shown by the imprint of the ligand on the surface of the target protein (blue, magenta and pink colored surfaces).

Image: 
© 2019 Rayan Naser

An iterative machine learning approach has identified elusive 800 million-year-old amino acid patterns that are responsible for facilitating protein interactions.

Leucine-aspartic acid (LD) motifs are short amino acid sequences embedded within some proteins to link them to cellular molecules that control cell adhesion, motility and survival. They are known to also play a role in cancer cell spreading and in cardiovascular and infectious diseases. LD motifs were first revealed in 1996 in a family of proteins called paxillin. Only three other LD motif-containing proteins have been discovered since then, and scientists do not know the importance of LD motifs or how many other types of proteins contain them.

KAUST structural biologist Stefan Arold and computational bioscientists Xin Gao and Vladimir Bajic combined the efforts of their teams to develop a machine learning tool that they called LD Motif Finder (LDMF) to scan through the human proteome and identify LD motif patterns. This was no small task given the tiny number of known LD-motif­-containing proteins that could be used to train the tool.

The team "taught" their computational tool using biophysical and structural data from known LD motifs and their proteins. To improve the accuracy of their algorithm, they included a round of experimental testing of its initial predictions and trained the tool to learn from these results.

A final step, performed in collaboration with KAUST colleagues Mariusz and Lukasz Jaremko, involved three-dimensional structural analyses of the association between newly identified LD motifs and known LD motif-binding proteins.

Using this integrative approach, the researchers were able to identify 12 new human proteins that carry functional LD motifs. "This gives us a good idea of how many of these motifs exist within the human proteome," says Arold. "It seems there are far fewer than researchers initially suggested. Of course, this does not mean that they are biologically irrelevant."

The researchers found that these proteins containing LD motifs had functions related to cell adhesion and morphogenesis, suggesting that LD motifs significantly define the proteins' cellular roles. Indeed, the researchers observed alterations in cell adhesion or spreading when fluorescently labeled LD motifs were injected into cultured human cells.

Given that the machine learning tool made it easy to scan whole proteomes, the team also investigated the genomes of mammals, birds, fish, worms, insects and microbes for LD motifs. This large-scale analysis allowed them to conclude that LD motif signaling evolved more than 800 million years ago in unicellular organisms, possibly by co-opting ancestral interaction sequences that label proteins for export out of the nucleus.

"The model, which is freely available online, is highly accurate and sensitive, but there is still room for improvement," says Ph.D. student Meshari Alazmi, first author of the study.

The team hopes to continue developing their model to study the evolution and prevalence of other short protein-protein interaction motifs across species.

Credit: 
King Abdullah University of Science & Technology (KAUST)

Hubble surveys gigantic galaxy

image: Galaxy UGC 2885 may be the largest one in the local universe. It is 2.5 times wider than our Milky Way and contains 10 times as many stars. This galaxy is 232 million light-years away, located in the northern constellation of Perseus.

Image: 
NASA, ESA, and B. Holwerda (University of Louisville).

To kickstart the 30th anniversary year of the NASA/ESA Hubble Space Telescope, Hubble has imaged a majestic spiral galaxy. Galaxy UGC 2885 may be the largest known in the local universe. It is 2.5 times wider than our Milky Way and contains 10 times as many stars.

Despite its gargantuan size, researchers are calling it a "gentle giant" because it looks as if it has been sitting quietly over billions of years, possibly sipping hydrogen from the filamentary structure of intergalactic space. This is fuelling modest ongoing star birth at a rate half that of our Milky Way. In fact, its supermassive central black hole is also a sleeping giant; because the galaxy does not appear to be feeding on much smaller satellite galaxies, it is starved of infalling gas.

A number of foreground stars in our Milky Way can be seen in the image, identified by their diffraction spikes. The brightest appears to sit on top of the galaxy's disc, though UGC 2885 is really 232 million light-years farther away. The giant galaxy is located in the northern constellation Perseus.

The galaxy has also been nicknamed "Rubin's galaxy", after astronomer Vera Rubin (1928-2016), by Benne Holwerda of the University of Louisville, Kentucky, who observed the galaxy with the Hubble Space Telescope.

"My research was in large part inspired by Vera Rubin's work in 1980 on the size of this galaxy," said Holwerda. Rubin measured the galaxy's rotation, providing evidence for dark matter that makes up most of the galaxy's mass. "We consider this a commemorative image. The goal of citing Dr. Rubin in our observation was very much part of our original Hubble proposal."

Researchers are still seeking to understand what led to the galaxy's monstrous size. "It's as big as you can make a disk galaxy without hitting anything else in space," added Holwerda.

One clue is that the galaxy is fairly isolated in space and doesn't have any nearby galaxies to crash into and disrupt the shape of its disc.

Did the monster galaxy gobble up much smaller satellite galaxies over time? Or did it just slowly accrete gas to make new stars? "It seems like it's been puttering along, slowly growing," Holwerda said. Using Hubble's exceptional resolution, his team is counting the number of globular star clusters in the galaxy's halo -- a vast shell of faint stars surrounding the galaxy. An excess of clusters would yield evidence that they were captured from smaller infalling galaxies over many billions of years.

The upcoming NASA/ESA/CSA James Webb Space Telescope could be used to explore the centre of this galaxy as well as the globular cluster population. The infrared capability of this telescope will give researchers a less impeded view of the underlying stellar populations that will complement Hubble's visible-light ability to track wispy star formation throughout the galaxy.

Credit: 
ESA/Hubble Information Centre

Boys who are bullied online may have more risky sex

A collaboration of researchers at Louisiana State University, University of Missouri, and University of Tennessee found that peer victimization is associated with adverse psychological and behavioral problems, including depression and risky health behaviors such as substance use and unprotected sex with multiple partners. In 2015, approximately one-third of high school students in the US reported having sex recently. Of these, 43% had not used a condom, 21% had drunk alcohol or used drugs before sexual intercourse, and 14% had not used any contraception.

Recent research suggests that adolescent boys who are cyber bullied pursue risky sexual behaviors more frequently than girls who are cyber bullied. Results may reflect a culture of toxic masculinity and highlight the need to pay special attention to male victims, who may be reluctant to self-identify, and therefore, at greater risk of negative health outcomes.

The study, "Peer victimization, depression and sexual risk behaviors among high school youth in the United States: a gender-based approach", by Youn Kyoung Kim, Mansoo Yu, Courtney Cronley and Miyoun Yang has been published in the International Journal of Adolescent Medicine and Health. The authors examined gender differences in the relationships between four types of peer victimization (school bullying, cyber bullying, physical dating violence, and sexual dating violence), depression, and risky sexual behaviors among US high school students.

The researchers analyzed the 2015 Youth Risk Behavior System Survey, a nationally representative survey of US high school students containing data from 5,288 individuals who reported having engaged in sexual intercourse. The results show that all types of peer victimization are related to symptoms of depression for both females and males, and physical and sexual dating violence are associated with increased risky sexual behaviors. However, school bullying does not predict risky sexual behaviors. Among males, cyber bullying predicts increased risky sexual behaviors and the relationship is greater when a boy is depressed.

"It is critical to create safe and private spaces for boys to share their experiences, and we hope that this research will encourage schools to consider efforts to destigmatize victimization through peer mentorship and open communication," said Youn Kyoung Kim.

Credit: 
De Gruyter

Removing body clock gene protects mice against pneumonia

Most living things have an internal body clock which regulates when they sleep and when they wake up. A complex set of genes turning on and off, make this body clock run over roughly 24 hours, and a gene known by the acronym BMAL1 is one of the master regulators of this clock, controlling many other body clock genes and pathways.

The internal body clock being out of alignment with the environment is why we get jet lag, but more recently, scientists have also found that the body clock affects immunity too.

"We've previously found that the mice were worse at fighting off the pneumococcal bacteria that cause pneumonia when they got infected during the day, compared to infection at night," said Oxford University's Professor David Ray, who led the study. "But we had no idea how this was happening."

To find out how the body clock might be influencing the body's infection fighting cells, Gareth Kitchen, a researcher at the University of Manchester, genetically engineered mice so that they didn't have the BMAL1 clock gene.

"We were really surprised to find that these mice, which had no clock in a set of immune cells, were more resistant to bacterial pneumonia,' said Professor Ray. 'Almost everything we've learnt about the body clock so far, whether it's studies in shift workers or experiments in mice, says that disrupting the body clock makes people and animals more likely to get ill, not less."

To find out what was making these mice pneumonia-resistant, the team focussed on a key immune cell, known as a macrophage. Macrophages are specialised cells in blood and tissue that detect, engulf and ultimately destroy bacteria and other harmful organisms that enter the body.

The researchers found that deleting the BMAL1 gene in the macrophages supercharged them, making them more mobile, and better able to engulf and destroy bacteria, both in a petri-dish, and inside the mice. The clock gene deletion set of a cascade of changes which ultimately triggered a switch which made the macrophages 'skeleton' (made up of a protein called actin) less rigid, making it easier for the cells to move and engulf bacteria.

When the researchers blocked the actin skeleton change, the macrophages were no longer supercharged, even with their clock genes deleted. This shows that it is the strengthening of the cells' actin skeleton that was making them more effective.

What's more, it was only the BMAL1 clock gene which controlled the actin cell skeleton switch in macrophages - the researchers found that deleting other body clock genes did not have the same effect.

"As we enter an era of bacterial resistance to antibiotics, it is becoming more and more important to understand how our innate immunity works," said Professor Ray. "We might be able to use some of the drugs currently being tested to change the body clock to supercharge macrophages, but our body clocks are also affected by things like when we sleep and eat."

Dr Kitchen, a clinician scientist who as an anaesthetist looks after critically unwell patients in intensive care and in the operation theatre said: "Multi-drug resistant bacteria is one of the biggest problems facing modern medicine, so discovering that BMAL1 may be a target for future medicines to combat infection is very exciting."

"In the future, doctors may change the time that vulnerable patients are offered meals or go to sleep, so that the patients' body clocks boost rather than hinder their innate immunity when they most likely to be exposed to infection."

The research team are now working out how to make immune cells more effective to help treat infections.

Credit: 
University of Oxford

Mindfulness makes it easier to forget your fears

Mindfulness has been shown to reduce negative emotions in both healthy individuals as well as patients with psychological problems. Studies have also shown that mindfulness is effective for treating clinical emotional problems like anxiety, depression, stress and trauma related disorders. The biological mechanisms that underlie these positive effects on emotional functioning are not sufficiently understood but brain imaging studies have shown that mindfulness training is associated with changes in regions of the brain previously known to be involved in extinction learning, making extinction a likely candidate. However, an actual effect of mindfulness training on extinction learning has never been demonstrated.

In a new study, researchers at University of Southern Denmark, Uppsala University, Lund University, Peking University and Icahn School of Medicine at Mount Sinai, can now show that mindfulness training facilitates extinction of conditioned fear reactions, producing lasting reductions in threat related arousal responses.

In this study, healthy subjects were randomly assigned to receive either 4 weeks of daily mindfulness training delivered through the Headspace mindfulness app, or were assigned to a wait list control condition. Subsequently, the participants underwent psychological experiments on two consecutive days in which conditioned fear reactions were established on day 1 and then immediately extinguished.

On day 2, the subjects returned and the lasting effects of extinction were evaluated.

Conditioned fear reactions were established by showing the participants neutral images on a computer screen and then some of the images were directly followed by an uncomfortable electric shock to the hand.

After a number of such pairings, the subjects showed elevated autonomic arousal responses just when viewing the pictures, demonstrating that conditioned fear reactions had been learnt.

Fear reactions were measured using skin conductance, an index for how much the subject is sweating, which is a corollary for the fight-or-flight response in humans.

Then, the researchers extinguished these reactions by repeatedly showing the images again but this time omitting the shocks.

In this way, the participants learnt that the images that previously signaled an upcoming uncomfortable shock no longer did so, and consequently subjects showed a substantial decrease in autonomic arousal when viewing the images.

After 24 hours, in order to test the retention of extinction learning, the participants returned to the lab, were hooked up to the shock apparatus and again shown the images they had viewed on the previous day, although no shocks were delivered.

This was the critical test of the study since extinction learning is normally unstable, and fear reactions typically return after a delay even when the subject has gone through successful extinction. In line with the researchers' hypotheses, the group that had been doing mindfulness training now showed lower fear reactions compared to the control group.

The fear reactions in the mindfulness group remained at the same low level they had been by the end of extinction the previous day indicating an improved ability to form and retain extinction memories, whereas the control group showed a substantial increase in fear reactions compared to extinction the previous day.

When comparing the groups reactions during conditioning and extinction on day 1, no differences could be observed, showing that the two groups learned and extinguished the conditioned fear reactions to a similar extent, and the authors conclude that mindfulness appears to have a specific effect on extinction retention.

According to the study's first author Johannes Björkstrand, the findings are interesting for a number of reasons.

- We can show that mindfulness does not only have an effect on subjective experiences of negative emotions, as has been shown previously, but that you can actual see clear effects on autonomic arousal responses, even with a limited amount of training. It is also interesting that the intervention appears to have a specific effect on extinction retention, which is in line with previous brain imaging studies on mindfulness, and also has some implications for how these types of interventions could be used to treat anxiety related problems in a clinical context.

Anxiety and trauma related disorders are often treated using exposure therapy, a psychological treatment that is based on extinction learning, but not everyone responds to these treatments. One possible explanation is that individuals with these disorders have been shown to have difficulties in forming lasting extinction memories when compared to healthy individuals, which could represent an underlying vulnerability that increases the risk of developing these types of problems to begin with and constitutes an impediment to successful treatment.

- Our results suggest, that if you combine mindfulness training with exposure therapy, maybe you can achieve larger and longer lasting treatment effects. In this way you could get at an underlying vulnerability factor and more people would respond to these treatments, but studies in clinical populations and actual treatment studies are needed before we can draw any firm conclusions in this matter, says Johannes Björkstrand.

The researchers now want to move forward and investigate the underlying neurobiological mechanisms that are involved.

- We are currently repeating the experiment with twice the number of participants, and the whole thing is carried out inside an fMRI-scanner equipped with an extra strong electromagnetic field so that we can measure their brain activity to a high degree of precision throughout all parts of the experiment. We hope to show that the effect is robust and that we can replicate the current findings, and also say what processes in the brain are involved in producing these effects. We just finished data-collection but we still have a rather large amount of analysis work to do before we arrive at any results, says senior author, associate professor Ulrich Kirk.

Credit: 
University of Southern Denmark Faculty of Health Sciences

Complex Innovative Trials: New guideline adoption could get medicines to patients faster

Complex Innovative Design (CID) trials could be transformed for the better, following the publication of recommendations, published today in the British Journal of Cancer* (Monday).

The authors believe, if implemented, the ten recommendations they've developed for CID trials could ultimately reduce the time it takes to get innovative treatments to patients with cancer.

They are now calling on clinicians, funders, regulators and the pharmaceutical industry to get behind the recommendations and work together to rapidly implement them.

CID trials are increasingly being used as an evaluation method by researchers, instead of traditional drug development pathways involving clinical trials from phases 1 to 4.

The CID approach enables researchers to carry out more complex trials that address multiple clinical questions at once. For example, a drug can be simultaneously evaluated for safety and efficacy with different cancer types, which can change as the trial progresses, accelerating the traditional route to drug licencing.

However, they can be challenging to conduct and there are currently no practical guidelines for teams that fund, design and conduct these trials in Europe.

The Experimental Cancer Medicine Centre (ECMC) network, funded by Cancer Research UK, the National Institute for Health Research (NIHR) and the health departments in Scotland, Wales and Northern Ireland, convened a working group of academics, funders, regulators, pharmaceutical industry representatives and patients to address this challenge**.

They developed ten key recommendations *** to cover each stage of the clinical trial pathway.

Each recommendation covers a specific stage of the clinical trial pathway including: trial planning and design, protocol development, patients and public involvement, patient-facing documentation, statistical analysis, defining leadership and oversight, dissemination of results, staff training, the approval process, funding, and evaluating the impact on public health.

Taken together, these recommendations could improve the conduct, quality and acceptability of oncology CID trials in clinical research. Furthermore, improving how different stakeholders interact, promote and share their learnings from CID studies, say the authors, will foster a clinical research environment that could enable CID trials to be carried out in a range of new clinical areas.

Professor Pam Kearns, director of the Cancer Research UK clinical trials unit at the University of Birmingham and co-author of the paper, said: "We owe it to our patients to bring potentially more effective novel treatments into the clinic as quickly as possible, and these recommendations will ensure we have good quality CID trials in place to deliver this promise."

Dr Aoife Regan, head of the ECMC programme office, said: "These recommendations show the power of the ECMC network as a convening force to help strengthen the position of the UK as a world leader in experimental cancer medicine. We hope these recommendations will have an impact not just for cancer research but for all complex trials across all disease types."

Nick Lemoine, Medical Director at the NIHR, said: "Getting promising new cancer treatments to patients who need them the most can take some time, so speeding up this process through Complex Innovative Design trials is a priority. With the expertise within the ECMC network and the new guidelines in place, the UK is now one of the best equipped countries to deliver these trials, which represent the future for evaluating new cancer drugs."

Debbie Keatley, a patient representative and co-author of the guidelines, said: "Patients tell us that they need information about trials in an easy to understand format and language. They also want reassurance that the results seen in the trials will be applicable to real patients seen in the clinic. We welcome these guidelines, which put the patient first."

Credit: 
Cancer Research UK