Culture

Throughout the pandemic, infectious disease experts and frontline medical workers have asked for a faster, cheaper and more reliable COVID-19 test. Now, leveraging the so-called "lab on a chip" technology and the cutting-edge genetic editing technique known as CRISPR, researchers at Stanford have created a highly automated device that can identify the presence of the novel coronavirus in just a half-hour.

"The microlab is a microfluidic chip just half the size of a credit card containing a complex network of channels smaller than the width of a human hair," said the study's senior author, Juan G. Santiago, the Charles Lee Powell Foundation Professor of mechanical engineering at Stanford and an expert in microfluidics, a field devoted to controlling fluids and molecules at the microscale using chips.

The new COVID-19 test is detailed in a study published on Nov. 4 in the journal Proceedings of the National Academy of Sciences. "Our test can identify an active infection relatively quickly and cheaply. It's also not reliant on antibodies like many tests, which only indicates if someone has had the disease, and not whether they are currently infected and therefore contagious," explained Ashwin Ramachandran, a Stanford graduate student and the study's first author.

The microlab test takes advantage of the fact that coronaviruses like SARS-COV-2, the virus that causes COVID-19, leaves behind tiny genetic fingerprints wherever they go in the form of strands of RNA, the genetic product of DNA. If the coronavirus's RNA is present in a swab sample, the person from whom the sample was taken is infected.

To initiate a test, liquid from a nasal swab sample is dropped into the microlab, which uses electric fields to extract and purify any nucleic acids like RNA that it might contain. The purified RNA is then converted into DNA and then replicated many times over using a technique known as isothermal amplification.

Next, the team used an enzyme called CRISPR-Cas12 - a sibling of the CRISPR-Cas9 enzyme associated with this year's Nobel Prize in Chemistry - to determine if any of the amplified DNA came from the coronavirus.

If so, the activated enzyme triggers fluorescent probes that cause the sample to glow. Here also, electric fields play a crucial role by helping concentrate all of the important ingredients - the target DNA, the CRISPR enzyme and the fluorescent probes - together into a tiny space smaller than the width of a human hair, dramatically increasing the chances they will interact.

"Our chip is unique in that it uses electric fields to both purify nucleic acids from the sample and to speed up chemical reactions that let us know they are present," Santiago said.

The team created its device on a shoestring budget of about $5,000. For now, the DNA amplification step must be performed outside of the chip, but Santiago expects that within months his lab will integrate all the steps into a single chip.

Several human-scale diagnostic tests use similar gene amplification and enzyme techniques, but they are slower and more expensive than the new test, which provides results in just 30 minutes. Other tests can require more manual steps and can take several hours.

The researchers say their approach is not specific to COVID-19 and could be adapted to detect the presence of other harmful microbes, such as E. coli in food or water samples, or tuberculosis and other diseases in the blood.

"If we want to look for a different disease, we simply design the appropriate nucleic acid sequence on a computer and send it over email to a commercial maker of synthetic RNA. They mail back a vial with the molecule that completely reconfigures our assay for a new disease," Ramachandran said.

The researchers are working with the Ford Motor Company to further integrate the steps and develop their prototype into a marketable product.

Archaeologists from The Australian National University (ANU) have discovered a rare child burial dating back 8,000 years on Alor Island, Indonesia.

The one-of-its-kind burial for the region is from the early mid-Holocene and gives important insights into burial practices of the time.

Lead researcher Dr Sofia Samper Carro said the child, aged between four and eight, was laid to rest with some kind of ceremony.

"Ochre pigment was applied to the cheeks and forehead and an ochre-coloured cobble stone was placed under the child's head when they were buried," she said.

"Child burials are very rare and this complete burial is the
only one from this time period," Dr Samper Carro said.

"From 3,000 years ago to modern times, we start seeing more child burials and these are very well studied. But, with nothing from the early Holocene period, we just don't know how people of this era treated their dead children. This find will change that."

Notably, the child's arm and leg bones were removed before interment and disposed of elsewhere.

"The lack of long bones is a practice that has been documented in several other burials from a similar time period in Java, Borneo and Flores, but this is the first time we have seen it in a child's burial," Dr Samper Carro said.

"We don't know why long bone removal was practised, but it's likely some aspect of the belief system of the people who lived at this time."

The estimated age of the child based on teeth correspond to a six- to eight-year-old child, but the skeleton is that of a four- to five-year-old child.

"We want to do some further paleo-health research to find out if this smaller skeleton is related to diet or the environment or possibly to being genetically isolated on an island," Dr Samper Carro said.

"My earlier work from Alor showed adult skulls were also small. These hunter-gatherers had a mainly marine diet and there is evidence to suggest protein saturation from a single food source can cause symptoms of mal-nourishment, which affects growth. However, they could have been eating other terrestrial resources such as tubers.

"By comparing other adult burials we have found from the same time period with this child burial in a future project, we hope to build a chronology and general view of burial practices in this region from between 12,000 to 7,000 years ago which at the moment is still scant."

DURHAM, N.C. -- A Duke Health-led research team has identified a key marker that will help speed effective vaccine designs for cytomegalovirus (CMV), the most common congenital infection worldwide and a leading cause of infant brain damage.

In a study appearing online Nov. 4 in Science Translational Medicine, the researchers describe an immune surrogate that demonstrates when a vaccine has elicited the necessary antibodies that protect against CMV infection. The finding is already being applied to screen potential vaccines.

"CMV has been recognized as a top priority for vaccine development for more than 20 years, yet we remain without an approved vaccine. This work provides a way to assure that current and future vaccine candidates stimulate an effective immune response," said senior author Sallie Permar, M.D., a professor in the departments of Pediatrics, Immunology, Molecular Genetics and Microbiology, and Pathology at Duke University School of Medicine.

"We are beyond due for vaccines to be developed to protect against this virus, which infects 40,000 infants a year in the United States alone, with a third of these children developing permanent hearing loss, brain damage or neuro-developmental delays," Permar said.

Permar and colleagues, including lead author Jennifer A. Jenks, an M.D./Ph.D. candidate at Duke, investigated the immune responses that protected against CMV infections in women who received the investigational protein vaccine gB/MF59. The main component of this vaccine was the CMV protein "gB," which the virus uses to enter human cells.

The investigational vaccine was expected to generate an immune response that could stop CMV from entering host cells. It was about 50-percent effective in preventing CMV infection in multiple Phase 2 clinical trials, but an acceptable CMV vaccine should be at least 70-percent effective.

The researchers found that protection against CMV infection was associated with the presence of antibodies in the blood that bind to the target protein gB when it is presented on a cell surface, but not to gB when it is in its soluble, free-floating form used in the gB/MF59 vaccine. This finding suggests that future CMV vaccines should be designed to target the appropriate conformation of gB. Additionally, the researchers report, the presence of these antibodies may be used to predict the potential efficacy of future candidate vaccines.

"This is an important immunologic endpoint for vaccine development and evaluation," Jenks said. "This could serve as a surrogate for assessing antiviral function and could aid in vaccine evaluation in preclinical and early-phase clinical trials."

For centuries, historians and scientists mostly agreed that when early human groups sought food, men hunted and women gathered. However, a 9,000-year-old female hunter burial in the Andes Mountains of South America reveals a different story, according to new research conducted at the University of California, Davis.

"An archaeological discovery and analysis of early burial practices overturns the long-held 'man-the-hunter' hypothesis," said Randy Haas, assistant professor of anthropology and the lead author of the study, "Female Hunters of the Early Americas." It was published today (Nov. 4) in Science Advances.

"We believe that these findings are particularly timely in light of contemporary conversations surrounding gendered labor practices and inequality," he added. "Labor practices among recent hunter-gatherer societies are highly gendered, which might lead some to believe that sexist inequalities in things like pay or rank are somehow 'natural.' But it's now clear that sexual division of labor was fundamentally different -- likely more equitable -- in our species' deep hunter-gatherer past."

In 2018, during archaeological excavations at a high-altitude site called Wilamaya Patjxa in what is now Peru, researchers found an early burial that contained a hunting toolkit with projectile points and animal-processing tools. The objects accompanying people in death tend to be those that accompanied them in life, researchers said. It was determined that the hunter was likely female based on findings by the team's osteologist, James Watson of The University of Arizona. Watson's sex estimate was later confirmed by dental protein analysis conducted by UC Davis postdoctoral researcher Tammy Buonasera and Glendon Parker, an adjunct associate professor.

Revealing a broader pattern

The surprising discovery of an early female hunter burial led the team to ask whether she was part of a broader pattern of female hunters or merely a one-off. Looking at published records of late Pleistocene and early Holocene burials throughout North and South America, the researchers identified 429 individuals from 107 sites. Of those, 27 individuals were associated with big-game hunting tools -- 11 were female and 15 were male. The sample was sufficient to "warrant the conclusion that female participation in early big-game hunting was likely nontrivial," researchers said. Moreover, the analysis identified the Wilamaya Patjxa female hunter as the earliest hunter burial in the Americas.

Statistical analysis shows that somewhere between 30 to 50 percent of hunters in these populations were female, the study said. This level of participation stands in stark contrast to recent hunter-gatherers, and even farming and capitalist societies, where hunting is a decidedly male activity with low levels of female participation, certainly under 30 percent, Haas explained.

The study was conducted in collaboration with multiple UC Davis labs. Parker, a forensic expert in the Department of Environmental Toxicology, helped determine sex through a proteomic technique he recently developed. In Professor Jelmer Eerkens' lab, Jenny Chen, an undergraduate researcher at the time of the study, discovered the distinct isotopic signature of meat consumption in the bones, further supporting the conclusion that the Wilamaya Patjxa female was a hunter.

While the research answers an old question about sexual division of labor in human societies, it also raises some new ones. The team now wishes to understand how sexual division of labor and its consequences in different times and places changed among hunter-gatherer populations in the Americas.

Researchers discovered that a specific brain region monitors food preferences as they change across thirsty and quenched states. By targeting neurons in that part of the brain, they were able to shift food choice preferences from a more desired reward (think: chocolate cake) to a less tasty one (think: stale bread).

Their findings, published in the journal Science Advances, built upon the same team's discovery two years ago that neural activity in this brain region called the ventral pallidum is related to the preference for different food options.

Working with rats, the researchers were able to demonstrate that this same area of the brain is tracking and updating food preferences in ways that shifted as physiological states progressed from extremely thirsty to happily quenched.

"Your brain has to weigh different possible outcomes or options in order to make good decisions that are necessary for survival," said Patricia Janak, senior author and Bloomberg Distinguished Professor of Psychological and Brain Sciences and Neuroscience at Johns Hopkins. "We knew the ventral pallidum is involved in that process. Exactly how the neurons there do that was still a bit of a mystery, especially in real time when the best decision for you to make right now can change based on your state."

David Ottenheimer, lead author and a former Johns Hopkins doctoral student who is now at the University of Washington, said he devised the research to determine how the neurons in the ventral pallidum related to the food decisions subjects made as their preference shifted due to changes in physiological state.

To study the question, researchers gave thirsty rats two options to choose from by selecting one of two levers. One lever provided plain water, the other a well-liked sugar water.

"At the beginning they picked the water when they were thirsty," Ottenheimer said. "At the end of the test when they were no longer thirsty they picked the sugar water, which tastes sweeter."

At the same time the team was monitoring the brain activity and found that the neurons
reflected the rats' choices for each reward.

"We saw that the neural activity when tasting the sucrose gradually increased over time while the neural activity when tasting the water decreased, which gave us evidence that the brain signal is closely related to the change in preference as the subjects became less thirsty and were less interested in the water," Ottenheimer said.

Remarkably, in a separate test, the researchers were able to artificially manipulate the ventral pallidum neurons to force a shift in preference from the more desired sugar water to a less desirable flavor.

"We hypothesize that the ventral pallidum neurons that are tracking our preferences may actually be involved in forming the choices we make when faced with food decisions," Ottenheimer said. "In the future, ventral pallidum may be a good therapeutic target to change our decision-making processes."

"These same circuits are responsible for choices made in addiction," Janak said. "So the knowledge we gain here can help in understanding how we prioritize drugs over other rewards"

New data from a Canadian-led team of astronomers, including researchers from the McGill Space Institute and McGill University Department of Physics, strongly suggest that magnetars - a type of neutron star believed to have an extremely powerful magnetic field - could be the source of some fast radio bursts (FRBs). Though much research has been done to explain the mysterious phenomenon, their source has thus far remained elusive and the subject of some debate.

First detection of an intense radio burst from a Galactic magnetar

On 28 April 2020, a team of approximately 50 students, postdocs and professors
from the Canadian Hydrogen Intensity Mapping Experiment (CHIME) Fast Radio Burst Collaboration detected an unusually intense radio burst emanating from a nearby magnetar located in the Milky Way. In a study published today in Nature, they show that the intensity of the radio burst was three thousand times greater than that of any magnetar measured thus far, lending weight to the theory that magnetars are at the origin of at least some FRBs.

"We calculated that such an intense burst coming from another galaxy would be indistinguishable from some fast radio bursts, so this really gives weight to the theory suggesting that magnetars could be behind at least some FRBs," said Pragya Chawla, one of the co-authors on the study and a senior PhD student in the Physics Department at McGill.

Competing theories about the origins of FRBs

FRBs were first discovered over a decade ago. Originally thought to be singular events, astronomers have since discovered that some of these high-intensity blasts of radio emissions - more intense than the energy generated by the Sun over millions to billions of years - in fact repeat.

One theory hypothesized FRBs to be extragalactic magnetars - young extremely magnetic neutron stars that occasionally flare to release enormous amounts of energy.

"So far, all of the FRBs that telescopes like CHIME have picked up were in other galaxies, which makes them quite hard to study in great detail," said Ziggy Pleunis, a senior PhD student in McGill's Physics department and one of the co-authors of the new study. "Moreover, the magnetar theory was not supported by observations of magnetars in our own galaxy as they were found to be far less intense than the energy released by extragalactic FRBs until now."

Magnetar origin for all FRBs remains to be confirmed

"However, given the large gaps in energetics and activity between the brightest and most active FRB sources and what is observed for magnetars, perhaps younger, more energetic and active magnetars are needed to explain all FRB observations," added Dr. Paul Scholz from the Dunlap Institute of Astronomy and Astrophysics at the University of Toronto.

Smoking-gun proof of a magnetar origin for some FRBs would come from the simultaneous detection of an extragalactic radio burst and an X-ray burst. However, this will likely only be possible for nearby FRBs. Fortunately, CHIME/FRB is discovering these in good numbers.

Rising sea levels will affect coasts and human societies in complex and unpredictable ways, according to a new study that examined 12,000 years in which a large island became a cluster of smaller ones.

Researchers reconstructed sea-level rise to produce maps of coastal changes at thousand-year intervals and found that today's Isles of Scilly, off the UK's south-west coast, emerged from a single island that only became the current configuration of more than 140 islands less than 1,000 years ago.

The study, led by the University of Exeter in partnership with Cornwall Archaeological Unit, Cardiff University and 14 other institutes, found that changes in both land area and human cultures happened at variable rates, and often out of step with the prevailing rate of sea-level rise.

With climate change now driving rapid sea-level rise, the team says the effects will not always be as simple as a forced human retreat from coasts.

"When we're thinking about future sea-level rise, we need to consider the complexity of the systems involved, in terms of both the physical geography and the human response" said lead author Dr Robert Barnett, of the University of Exeter.

"The speed at which land disappears is not only a function of sea-level rise, it depends on specific local geography, landforms and geology.

"Human responses are likely to be equally localised. For example, communities may have powerful reasons for refusing to abandon a particular place."

The researchers developed a new 12,000-year sea-level curve for the Isles of Scilly, and looked at this alongside new landscape, vegetation and human population reconstructions created from pollen and charcoal data and archaeological evidence gathered. The new research extends and enhances data collected by the Lyonesse Project (2009 to 2013), a study of the historic coastal and marine environment of the Isles of Scilly.

These findings suggest that during a period between 5,000 and 4,000 years ago land was rapidly becoming submerged. In response to this period of coastline reorganisation, people appeared to adapt to, rather than abandon, the new landscape.

By the Bronze Age (after 4400 years ago), the archaeological record suggests the area had a permanent population - and instead of leaving the islands, it appears that there may have been a "significant acceleration of activity".

The reasons for this are unclear, but one possibility is that new shallow seas and tidal zones provided opportunities for fishing, shellfish collection and hunting wildfowl.

This period of rapid land loss happened at a time of relatively slow sea-level rise - because lots of Scilly's land at that point was relatively flat and close to sea level.

The study found that between 5000 and 4,000 years ago, land was being lost at a rate of 10,000 m2 per year, which is equivalent to a large international rugby stadium. However, about half of this land was turning into intertidal habitats, which may have been able to support the coastal communities.

Charlie Johns (Cornwall Archaeological Unit) co-director of the Lyonesse Project said "This new research confirms that the period immediately before 4,000 years ago saw some of the most significant loss of land at any time in the history of Scilly -- equivalent to losing two-thirds of the entire modern area of the islands".

After 4,000 years ago, the island group continued to be submerged by rising sea levels, even during modest (e.g., 1 mm per year) rates of sea-level rise.

"It is clear that rapid coastal change can happen even during relatively small and gradual sea-level rise," said Dr Barnett.

"The current rate of mean global sea-level rise (around 3.6 mm per year) is already far greater than the local rate at the Isles of Scilly (1 to 2 mm per year) that caused widespread coastal reorganisation between 5,000 and 4,000 years ago.

"It is even more important to consider the human responses to these physical changes, which may be unpredictable.

"As can be seen today across island nations, cultural practices define the response of coastal communities, which can result in polarised agenda, such as the planned relocation programmes in Fiji versus the climate-migration resistance seen in Tavalu.

"In the past, we saw that coastal reorganisation at the Isles of Scilly led to new resource availability for coastal communities.

"It is perhaps unlikely that future coastal reorganisation will lead to new resource availability on scales capable of supporting entire communities.

"More certain though, is that societal and cultural perspectives from coastal populations will be critical for responding successfully to future climate change."

The arthropods have been among the most successful animals on Earth since the Cambrian Period, about 520 million years ago. They are the most familiar and ubiquitous, and constitute nearly 80 percent of all animal species today, far more than any other animals.

But how did arthropods evolve and what did their ancestors look like? These have been a major conundrum in animal evolution puzzling generations of scientists for more than a century.

Now researchers from the Nanjing Institute of Geology and Palaeontology of the Chinese Academy of Sciences (NIGPAS) have discovered a shrimp-like fossil with five eyes, which has provided important insights into the early evolutionary history of arthropods. The study was published in Nature on Nov. 4.

The fossil species, Kylinxia, was collected from the Chengjiang fauna in southwest China's Yunnan Province. The fauna documents the most complete early animal fossils in the Cambrian time.

Prof. HUANG Diying, corresponding author for the study from NIGPAS, said, "Kylinxia is a very rare chimeric species. It combines morphological features from different animals, which is analogous to 'kylin,' a chimeric creature in traditional Chinese mythology."

"Owing to very special taphonomic conditions, the Kylinxia fossils exhibit exquisite anatomical structures. For example, nervous tissue, eyes and digestive system - these are soft body parts we usually cannot see in conventional fossils," said Prof. ZHAO Fangchen, co-corresponding author of the study.

Kylinxia shows distinctive features of true arthropods, such as a hardened cuticle, a segmented trunk and jointed legs. However, it also integrates the morphological characteristics present in very ancestral forms, including the bizarre five eyes of Opabinia, known as the Cambrian "weird wonder," as well as the iconic raptorial appendages of Anomalocaris, the giant apex predator in the Cambrian ocean.

Among the Chengjiang fauna, Anomalocaris is a top predator that can reach two meters in body length, and has been regarded as an ancestral form of arthropod. But huge morphological differences exist between Anomalocaris and true arthropods. There is a great evolutionary gap between the two that can hardly be bridged. This gap has become a crucial "missing link" in the origin of arthropods.

The research team conducted detailed anatomical examinations of the fossils of Kylinxia. They demonstrated that the first appendages in Anomalocaris and true arthropods were homologous. The phylogenetic analyses suggested that there was affinity between the front appendages of Kylinxia, small predatory appendages in front of the mouth of Chelicerata (a group that includes spiders and scorpions) and the antennae of Mandibulata (a subdivision of arthropods including insects such as ants and bees).

"Our results indicate that the evolutionary placement of Kylinxia is right between Anomalocaris and the true arthropods. Therefore, our finding reached the evolutionary root of the true arthropods," said Prof. ZHU Maoyan, a co-author of the study.

"Kylinxia represents a crucial transitional fossil predicted by Darwin's evolutionary theory. It bridges the evolutionary gap from Anomalocaris to true arthropods and forms a key "missing link" in the origin of arthropods, contributing strong fossil evidence for the evolutionary theory of life," said Dr. ZENG Han, first author of the study.

New York University researchers have created a "developmental atlas" of gene expression in neurons, using gene sequencing and machine learning to categorize more than 250,000 neurons in the brains of fruit flies. Their study, published in Nature, finds that neurons exhibit the most molecular diversity during development and reveals a previously unknown type of neurons only present before flies hatch.

"Diversity of the different cell types that make up our brains can only be fully understood in light of their developmental history," said NYU Biology Professor Claude Desplan, the study's senior author.

Brains are composed of thousands of different types of neurons. Despite sharing the same genetic information, neurons achieve this diversity by turning on different sets of genes in each neuron type and at each point in their development.

To understand the diversity of brain cells, researchers have long studied fruit flies, whose brains, although much simpler than those of humans, can be used as a model system. Researchers previously identified the roughly 60,000 cells and 200 neuronal types that make up fruit flies' optic lobes, the areas of the brain that process visual information, including color vision and detection of objects and motion.

In their new study in Nature, researchers in Desplan's lab sought to thoroughly characterize the diversity of neurons in the optic lobe and build a "developmental atlas" of gene expression, comparing cells in the brains of adult flies and exploring differences during development.

The researchers created their "atlas" by taking advantage of a form of a recently invented technique known as single-cell mRNA sequencing, which allowed them to capture and sequence mRNA from more than 250,000 single cells. Using a combination of machine learning approaches, they assigned each of these cells to a specific cell type throughout development.

"Our datasets almost completely account for the known neuronal diversity of the optic lobes and can serve as a paradigm to understand brain development across species," said Neset Özel, a postdoctoral associate at NYU and one of the study's lead authors. "The 'atlas' constitutes an enormous resource for the research community: we can now simply look up whether a particular gene is active or not in any cell type of our choice and at any point during its development."

While building their "developmental atlas," the researchers made several discoveries. First, they found a completely new type of neurons in fruit flies, which is present only on the surface of the optic lobe during development but is removed through programmed cell death right before the flies hatch.

"While we do not yet understand the functions of these previously unknown neurons, neurons with very similar properties--called Cajal-Retzius cells--also exist in mammalian brains, and they are critical for proper brain development," said Felix Simon, a biology doctoral student at NYU and the other lead author of the study.

In addition, the researchers found that neurons exhibit the highest levels of molecular diversity during development compared to adult neurons, allowing cells during development to form connections with specific partner cells--and avoid the wrong ones. As a result, neurons can gain distinct features and functions solely due to their developmental history, even though their physiological properties in adult brains might be identical.

"This has large implications for the studies of neurodevelopmental disorders. Disruptions to neural circuit function could occur entirely due to defects in certain genetic programs that are only transiently active during development and would be impossible to understand by simply looking at the end result," explained Özel.

Finally, the study revealed that neurons that look identical in form can express different sets of genes in the upper versus lower part of the brain. These differences can give flies the ability to perform different calculations on the visual information they receive--for instance, the sky versus the ground.

A new study suggests that it is possible to design drugs that can target a type of shape-shifting protein involved in Alzheimer's disease, which was previously thought to be undruggable.

A team of researchers, led by the University of Cambridge, have identified a new mechanism of targeting amyloid-beta, a protein fragment that clumps together and kills healthy brain cells in people with Alzheimer's disease.

Working with colleagues from Imperial College London, Institut Pasteur, and the University of Florence, the researchers found that it is possible for a drug-like molecule to target amyloid-beta in its disordered state, reducing its ability to form the toxic clusters which are the hallmark of Alzheimer's disease. The results, reported in the journal Science Advances, could form the basis of a new avenue for the development of potential treatments for the disease.

"Amyloid-beta is a disordered protein, a type of target that is elusive for standard therapeutic approaches," said Professor Michele Vendruscolo from Cambridge's Centre for Misfolding Diseases, who led the research. "It is constantly changing shape, so traditional drug discovery techniques don't work on it. By revealing a new drug-binding mechanism, we have extended traditional drug discovery approaches based on the optimisation of the binding affinity to include disordered proteins."

Most drugs work by binding proteins through what is often described as a lock-and-key mechanism, where a drug fits into a protein's grooves like a key in a lock. However, since they are often changing shape, disordered proteins such as amyloid-beta don't have stable 'locks' for drugs to bind to, which is why they are considered 'undruggable.'

The approach developed by the researchers is based on the so-called disordered binding mechanism that they discovered, where small molecules form a disordered complex with the protein target, so that it is like the protein and the drug are 'dancing' with one another.

The researchers characterised this new mechanism using a combination of biophysical experiments, mathematical modelling, in vivo experiments and computation.

First, they tested the aggregation of amyloid-beta in the presence of the compound in in vitro assays. Data from these experiments allowed the researchers to build a mathematical model of how the drug was able to inhibit the aggregation of amyloid-beta at the microscopic level.

The team also used high-performance computing methods to study the binding interaction at the atomic level. These intensive calculations allowed the researchers to 'see' how the binding was occurring at the atomic level, which is otherwise almost impossible to observe experimentally. Further tests were then carried out in nematode worms, which are often used as a model organism to study Alzheimer's disease.

"In contrast to the traditional lock-and-key binding mechanism, in which a drug tightly interacts with its target in a specific conformation, we found that both the small molecule and the disordered protein remained extremely dynamic, and that the small molecule interacted with many parts of the protein," said Gabriella Heller, Schmidt Science Fellow and the study's first author.

"This way of stabilising native states of proteins is a powerful drug discovery strategy, which has so far been extremely challenging for disordered proteins," said Vendruscolo.

Amyloid beta, the protein which the team targeted, is closely associated with Alzheimer's disease as it is the primary component of senile plaques, which are characteristically found in the brains of the people affected by the disease.

While this research is still preliminary in terms of clinical translation, it demonstrates that targeting the formation of these plaques by preventing the aggregation of amyloid-beta is a major therapeutic strategy. To date the mainstream approach has been to develop antibodies to bind to the aggregates, promoting their removal and interfering with their self-assembly.

"Disordered proteins are also involved in a wide range of diseases including cancer and cardiovascular disease. We hope that we can extend this understanding to also target disordered proteins involved in other diseases," said Heller.

Exposure to high temperatures in pregnancy is associated with an increase in adverse pregnancy outcomes, especially preterm birth and stillbirth, and among women in lower socioeconomic groups, finds a study published by The BMJ today.

Although the effects may appear small in size, the researchers say the findings "could have a major impact on public health as exposure to high temperatures is common and escalating." Moreover, conditions such as preterm birth often have lifelong implications for affected newborns.

Increases in global temperatures raise concerns about heat impacts on health, especially in vulnerable groups such as the elderly, those living in poverty, and the chronically ill.

Previous evidence reviews have found associations between exposure to high temperatures and pregnancy outcomes, but have included few studies and have not assessed differences across population groups and by type of heat exposure.

So an international team of researchers set out to assess whether exposure to high temperatures in pregnancy is associated with increased risk for preterm birth, low birth weight and stillbirth.

They analysed the results of 70 studies, set in 27 countries, seven of which were low and middle income countries, that reported associations between high temperatures and preterm birth, birth weight and stillbirths.

Differences in study design and quality of evidence were taken into account.

WHO estimates that 15 million babies are born preterm each year, the leading cause of death among children under 5. The average rate of preterm birth in the studies was 5.6%, much lower than the global average of about 10%.

Of the 47 studies that assessed preterm births, 40 reported that preterm births were more common at higher than lower temperatures. Further analysis showed that the odds of a preterm birth rose, on average, by 5% per 1°C increase in temperature and by 16% during heat waves than on non-heatwave days.

Nearly 2 million stillbirths occur each year worldwide. The average stillbirth rate was 6.2 per 1000 births in the eight included studies, about half the rates documented in many lower-income countries.

All eight studies detected an increase in stillbirths at higher temperatures, with stillbirths increasing by 5% per 1°C rise in temperature. In most cases, associations between temperature and stillbirth were most pronounced in the last week or month of pregnancy.

Low birth weight, associated with a range of short and long-term consequences, occurred on average in 3% of infants in the included studies. Of the 28 studies that assessed birth weight, 18 found an increased risk at higher temperatures, but generally the impacts of temperature on weight were small, with most studies reporting only minor changes.

However, the researchers point out that, "even apparently minor decrements in birth weight could have a major impact on public health as exposure to high temperatures is common and escalating."

Finally, associations between temperature and outcomes were largest among women in lower socioeconomic groups, suggesting that pregnant women in low and middle income countries may be at particular risk from heat exposure, they add.

This review was based on observational studies, of which about a third were of low quality, so no firm conclusions can be drawn about cause and effect. The researchers also point to limitations, such as differences in temperature measures between studies, and the possibility that other factors, such as air pollution, may have had an effect on pregnancy outcomes.

Nevertheless, they say the review included more studies than previous reviews, allowing for comparisons of three outcomes and a more comprehensive assessment of heat sensitivity in pregnancy.

As such, they say the review "highlights the need to identify interventions targeting heat related conditions in pregnant women, especially in women at the age extremes and in lower socioeconomic groups, and to determine their effectiveness."

They argue that pregnant women "merit a place alongside the groups typically considered as at high risk for heat related conditions."

"Given increases in the frequency and intensity of heatwaves, the number of pregnant women exposed to these conditions worldwide, and the significant individual and societal burdens associated with preterm birth and stillbirth, research and policy initiatives to deal with these connections are a high priority," they conclude.

Some claim that machine learning technology has the potential to transform healthcare systems, but a study published by The BMJ finds that machine learning models have similar performance to traditional statistical models and share similar uncertainty in making risk predictions for individual patients.

The NHS has invested £250m ($323m; €275m) to embed machine learning in healthcare, but researchers say the level of consistency (stability) within and between models should be assessed before they are used to make treatment decisions for individual patients.

Risk prediction models are widely used in clinical practice. They use statistical techniques alongside information about people, such as their age and ethnicity, to identify those at high risk of developing an illness and make decisions about their care.

Previous research has found that a traditional risk prediction model such as QRISK3 has very good model performance at the population level, but has considerable uncertainty on individual risk prediction.

Some studies claim that machine learning models can outperform traditional models, while others argue that they cannot provide explainable reasons behind their predictions, potentially leading to inappropriate actions.

What's more, machine learning models often ignore censoring - when patients are lost (either by error or by being unreachable) during a study and the model assumes they are disease free, leading to biased predictions.

To explore these issues further, researchers in the UK, China and the Netherlands set out to assess the consistency of machine learning and statistical techniques in predicting individual level and population level risks of cardiovascular disease and the effects of censoring on risk predictions.

They assessed 19 different prediction techniques (12 machine learning models and seven statistical models) using data from 3.6 million patients registered at 391 general practices in England between 1998 and 2018.

Data from general practices, hospital admission and mortality records were used to test each model's performance against actual events.

All 19 models yielded similar population level performance. However, cardiovascular disease risk predictions for the same patients varied substantially between models, especially in patients with higher risks.

For example, a patient with a cardiovascular disease risk of 9.5-10.5% predicted by the traditional QRISK3 model had a risk of 2.9-9.2% and 2.4-7.2% predicted by other models.

Models that ignored censoring (including commonly used machine learning models) substantially underestimated risk of cardiovascular disease.

Of the 223,815 patients with a cardiovascular disease risk above 7.5% with QRISK3 (a model that does consider censoring), 57.8% would be reclassified below 7.5% when using another type of model, explain the researchers.

The researchers acknowledge some limitations in comparing the different models, such as the fact that more predictors could have been considered. However, they point out that their results remained similar after more detailed analyses, suggesting that they withstand scrutiny.

"A variety of models predicted risks for the same patients very differently despite similar model performances," they write. "Consequently, different treatment decisions could be made by arbitrarily selecting another modelling technique."

As such, they suggest these models "should not be directly applied to the prediction of long term risks without considering censoring" and that the level of consistency within and between models "should be routinely assessed before they are used to inform clinical decision making."

November 4, 2020 (ATLANTA) - As wildlife populations decline around the globe, understanding the natural and human-induced factors that influence their growth is critical for determining the risk of population declines and developing effective conservation strategies.

In a new study by the Dian Fossey Gorilla Fund and University of California Davis, "Violent encounters between social units hinder the growth of a high-density mountain gorilla population," in the journal Science Advances, scientists used five decades of data to examine the role of social behavior in explaining fluctuations in the growth rate of a subpopulation of mountain gorillas monitored by the Fossey Fund.

The researchers found a dramatic slowing of the population growth rate as a result of social factors, namely increases in infant mortality resulting from violent encounters between groups living at higher density and with more overlap in their home ranges.

"This is one of the few studies to demonstrate the considerable impact that social behavior can have on whether or not a population grows," says Dr. Winnie Eckardt, co-lead author of the study and research manager at the Fossey Fund.

Roughly 600 of the estimated 1,063 remaining mountain gorillas live in the Virunga massif, a small forest spanning the countries of Rwanda, Uganda and the Democratic Republic of the Congo.

While small, the population has grown significantly since the early 1980s, when there were estimated to be just 250 individuals. Conservation measures implemented since then in this 430-square-kilometer forest led to a remarkable recovery of the Virunga mountain gorilla population. Repeated censuses during the 1980s and early 2000s, however, found the population growth to be uneven, with the subpopulation monitored by the Fossey Fund experiencing a faster growth rate than the rest of the population.

By 2006, this study population was composed of three large stable groups, each with multiple silverbacks. While the average gorilla group numbers 10 individuals, these groups ranged from 25 to a record 65 gorillas and included up to eight silverbacks.

When the young silverbacks in these groups started challenging the older group leaders, the resulting social instability led to a series of group fissions and formations. As a result, an area previously shared by just three groups was now occupied by up to 11 smaller groups, with fewer silverbacks per group.

Expansion of these groups into new areas was limited by the presence of agricultural fields immediately next to the park and the presence of other gorilla groups. The threefold increase in group density resulted in higher overlap in home ranges between groups and more frequent intergroup interactions. Such interactions are often violent, as males hoping to attract females target other males and their infants. As a result, infant mortality increased by 57%, contributing to slowing the annual population growth rate from 5.05% to 2.37%.

"Before 2007, we would talk about intergroup encounters for months because they were so rare," recalls Eckardt. "After that, they began to happen with such frequency that we could hardly keep up with documenting them."

One implication of the findings is that in socially living species, the density of groups rather than the density of individuals may play a larger role in regulating population growth. "Scientists often talk about how many individuals an environment can hold, also known as carrying capacity," say co-author Jean Paul Hirwa, the Fossey Fund's gorilla program manager. "But what these data clearly show is that for social species, this number can depend on how the animals chose to organize themselves. For example, 100 gorillas living in three groups, as we saw in the 2000s, likely require less space than 100 gorillas living in 10 groups."

"The Virunga gorilla population has been increasing for almost 40 years, but its habitat has not. As the gorilla density reaches unusually high value, scientists fear that between-group aggression and stress will significantly affect the welfare of the animals," says Dr. Damien Caillaud, a co-lead author of the study and associate professor of anthropology at UC Davis.

The study also shows the challenges for the broader Virunga mountain gorilla population. Other mountain gorilla subpopulations within the region now look similar to the study groups in the 2000s, with high growth rates, large sizes and multiple males. Should they undergo a similar set of social changes, this could result a further slowing of the overall growth of the population.

"This study highlights the value of long-term data to understanding the ever-changing population dynamics of a species, which is ultimately linked to its conservation," says Dr. Tara Stoinski, co-author and CEO of the Fossey Fund. "Mountain gorillas are an incredible conservation success story, but their population is very small--just over 1,000 individuals. Our hope is that improving our understanding of what factors are influencing the population's growth will aid in developing effective conservation strategies."

PHILADELPHIA - Multiple sclerosis (MS) is an autoimmune disorder that develops as the body's immune system attacks the central nervous system. Specifically, it attacks the protective layer surrounding nerve cells, called the myelin sheath. Current MS therapies aim to counter this inflammatory response by suppressing the immune system, which can lead to serious side effects like a higher risk of infection, and even cancer. Jefferson researchers have found a way to prevent immune cells from attacking myelin and halt disease progression, while leaving the rest of the immune system intact, in mouse models of MS. The study was published in Science Translational Medicine on November 4th.

"There are many possible immune-activating antigens in the myelin sheath, but the biggest hurdle is that we don't know which component of myelin is triggering the immune response in MS patients," says senior author Abdolmohamad Rostami, MD, PhD, Professor and Chairman of the Department of Neurology at Sidney Kimmel Medical College - Thomas Jefferson University and Vickie and Jack Farber Institute for Neuroscience - Jefferson Health. "Previous studies have used single myelin antigens or combinations of antigens to prevent auto-immunity in animal models, but in humans they have had limited success."

For answers, the researchers turned to cells called oligodendrocytes. These cells wrap their cell membrane around nerve cells to produce the myelin sheath. Tiny sacs called extracellular vesicles (EVs) can be harvested from cultured oligodendrocytes. The researchers found that these EVs contain almost all the relevant myelin antigens. With all of the antigens present, there'd be a higher chance that these vesicles could halt the autoimmune attack on myelin.

"The neat thing about these EVs is that they give us an opportunity to treat the disease in an antigen-specific way, without having to know the exact identity of the target antigen," explains Dr. Rostami. "It covers all the bases."

The researchers were able to safely inject the EVs intravenously in three different mouse models of MS representing early and late stages of the disease. When administered before disease developed, the EVs had a prophylactic effect, preventing the onset of symptoms like decrease in mobility and paralysis. When given after disease onset, EVs significantly reduced severity of disease in all three models, to the point that the animals could walk again.

"The antigens involved in the auto-immune response can differ between MS patients, and even change over time in an individual patient," explains Dr. Rostami. "The fact that our approach was effective in different experimental models shows this could act as a universal therapy."

Importantly, the researchers found that the experimental therapy only affected immune cells that were attacking the myelin layer. The rest of the immune system was intact and not weakened at all.

"This is a huge advantage of our antigen-specific method over current therapies, which are like a sledgehammer to the immune system," says Dr. Rostami, "and what makes it so novel."

Translating the approach to the clinical setting, the team found that they were able to isolate the vesicles from human-derived oligodendrocytes. These human vesicles, like those from mice, also contained multiple myelin antigens, and therefore could have the same therapeutic effect in patients.

Dr. Rostami and his team are now working on getting the intravenous EVs approach patented, which could be a revolutionary step for MS treatment.

"This study was made possible by a talented group of scientists, especially Giacomo Casella, a postdoctoral fellow in our laboratory, and Bogoljub Ciric, and Guang-Xin Zhang, faculty members here at Jefferson," says Dr. Rostami.

What The Study Did: Researchers investigated whether loosening of state firearm restrictions in Missouri were associated with changes in rates of suicide by firearms among young people ages 14 to 24.

Authors: Apurva Bhatt, M.D., of the University of Missouri-Kansas City/Center for Behavioral Medicine in Kansas City, is the corresponding author.

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

(doi:10.1001/jamanetworkopen.2020.24303)

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