Culture

Firefighting is a race against time. Exactly how much time? For firefighters, that part is often unclear. Building fires can turn from bad to deadly in an instant, and the warning signs are frequently difficult to discern amid the mayhem of an inferno.

Seeking to remove this major blind spot, researchers at the National Institute of Standards and Technology (NIST) have developed P-Flash, or the Prediction Model for Flashover. The artificial-intelligence-powered tool was designed to predict and warn of a deadly phenomenon in burning buildings known as flashover, when flammable materials in a room ignite almost simultaneously, producing a blaze only limited in size by available oxygen. The tool's predictions are based on temperature data from a building's heat detectors, and, remarkably, it is designed to operate even after heat detectors begin to fail, making do with the remaining devices.

The team tested P-Flash's ability to predict imminent flashovers in over a thousand simulated fires and more than a dozen real-world fires. Research, just published in the Proceedings of the AAAI Conference on Artificial Intelligence, suggests the model shows promise in anticipating simulated flashovers and shows how real-world data helped the researchers identify an unmodeled physical phenomenon that if addressed could improve the tool's forecasting in actual fires. With further development, P-Flash could enhance the ability of firefighters to hone their real-time tactics, helping them save building occupants as well as themselves.

Flashovers are so dangerous in part because it's challenging to see them coming. There are indicators to watch, such as increasingly intense heat or flames rolling across the ceiling. However, these signs can be easy to miss in many situations, such as when a firefighter is searching for trapped victims with heavy equipment in tow and smoke obscuring the view. And from the outside, as firefighters approach a scene, the conditions inside are even less clear.

"I don't think the fire service has many tools technology-wise that predict flashover at the scene," said NIST researcher Christopher Brown, who also serves as a volunteer firefighter. "Our biggest tool is just observation, and that can be very deceiving. Things look one way on the outside, and when you get inside, it could be quite different."

Computer models that predict flashover based on temperature are not entirely new, but until now, they have relied on constant streams of temperature data, which are obtainable in a lab but not guaranteed during a real fire.

Heat detectors, which are commonly installed in commercial buildings and can be used in homes alongside smoke alarms, are for the most part expected to operate only at temperatures up to 150 degrees Celsius (302 degrees Fahrenheit), far below the 600 degrees Celsius (1,100 degrees Fahrenheit) at which a flashover typically begins to occur. To bridge the gap created by lost data, NIST researchers applied a form of artificial intelligence known as machine learning.

"You lose the data, but you've got the trend up to where the heat detector fails, and you've got other detectors. With machine learning, you could use that data as a jumping-off point to extrapolate whether flashover is going to occur or already occurred," said NIST chemical engineer Thomas Cleary, a co-author of the study.

Machine-learning algorithms uncover patterns in large datasets and build models based on their findings. These models can be useful for predicting certain outcomes, such as how much time will pass before a room is engulfed in flames.

To build P-Flash, the authors fed their algorithm temperature data from heat detectors in a burning three-bedroom, one-story ranch-style home -- the most common type of home in a majority of states. This building was of a digital rather than brick-and-mortar variety, however.

Because machine learning algorithms require great quantities of data, and conducting hundreds of large-scale fire tests was not feasible, the team burned this virtual building repeatedly using NIST's Consolidated Model of Fire and Smoke Transport, or CFAST, a fire modeling program validated by real fire experiments, Cleary said.

The authors ran 5,041 simulations, with slight but critical variations between each. Different pieces of furniture throughout the house ignited with every run. Windows and bedroom doors were randomly configured to be open or closed. And the front door, which always started closed, opened up at some point to represent evacuating occupants. Heat detectors placed in the rooms produced temperature data until they were inevitably disabled by the intense heat.

To learn about P-Flash's ability to predict flashovers after heat detectors fail, the researchers split up the simulated temperature recordings, allowing the algorithm to learn from a set of 4,033 while keeping the others out of sight. Once P-Flash had wrapped up a study session, the team quizzed it on a set of 504 simulations, fine-tuned the model based on its grade and repeated the process. After attaining a desired performance, the researchers put P-Flash up against a final set of 504.

The researchers found that the model correctly predicted flashovers one minute beforehand for about 86% of the simulated fires. Another important aspect of P-Flash's performance was that even when it missed the mark, it mostly did so by producing false positives -- predictions that an event would happen earlier than it actually did -- which is better than the alternative of giving firefighters a false sense of security.

"You always want to be on the safe side. Even though we can accept a small number of false positives, our model development places a premium on minimizing or, better yet, eliminating false negatives," said NIST mechanical engineer and corresponding author Wai Cheong Tam.

The initial tests were promising, but the team had not grown complacent.

"One very important question remained, which was, can our model be trusted if we only train our model using synthetic data?" Tam said.

Luckily, the researchers came across an opportunity to find answers in real-world data produced by Underwriters Laboratories (UL) in a recent study funded by the National Institute of Justice. UL had carried out 13 experiments in a ranch-style home matching the one P-Flash was trained on, and as with the simulations, ignition sources and ventilation varied between each fire.

The NIST team trained P-Flash on thousands of simulations as before, but this time they swapped in temperature data from the UL experiments as the final test. And this time, the predictions played out a bit differently.

P-Flash, attempting to predict flashovers up to 30 seconds beforehand, performed well when fires started in open areas such the kitchen or living room. But when fires started in a bedroom, behind closed doors, the model could almost never tell when flashover was imminent.

The team identified a phenomenon called the enclosure effect as a possible explanation for the sharp drop-off in accuracy. When fires burn in small, closed-off spaces, heat has little ability to dissipate, so temperature rises quickly. However, many of the experiments that form the basis of P-Flash's training material were carried out in open lab spaces, Tam said. As such, temperatures from the UL experiments shot up nearly twice as fast as the synthetic data.

Despite revealing a weak spot in the tool, the team finds the results to be encouraging and a step in the right direction. The researchers' next task is to zero in on the enclosure effect and represent it in simulations. To do that they plan on performing more full-scale experiments themselves.

When its weak spots are patched and its predictions sharpened, the researchers envision that their system could be embedded in hand-held devices able to communicate with detectors in a building through the cloud, Tam said.

Firefighters would not only be able to tell their colleagues when it's time to escape, but they would be able to know danger spots in the building before they arrive and adjust their tactics to maximize their chances of saving lives.

EUGENE, Ore. -- June 1, 2021 -- Businesses typically rely on banks and financial markets for financing, but credit provided by suppliers also can play an important role, especially in manufacturing. Yet why firms lend and borrow extensively from each other is still an open question.

In a paper online ahead of print in the Journal of Financial Economics, "Trade Credit and Profitability in Production Networks," Youchang Wu, an associate professor at the University of Oregon, and coauthor Michael Gofman, an assistant professor at the University of Rochester, examined trade credit from a new angle.

They noted that for an average nonfinancial firm in North America, the outstanding amount of trade credit it receives from suppliers is about 21 percent of annual production costs. Moreover, most firms simultaneously borrow from their suppliers and lend to their customers, with the average outstanding amount of trade credit provided to customers at around 15 percent of annual sales.

Previous studies on trade credit, they noted, have focused on a firm's role either as a lender or a borrower of trade credit, ignoring the fact that trade credit flows along supplier-customer links in complex production networks.

Using a comprehensive database of supplier-customer relationships from 2003 to 2018, Wu and Gofman analyzed more than 200,000 supply chains formed by more than 5,600 nonfinancial firms. By locating a firm in the supply chain, their study accounts for a firm's dual role as a supplier and a customer. This novel approach allowed the researchers to uncover new details about trade credit within and across supply chains.

In particular, they found that within the supply chain, more upstream firms borrow more from suppliers, lend more to customers and hold more net trade credit, despite appearing to have weaker financing capacity than more downstream firms.

The length of the supply chains they examined varies significantly.

An example of a longer supply chain is one in which Intermolecular Inc. supplies advanced materials to Micron Technology Inc., which creates computer memory and computer data storage that it provides to Nvidia Corp., which uses them to manufacture graphics cards it supplies to Tesla. In contrast, a short supply chain example is one in which Sensata Technology provides sensors directly to Tesla. In longer supply chains, firms tend to be more profitable, and the increase in trade credit provision from the lower to the upper level of the chain is more gradual.

Both within and across supply chains, the authors noted that there is an almost one-to-one correspondence between the variation in the trade credit a firm provides and the variation in the trade credit it receives. These findings are less consistent with the idea of financially strong firms lending to financially weak firms, an implication of the financing advantage theory.

"Our findings are more consistent with the recursive moral hazard theory of trade credit," said Wu, who teaches in the Department of Finance at the Lundquist College of Business and is the John B. Rogers Research Scholar and coordinator of the UO's finance doctoral program.

"This theory argues that more upstream firms have more severe incentive problems, especially when they are not that profitable, because the quality of their products is revealed only after a long delay," he said. "Thus, more net trade credit provided by upstream firms helps to align incentives."

The authors did, however, find evidence that a firm's provision of trade credit is related to its financial status during an economic downturn. For instance, during the 2008-2009 financial crisis, upstream firms experienced a larger decline in profit margins than did downstream firms, and net provision of trade credit dropped significantly, suggesting that financial strength plays a more important role in determining the provision and use of trade credit during a crisis period.

Overall, Wu and Gofman's systematic study highlights variations in trade credit practices across firms, which can help both researchers and practitioners better understand the role of trade credit in production networks as well as examine other economic and financial questions related to supply chains.

In ride-sharing, trips of two or more customers with similar origins and destinations are combined into a single cab ride. The concept can make a significant contribution to sustainable urban mobility. However, its acceptance depends on human needs and behavior. For example, while shared rides typically offer a financial advantage, passengers might suffer drawbacks in terms of comfort and trip duration. These factors give rise to different adoption behaviors that explain usage patterns observed in 360 million real-world ride requests from New York City and Chicago in 2019. The study has now been published in the journal Nature Communications.

Ride-sharing (or ride-pooling) is most efficient in places with high demand and a large number similar ride requests. Still, it has been difficult to answer if and under what conditions people are actually willing to adopt ride-sharing. In their study, the researchers decipher the complex incentive structure underlying the decision of whether or not to adopt ride-sharing. In a game-theoretic model, they describe the sharing adoption of all users who book rides from the same location.

The researchers demonstrate how interactions between those individuals lead to two qualitatively different patterns of acceptance. In one, willingness to share rides is consistently high. In the other case, however, the willingness to share rides decreases as the overall demand for rides increases. If there are only few users in the system, the number of ride-sharing bookings increases with the number of ride requests, yet if there are many users, the usage levels out. The relative amount of shared ride requests therefore decreases - despite optimized routing with shorter detours for the passengers when demand is high.

"Passengers speculate on being able to take advantage of the cheaper fare when sharing a ride, but they actually hope to be transported alone and thus directly from A to B due to low demand for rides," explains David Storch, a doctoral student at the Chair of Network Dynamics and lead author of the study. When demand is high, for example during typical rush hours, the prospect of being transported as a single passenger is lower - "Passengers almost certainly lose comfort as they share a ride. They tend to book the more expensive fare more often to travel alone."

In an analysis of more than 360 million real trip requests in New York City and Chicago, the researchers were able to identify the demand patterns they had previously found in their model, supporting the validity of their findings. The analysis shows that, depending on the starting point of the trip, both adoption patterns exist in parallel in the two cities. Malte Schröder, research associate at the Chair, interprets the results as follows: "Since both adoption patterns coexist in cities, a moderate increase of the financial incentives is probably already sufficient to strongly increase the acceptance of ride-sharing in other places and for other user groups."

Besides common symptoms such as fever, cough and respiratory distress, some children have an atypical form of COVID-19 known as multisystem inflammatory syndrome in children (MIS-C), characterized by persistent fever and inflammation of several organs, such as the heart and intestines, as well as the lungs to a lesser extent. Reports of MIS-C have been increasingly associated with severe cases and deaths in several countries including Brazil since the onset of the pandemic.

Researchers affiliated with the University of São Paulo's Medical School (FM-USP) and Adolfo Lutz Institute in Brazil performed the largest series of autopsies to date on children who died from COVID-19. Their findings show that the ability of SARS-CoV-2 to invade and damage several organs is one of the factors leading to MIS-C, producing a wide array of clinical manifestations that include abdominal pain, heart failure and seizures, as well as persistent fever.

The study was supported by São Paulo Research Foundation - FAPESP
and reported in an article in EClinicalMedicine, a Lancet group journal.

"The direct action of the virus on the tissue of various organs is one of the reasons why children with this syndrome have an exacerbated and altered inflammatory response to infection," Marisa Dolhnikoff, last author of the article, told. Dolhnikoff is a professor at FM-USP.

The researchers performed autopsies on five children who died from COVID-19 in São Paulo: one boy and four girls aged between 7 months and 15 years. Two were seriously ill before being infected by SARS-CoV-2, one with cancer and the other with a congenital genetic disorder.

The other three were previously healthy and developed MIS-C with different clinical manifestations. One had myocarditis (inflammation of the heart muscle), another had colitis (inflammation of the bowel), and a third had acute encephalopathy (brain damage) with seizures.

A minimally invasive technique, ultrasound-guided with coaxial and punch needles, was used to collect tissue samples from all major organs. The presence of SARS-CoV-2 in the samples was determined by real-time reverse transcription polymerase chain reaction (RT-PCR, the technique also used to diagnose COVID-19) and by immunohistochemistry, in which antibodies were deployed to detect the viral nucleocapsid protein (N) and one of the spike proteins (S2).

Histopathological analysis showed that both children with severe pre-existing disease had "classic" severe COVID-19, characterized by acute respiratory distress due to extensive damage to the lung alveoli caused by SARS-CoV-2. The virus was also detected in other organs.

The three previously healthy children were found to have inflammatory lesions outside the lungs, such as myocarditis and colitis. The virus was detected in heart endothelial and muscle cells from the patient with myocarditis, in intestinal tissue from the child with acute colitis, and in brain tissue from the patient with acute encephalopathy.

"We found that SARS-CoV-2 had spread throughout the body via the blood vessels, infecting various types of cell and tissue in these children. The clinical manifestations varied according to the organ targeted," Dolhnikoff said. "It's important for pediatricians to watch out for these possible differences in the clinical manifestations of COVID-19 in children of all ages so that the infection is diagnosed and MIS-C can be treated early on."

MIS-C may occur a few days or weeks after infection by SARS-CoV-2. The runaway inflammatory reaction was thought to occur whether or not the virus was still in the organism, as a result of the immune response, but the study found evidence that the manifestations of MIS-C are also triggered by the direct action of the virus on the cells of infected organs.

"We're not saying everything described to date about pediatric multisystem inflammatory syndrome is wrong. We're merely adding the observation that the damage done to tissues by the virus is associated with this exacerbated inflammatory response in children, and is very probably a key component in its induction," Dolhnikoff said.

Why some children respond to infection by SARS-CoV-2 with the exacerbated inflammation that characterizes MIS-C is unknown, but the answer may include a genetic component.

Endothelial cells targeted

The researchers found that the virus's main targets included endothelial cells, which line blood vessels of all sizes and regulate exchanges between the bloodstream and the surrounding tissues. "One hypothesis is that when an endothelial cell is infected it activates bloodstream mediators that trigger an inflammatory cascade and the other reactions observed in children with MIS-C, such as persistent fever, colitis, myocarditis and encephalitis," said Amaro Nunes Duarte Neto, first author of the article. Duarte Neto is an infectious disease specialist and pathologist at FM-USP and Adolfo Lutz Institute.

"The virus induces these reactions in the cells, but it's the immune system that produces a response with adverse effects on the patient," he said. "It's not an autoimmune response, however, like what we see in lupus, psoriasis or inflammatory arthritis, which also involve damage to blood vessels. In MIS-C, the virus is involved directly."

Electron microscopy analysis by Elia Caldini, a professor at FM-USP, supported these conclusions. Electron microscopes magnify viral particles more than 50,000 times directly, without the use of reagents. The technique enabled the researchers to describe alterations in cell cytoplasm associated with the presence of the virus.

"To confirm our identification of the virus unequivocally, we were the first to use immunolabeling of SARS-CoV-2 in conjunction with electron microscopy," Caldini said. "We coupled colloidal gold particles to the specific antibodies used in light microscopy against structural viral proteins."

The researchers also detected microthrombi (small blood clots) for the first time in children. This had already been observed and reported in adults. "Phenomena relating to blood clotting should always be considered in COVID-19.

Our electron microscopy analysis showed that capillary blood vessels in all organs were obstructed by accumulated red and white blood cells, cellular debris, and fibrin, with disruption of the endothelial wall," Caldini said.

In a new study published in Proceedings of the National Academy of Sciences (PNAS), a research team of the Institute of Complex Systems of the University of Barcelona (UBICS) analysed the time evolution of real complex networks and developed a model in which the emergence of new nodes can be related to pre-existing nodes, similarly to the evolution of species in biology.

This new study analyses the time evolution of the citation network in scientific journals and the international trade network over a 100-year period. According to M. Ángeles Serrano, ICREA researcher at UBICS, "what we observe in these real networks is that both grow in a self-similar way, that is, their connectivity properties remain invariable over time, so that the network structure is always the same, while the number of nodes increases".

This self-similarity in growth, which is surprising per se, has been explained by the researchers using a model named geometric branching growth (GBG). In this model, the new nodes come from pre-existing nodes, in a similar way to family trees. For instance, in the world trade network, countries are nodes, and therefore they branch off, and transactions correspond to the links. The key property that characterizes the evolution of systems in study, and therefore the model, is inheritance. In the example, when a country is divided, the new sovereign countries inherit the richness and the trade partners of the original state.

This model is related to a previous study that enabled the production of self-similar reduced versions of complex networks, through a geometric renormalization. In these previous studies, scientists found that the connectivity in complex networks at different time scales is regulated by the same principles. "What we see in the new paper --notes the researcher-- is that these same principles remain over time too".

When both models are combined --GBG and geometric renormalization--, we can create copies of the original network in a wide range of measures, larger and smaller than the original one. "This way, we could predict descendant and ascendant nodes, or study phenomena that depend on the size of the network", highlights Serrano. "Networks present a fractal structure in time and space", the expert adds.

These branching processes are the base of the complex evolution of many real systems. "In short, both models enable us to understand interactions in real systems at different scales, one of the keys to understand and predict what their evolution will be like", concludes the expert.

Stigma and high care needs can present barriers to the provision of high-quality primary care for people with opioid use disorder (OUD) and those prescribed opioids for chronic pain. A study published in PLOS Medicine by Tara Gomes at the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Canada and colleagues suggests that people treated for an opioid use disorder were less likely to find a new primary care provider (PCP) within one year of termination of enrolment with the previous physician.

People with substance use disorders often have complex medical needs, requiring regular access to primary care physicians. However, some physicians may be less willing to treat these patients due to stigma, high health care needs, or discomfort prescribing opioids. To assess differences in access to primary care, researchers conducted a retrospective cohort study, analysing records of 154,790 Ontario residents who lost their enrolment with a primary care physician between 2016 and 2017. They assigned individuals to one of three groups based on their history of opioid use: no opioid use, opioid pain therapy, and opioid agonist therapy (for OUD). The authors then analyzed the number of people from each group who had found a primary care provider within a year.

The researchers found that people receiving opioid agonist therapy were 45% less likely to secure another primary care physician in the next year compared to opioid unexposed individuals. The study was limited in that the authors were unable to identify people with OUD if they were not in treatment and could not identify people who received care from walk-in clinics. However, the research is an important step in identifying inequities in access to primary care and management of complex chronic conditions.

According to the authors "Ongoing efforts are needed to address stigma and discrimination faced by people who use opioids within the health care system, and to facilitate access to high quality, consistent primary care services for chronic pain patients and those with OUD".

Dr. Gomes also notes, "There are considerable barriers to accessing primary care among people who use opioids, and this is most apparent among people who are being treated for an opioid use disorder. This highlights how financial disincentives within the healthcare system, and stigma and discrimination against people who use drugs introduce barriers to high quality care".

A new analysis of adults aged 80 years and older shows that a healthier lifestyle is associated with a lower risk of cognitive impairment, and that this link does not depend on whether a person carries a particular form of the gene APOE. Xurui Jin of Duke Kunshan University in Jiangsu, China, and colleagues present these findings in the open-access journal PLOS Medicine.

The APOE gene comes in several different forms, and people with a form known as APOE ε4 have an increased risk of cognitive impairment and Alzheimer's disease. Previous research has also linked cognitive function to lifestyle factors, such as smoking, exercise, and diet. However, it has been unclear whether the benefits of a healthy lifestyle are affected by APOE ε4, particularly for adults over 80 years of age.

To clarify the relationship between APOE ε4 and lifestyle, Jin and colleagues examined data from 6,160 adults aged 80 or older who had participated in a larger, ongoing study known as the Chinese Longitudinal Healthy Longevity Survey. The researchers statistically analyzed the data to investigate links between APOE ε4, lifestyle, and cognition. They also accounted for sociodemographics and other factors that could impact cognition.

The analysis confirmed that participants with healthy lifestyles or intermediately healthy lifestyles were significantly less likely to have cognitive impairment than those with an unhealthy lifestyle, by 55 and 28 percent, respectively. In addition, participants with APOE ε4 were 17 percent more likely to have cognitive impairment than those with other forms of APOE.

A previous study suggested that in individuals at low and intermediate genetic risk, favorable lifestyle profiles are related to a lower risk of dementia compared to unfavorable profiles. But these protective associations were not found in those at high genetic risk. However, the investigation showed the link between lifestyle and cognitive impairment did not vary significantly based on APOE ε4 status which represented the genetic dementia risk. This suggests that maintaining a healthier lifestyle could be important for maintaining cognitive function in adults over 80 years of age, regardless of genetic risk.

This cross-sectional study emphasized the importance of a healthy lifestyle on cognitive health. While further research will be needed to validate these findings among different population, this study could help inform efforts to boost cognitive function for the oldest of adults.

In the next step, the team will explore this association using the AD polygenetic risk score (AD-PRS) and explore the interactive relationship between AD-PRS and lifestyle on cognition with the longitudinal data.

While the term "supergene" may bring to mind the genetic hocus-pocus of Peter Parker's transformation into Spiderman, supergenes are actually fairly common phenomena in the realm of biology. A supergene refers to a genomic region containing multiple genes or genetic elements that are tightly linked, allowing genetic variants across the region to be co-inherited. Supergenes may arise when there is a clear benefit to inheriting specific combinations of biological traits together. Perhaps the most well-known examples of supergenes are sex chromosomes, which allow traits that are beneficial to the reproductive success of one sex to be co-inherited. In humans, this explains the prevalence of male-specific genes on the Y chromosome. While the concept of supergenes arose nearly a century ago, until recently, the study of their origin, evolution, and eventual fate was largely theoretical. Now, however, thanks to advances in genomic sequencing and computational biology, scientists can put those theories to the test with real-world data. In a recent review published in Genome Biology and Evolution titled " The genomic architecture and evolutionary fates of supergenes ", Associate Professor Tanja Slotte and her colleagues at Stockholm University in Sweden discuss new findings in the field of supergene evolution and reveal how the genomic architecture of a supergene is inextricably tied to its evolutionary fate.

"There is a rich history in evolutionary biology when it comes to the study of supergenes," says Slotte. "What I like about this topic is that there are theoretical models of supergene evolution to draw on, and at the same time, we can now thoroughly test those expectations empirically using genomic data or explore the expected effects of different genomic architectures using simulations." In particular, these new approaches can be used to assess the validity of some of the more well-established theories about supergenes.

Classical models posit that supergenes arise following the establishment of mutations at a minimum of two sites, followed by sequential accumulation of additional mutations. Selection for specific combinations of variants acts to suppress recombination, thus strengthening the linkage between mutations. This suppression of recombination often occurs through inversions, in which a genomic region is flipped on the chromosome, effectively inhibiting recombination. Because recombination enables the removal of deleterious mutations, however, once it has stopped, the supergene may degenerate through the accumulation of single-nucleotide mutations, as well as insertions, deletions, and the replication of transposable elements. Notably, this last characteristic of supergenes has made them particularly difficult to study until now. Notes Slotte, "This is a very good time for studying supergene evolution. Thanks to long-read sequencing and improved bioinformatic methods we can now obtain high-quality assemblies, including well assembled supergenic regions. This is not a trivial task, as non-recombining regions are often highly repetitive and therefore difficult to assemble."

In their review, Slotte and her collaborators discuss the ways in which new sequence data has challenged some classical supergene models. "One aspect that I find really fascinating is how empirical genomic studies are still yielding surprises when it comes to the origin and the genetic architecture of classic supergenes," says Slotte. An example of this is the case of the supergene governing wing pattern mimicry in the butterfly Heliconius numata. H. numata exhibits Müllerian mimicry, displaying one of seven different wing patterns, each of which mimics a different local species of the poisonous butterfly Melinaea, thus reinforcing their protection against predators. Recent data show that, rather than arising via the classical model of sequential mutation followed by inversion, the inverted chromosomal arrangement in H. numata arose via introgression from another Heliconius species. According to Slotte, this is a scenario that should be further explored using simulations and modeling.

Another surprise stemmed from recent studies of the S-locus supergene governing heterostyly in primroses. Heterostyly is a common plant adaptation resulting in the presence of two distinct flower morphs (S- and L-morphs) within a species. In each morph, the male and female reproductive organs in the flower are arranged in such a way that it is difficult for an individual plant to fertilize itself, limiting inbreeding and promoting outcrossing. Classical theories posited that S-morph flowers were heterozygotes (carrying two different versions of the S-locus supergene), while L-morph flowers were homozygotes (carrying two identical versions). Instead, new evidence reveals that primroses with S-morph flowers harbor an insertion spanning five genes that is absent from L-morph primroses, making S-morph plants hemizygotes (carrying a single copy of the S-locus).

In their paper, Slotte and colleagues further take advantage of advances in bioinformatics and computational biology to reveal new insights into supergene evolution. "When it comes to delineating expected patterns of evolution," says Slotte, "we benefit enormously from new efficient and flexible simulation software." Indeed, based on the new findings regarding the primrose S-locus supergene, Slotte and her co-authors used SLiM, a forward simulation program, to compare two hypothetical S-locus systems: the classic inversion model and the new model, in which an insertion leads to a supergene that is hemizygous in S-morphs. Their results revealed that the inversion accumulated more than six times more deleterious mutations than the hemizygous region and that each of these mutations on average had more deleterious effects, demonstrating that the specific genomic architecture of a supergene has a powerful effect on its ultimate degeneration and evolutionary fate.

In addition to the insights revealed by new sequence data and simulations, scientists have an unprecedented opportunity to study supergene functionality thanks to new genetic and molecular biology tools. According to Slotte, "Elucidating the function of genes located in supergenes has long been difficult, as by definition it is challenging to fine-map anything in a non-recombining region, but with the help of new genome editing techniques, this is now becoming increasingly feasible." In particular, Slotte hopes to use a combination of these approaches to study a new supergene target: "I recently got a great opportunity to bring this work to a new level through a Starting Grant from the European Research Council to study the supergene that governs heterostyly in wild flaxseed species (Linum). This work is now ongoing, and I am very excited about using this system to study supergene and plant mating system evolution."

A clinical trial examining the efficacy of two devices to monitor and detect atrial fibrillation (AF), or an irregular heartbeat, in ischemic stroke patients--one an implantable device that monitors over 12 months, the other an external device that monitors over a 30-day period--found the implantable device is more than three times more effective in detecting AF, and both are a significant improvement over the current standard of care in Alberta, Canada.

The Post-Embolic Rhythm Detection With Implantable Versus External Monitoring (PER DIEM) study, led jointly by University of Alberta and University of Calgary researchers, was published today in the journal JAMA. The findings are expected to significantly change practice in how clinicians look for AF in Albertan patients following ischemic stroke.

"We know that (the current method of monitoring) isn't as effective as it could be in picking up atrial fibrillation from this study because regardless of which arm of the study patients went into, we were picking up anywhere from five to 15 per cent extra atrial fibrillation," said Brian Buck, a stroke neurologist and associate professor of medicine at the U of A. "We found in the study there were a lot of patients with undetected atrial fibrillation, even after they received the standard cardiac monitoring."

Atrial fibrillation causes about one in four strokes in Alberta. Detecting it early is key to preventing further disabling strokes in patients who have already experienced ischemic stroke, a type of stroke caused by a blockage in an artery that supplies blood to the brain. If atrial fibrillation is detected, clinicians have treatments--mainly blood thinners--that can reduce the risk of stroke by almost 70 per cent.

The standard test in Alberta for AF is a 24-hour electrocardiogram monitor. In the PER DIEM trial, 300 Albertan patients who had suffered a stroke were randomized to one of two new devices that can monitor for AF for longer durations. The study showed that the implantable device picked up three times more new AF than the 30-day monitor (15 per cent versus five per cent). All of the patients in the clinical trial with new AF were started on blood thinners.

"We didn't expect that we would get such a dramatic increase with the longer recording, even though it intuitively makes sense," said study co-author Michael Hill, professor of neurology at the University of Calgary and senior medical director for stroke with Alberta Health Services' Cardiovascular and Stroke Strategic Clinical Network. "Most people suspected that detection rates apply to only certain subtypes of ischemic stroke. This study showed that theory is not correct."

"We believe that those patients that were identified with atrial fibrillation are now, for the rest of their lives, going to have a much lower risk of having a stroke in the future," added Buck, who is also a member of the U of A's Neuroscience and Mental Health Institute.

One of the patients who took part in the trial was Norman Mayer, the sitting mayor of the central Alberta community of Camrose for the past 32 years. Mayer recalls being admitted to the emergency department about five years ago after not feeling well and experiencing sudden pain. After examination, the clinicians on duty informed him that he had likely experienced a minor stroke.

After being stabilized, Mayer was informed of the clinical trial and given the option of participating. After giving his consent, he was randomly assigned to the group of patients who were given the implantable monitoring device.

"It was the luck of the draw, and the advantage of it was that it's inconspicuous and wearing (an external device) would not have been very appealing to me," said Mayer. "So I had (the implantable device) tucked into my chest. It's there and nobody knows about it except for me and my doctor.

"It gives you a bit of a comfort level, I guess. It's not bothering you. It's just there and a part of life," he added. "It gives you the feeling that if something was to go wrong, somebody's going to be in touch to let you know (what steps need to be taken)."

With better monitoring, clinicians may be able to diagnose much more AF after stroke and dramatically reduce the risk of future disabling stroke. According to the Canadian Coordinating Office for Health Technology Assessment (CADTH), the external device costs about $1,000 per patient to administer, while the implantable device typically costs over $5,000 per patient. The implantable device had the added advantage of remote monitoring, reducing the need for trips to the hospital--an important consideration for rural Albertans. The team says an in-depth cost-benefit analysis is needed to determine the best approach to providing superior care while also providing savings for the health-care system.

"The biggest problem with stroke is that it dramatically impacts people's lives. So you take a healthy, independent person with a big disabling stroke, and they often end up being dependent on others for help with care. So that's terrible for patients and it's very expensive for the system. If you can prevent even a few of those big disabling strokes per year, it helps the person and reduces the burden on the health system," said Buck.

"This new evidence will help guide selection of what strategy is best going forward," added Hill. "We need to go beyond (24-hour monitoring) for Albertan patients. But if the system is going to pay for this technology, we need to know more definitively that patients are going to end up with lower stroke rates in the future."

The researchers say studies to this point have shown a trend in that direction, but more work is needed to prove it definitively. They hope to address those questions in future research.

Aerosol reductions that would take place as countries meet climate goals could contribute to global cooling and prevent more than one million annual premature deaths over a decade, according to a new study from the University of California San Diego.

The landmark Paris Agreement of 2016 does not address emissions of aerosols--fine particulates like soot that cause pollution. Nonetheless, findings from the recent study authored by researchers at UC San Diego's Scripps Institution of Oceanography and the School of Global Policy and Strategy suggests that aerosol accounting should be explicitly incorporated into international climate policy.

It is crucial because as countries implement their greenhouse gas reduction targets under the Paris climate agreement, their choices about which sectors to target will also reduce aerosols that are co-emitted, which will have major impacts to public health and global temperatures.

"Joint consideration of greenhouse gases and aerosols is critical," said Pascal Polonik, a Ph.D. student at Scripps Oceanography and first author of the paper published in Earth's Future. "Polluting particles, known as aerosols, are emitted in tandem with greenhouse gases but aren't accounted for. While all greenhouse gas emissions might be thought of as unambiguously harmful, aerosols are more complicated. All aerosols are harmful to human health but they also often help counteract global warming by cooling the Earth's surface."

It is estimated that emissions of aerosols from burning fossil fuels like coal and diesel are responsible for nine million premature deaths worldwide. Though most aerosols have a cooling effect because they reflect sunlight, certain types, such as black carbon have a warming effect.

The UC San Diego team wanted to explore the tradeoffs countries would face by taking aerosols into consideration while concurrently making CO2 cuts to implement Paris pledges.

Their model provides a country-by-country breakdown of the impacts of aerosol reductions across the eight economic sectors which cause emissions. For each country, the authors consider three scenarios. The first scenario prioritizes air quality, targeting aerosol cuts to the "dirtiest" sectors that emit the most solid particles. The second prioritizes temperatures by targeting industries that emit aerosols that most contribute to warming and the third, dubbed the "politically expedient" approach, reduces emissions from all economic sectors equally.

Preventing as many as one million premature deaths per year by cutting emissions from certain sectors first

Under these three approaches, the authors find that by 2030, the three scenarios would yield prevention of as many as one million premature deaths every year and global temperature differences of the same magnitude as those from greenhouse gas reductions.

The study demonstrates the importance of domestic decisions for reducing emissions because making cuts to certain sectors can produce cleaner air and save more lives, or further reduce warming.

For example, the U.S. could choose to save more lives by targeting aerosol emissions in the industrial production, shipping, or residential/commercial sectors. It could also choose to limit warming more with cuts to the solvents, residential/commercial and waste sectors.

To the authors' surprise, the third scenario, which may be most politically feasible to implement as policy, can lead to both more deaths and less cooling in certain places, such as Africa, China, the Middle East and South America.

"Implementing cuts equally and making each industry do their fair share may be the easiest way to implement climate policy in a democratic society like the U.S. where there are many competing political interests," said co-author Kate Ricke, assistant professor with Scripps Oceanography and the School of Global Policy and Strategy. "However, there are real benefits to being thoughtful about how aerosols factor into climate policy outcomes. There may be big benefits to cutting emissions from certain sectors first."

The research is critical to the U.S., as it is currently renegotiating its Paris agreement climate pledge.

"Our analysis does indicate some considerable tradeoffs between temperature and health outcomes that will need to be contended with in meeting near-term emission reductions goals," said Jennifer Burney, the Marshall Saunders Chancellor's Endowed Chair in Global Climate Policy and Research at the School of Global Policy and Strategy.

In India, for example, emission cuts in the transportation sector could save more lives, while cuts in the residential sector would produce more cooling.

The authors note that because the tradeoffs vary considerably for each region, countries are likely to have different priorities for weighing reduction of warming versus protection of public health when making climate policy decisions.

The conclusion, they emphasize, is that there are many ways to achieve the same magnitude of greenhouse gas reduction pledged in the Paris Agreement, but the aerosol emissions that "ride along" with those cuts may vary a lot depending on which sectors are targeted. As such, the authors write, "we believe that this is a strong case for explicitly considering aerosols when constructing climate policy."

BOSTON - For patients who have experienced certain common types of stroke, a small chip inserted under the skin may help physicians predict their likelihood of experiencing a second stroke, and therefore their likelihood of benefiting from preventive therapy. The findings come from a recent clinical trial published in the Journal of the American Medical Association and led by investigators at Massachusetts General Hospital (MGH) and Northwestern University Feinberg School of Medicine.

Each year, approximately 800,000 strokes occur in the United States, and as many as one-fourth occur in people who experienced a previous stroke. Investigators have been searching for ways to identify patients who are likely to experience a recurrent stroke, as these individuals could be candidates for taking certain medications such as blood thinners. One group of patients who face an elevated risk of recurrent strokes are those with atrial fibrillation--an irregular and often rapid heart rate--that often goes undetected and untreated. (Irregular heartbeats can allow blood to pool in the heart, which can cause clots to form and travel to the brain.)

Recent research has shown that a small chip inserted under the skin can monitor the heart rate and rhythm, and help physicians detect atrial fibrillation in patients who previously experienced what's called a cryptogenic stroke, one with no identified cause despite thorough patient testing. Now investigators have tested the chip--less than 1¾? long and 1/6? thick and called an insertable cardiac monitor--in patients who experienced a stroke caused by narrowing of a large artery like the carotid artery, or blockage of a small artery deep in the brain where atrial fibrillation would be unexpected.

In the Stroke of Known Cause and Underlying Atrial Fibrillation (STROKE AF) trial, 492 patients were randomized and completed 12 months of follow-up after receiving either an insertable cardiac monitor within 10 days of an initial stroke or usual care consisting of external cardiac monitoring through electrocardiograms or other tracking methods.?

The chip detected atrial fibrillation in 12.1% of patients, compared with 1.8% detected through usual care. The team noted that the episodes of atrial fibrillation were not brief, with most lasting at least one hour. Most stroke experts would recommend that patients with this degree of atrial fibrillation start taking blood thinners to prevent a future stroke.

"We found that a significant minority of patients with stroke not thought to be related to atrial fibrillation actually have atrial fibrillation, but we can only find it with an implantable monitor," says lead author Richard A. Bernstein, MD, PhD, a professor of Neurology at Northwestern University Feinberg School of Medicine.

Adds senior author Lee H. Schwamm, MD, C. Miller Fisher Chair of Vascular Neurology at MGH: "Based on the study findings, we believe that patients with stroke who are similar to those in the STROKE AF Trial should now undergo long-term cardiac monitoring with an insertable cardiac monitor to identify unsuspected atrial fibrillation."

Schwamm notes that for every eight patients monitored, clinicians could expect to find atrial fibrillation in one of them in the first year. "This could dramatically change the treatment recommendations by their doctor," he says.

Next steps in this research include identifying patient factors that predict the development of atrial fibrillation and the duration and extent of the arrhythmia. Additional studies are being explored to further understand the association of silent atrial fibrillation and recurrent stroke of all types.

Irvine, CA - June 1, 2021 - A new study analyzing the association between an individual's genetics (genotype) and their observable characteristics resulting from the interaction of genetics and the environment (phenotype), contributes new knowledge to the understanding of human complex traits and diseases.

The study titled, "An atlas of alternative polyadenylation quantitative trait loci (3?aQTLs) contributing to complex trait and disease heritability," was recently published in Nature Genetics. Led by University of California, Irvine professor of bioinformatics Wei Li, PhD, the Grace B. Bell chair of the Department of Biological Chemistry at UCI's School of Medicine, this new research unlocks how much differences in people's genes account for differences in their traits and what can be attributed to the effects of the surrounding environment.

"Our research is of particularly importance as it offers interpretations that explain how natural variations can shape human phenotypic diversity and tissue-specific diseases," said Li. "Our most exciting finding was that certain events in human genes can explain a substantial proportion of trait heritability."

It was well known that 3'-UTR alternative polyadenylation (APA) occurs in approximately 70 percent of human genes and substantively impacts cellular processes such as proliferation, differentiation and tumorigenesis. But, until now, the association of APA events with disease risk and complex human traits was not well understood.

Genome-wide association studies have identified thousands of noncoding variants associated with human traits and diseases. However, the functional interpretation of these variants has proven to be a major challenge. In this study, researchers constructed a multi-tissue atlas of human 3? UTR alternative polyadenylation (APA) quantitative trait loci (3?aQTLs), containing approximately 0.4 million common genetic variants associated with the APA of target genes, identified in 46 tissues isolated from 467 individuals (Genotype-Tissue Expression Project).

"From our findings we could show that specific molecular features associated with human phenotypic variations contribute substantially to the molecular mechanisms underlying human complex traits and diseases," explained Li.

The research team is continuing to study these molecular mechanisms to test the novel 3?aQTLs genes for diabetes, prostate cancer, Alzheimer's Disease and Amyotrophic lateral sclerosis (ALS).

Older adults with cognitive impairment are two to three times more likely to fall compared with those without cognitive impairment. What's more, the increasing use of pain medications for chronic pain by older adults adds to their falls risk. Risks associated with falls include minor bruising to more serious hip fractures, broken bones and even head injuries. With falls a leading cause of injury for people aged 65 and older, it is an important public health issue to study in order to allow these adults increased safety and independence as they age.

Although elevated risk of falls due to use of pain medication by older adults has been widely studied, less is known about how pain medication use affects falls risk of older adults living with cognitive impairment. In a study recently published in Age and Ageing, researchers at Texas A&M University examined a national sample to identify the relationship between pain medication use and falls among older adults based on their cognitive status. The team included Texas A&M Health Center for Population Health and Aging postdoctoral research associate, Aya Yoshikawa, DrPH; center co-director Matthew Lee Smith, PhD, MPH; and center founding director Marcia G. Ory, PhD, MPH.

Using data from the National Health and Aging Trends Study (NHATS), the team analyzed associations between pain medication use and recent falls by cognitive status. The data used were self-reported measures except for cognitive test scores, which were derived from the NHATS validated algorithm based on physician diagnosis, cognitive domain (memory, orientation and executive function) test scores, and AD8 Dementia Screening Interview test scores.

Falls were identified as "yes" or "no" answers to the definition of "any fall, slip, or trip in which you lose your balance and land on the floor or ground or at a lower level" in the past month. Frequency of taking pain medication in the past month was identified as seven days a week, five to six days a week, two to four days a week, once a week or less, and never. Information about specific pain medications was not identified in this study.

Additional measures included age, race/ethnicity, education, living arrangement, balance or coordination problems, being bothered by pain, and number of chronic conditions.

The researchers found that among the 7,491 community-dwelling participants in the study, 8.3 percent had possible dementia while 8.2 percent had probable dementia.

"Although there was no significant difference in being bothered by pain by cognitive status, people living with dementia took medication for pain more frequently than those with no dementia," Yoshikawa said. "Older age, not non-Hispanic white race/ethnicity, lower levels of education, living alone, and having more chronic conditions were associated with people living with dementia versus those with no dementia. People living with dementia were more likely to report at least one fall in the past month and worry about falling down and balance/coordination."

In addition, researchers found increased likelihood of recent falls was associated with pain medication among persons with probable dementia, and that taking pain medication two days a week or more was also associated with an increased risk of falls among those with probable dementia.

"These results support that the risk of falls associated with pain medication is elevated among those with higher levels of cognitive impairment," Yoshikawa said. "The different relationships of pain medication with falls by cognitive status can be partly explained by the severity of cognitive impairment among older adults."

Finally, the researchers note that the findings in this study have practical implications for falls prevention strategies and programs.

"To address the risk of falls associated with pain medication, especially for probable dementia, it is essential to conduct screening and medication reconciliation in the health care system. The provision of education about pain medication and alternative pain management programs is critical to preventing falls," Yoshikawa said. "There is need for fall prevention programs that encourage both exercise training for improving one's balance and reducing worry about falling down through fall management strategies."

Researchers world-wide are focused on clearing the toxic mutant Huntingtin protein that leads to neuronal cell death and systemic dysfunction in Huntington's disease (HD), a devastating, incurable, progressive neurodegenerative genetic disorder. Scientists in the Buck Institute's Ellerby lab have found that the targeting the protein called FK506-binding protein 51 or FKBP51 promotes the clearing of those toxic proteins via autophagy, a natural process whereby cells recycle damaged proteins and mitochondria and use them for nutrition.

Publishing in Autophagy , researchers showed that FKBP51 promotes autophagy through a new mechanism that could avoid worrisome side effects associated with rapamycin, an immune-suppressing drug which also extends lifespan in mice. They show both rapamycin and the small pharmacological inhibitor of FKBP51, SAFit2, protect HD neurons but that the mechanisms of the two drugs are distinct.

The possibility of avoiding the negative side effects of rapamycin

Researchers focused on a family of binding proteins called FKBP's and specifically on FKBP51, which was most changed in mouse and human stem cell models of HD. During the course of the study scientist found that FKBP51 acts on a pathway independent of mTOR (mammalian Target of Rapamycin), which is associated with rapamycin. Scientists also identified a small molecule, SAFit2, which crossed the blood-brain barrier and promoted autophagy and reduced the toxic disease-causing protein through that mTOR-independent pathway.

"Rapamycin can have both positive and negative effects and this new molecule could give us a way to go after the toxic proteins without those complications," said Buck Professor Lisa Ellerby, PhD, director of the study, who added that the findings are also significant for the aging field. "We know that FKBP's get dysregulated during aging, a phenomena which likely contributes to the accumulation of toxic proteins associated with other age-related diseases. SAFit2, which is neuroprotective, could give us another option to promote autophagy and clear out disease-causing proteins or proteins accumulated during disease and aging which are correlated with other conditions." FKPB51 has been implicated in Parkinson's and Alzheimer's diseases as well as post-traumatic stress disorder and schizophrenia.

The first author of the work, Barbara Bailus, PhD, is a former postdoc in the Ellerby lab. "The fact that SAFit2 crosses the blood brain barrier is significant," said Bailus, who is now an Assistant Professor of Genetics at the Keck Graduate Institute in Claremont, CA. "In our mouse models of HD, the small molecule interacted with FKPBP51 and cleared toxic proteins in both the cortex and the striatum which is part of the neural circuit necessary for voluntary movement."

The Ellerby lab will do pre-clinical work with SAFit2, which was developed by a collaborator, Dr. Felix Hausch, PhD, at the Technical University in Darmstadt, Germany.

Current status of clinical trials for HD

The recent failure of an experimental drug tested in Europe and Canada against HD highlights the desperation of patients who are forced to deal with a malady that usually sees it victims dying about 20 years following the onset of observable symptoms. The drug was developed by Ionis and Roche, and is an antisense oligonucleotide (ASO). It was designed to silence the gene responsible for HD, and had to be injected into the fluid-filled space between the thin layers of tissue that cover the brain and spinal cord. While the details of the failed trial are not published yet, Ellerby says the drug appeared not to diffuse into the entire brain, the ASOs may have unanticipated toxic effects and the ASOs do not reach all affected peripheral tissues. HD affects coordination and leads to cognitive decline and psychiatric problems.

"While we had hoped that this drug would ultimately work for patients in desperate need of treatment, those of us in the field have been aware that we need less invasive treatments for HD that are more likely to be easily tolerated," said Ellerby. "I don't know if we'll be able to do that with this small molecule, but at this point it does show potential and we look forward to evaluating its effects in pre-clinical experiments."

Despite a name straight from a Tarantino movie, natural killer (NK) cells are your allies when it comes to fighting infections and cancer. If T cells are like a team of specialist doctors in an emergency room, NK cells are the paramedics: They arrive first on the scene and perform damage control until reinforcements arrive.

Part of our innate immune system, which dispatches these first responders, NK cells are primed from birth to recognize and respond to danger. Learning what fuels NK cells is an active area of research in immunology, with important clinical implications.

"There's a lot of interest right now in NK cells as a potential target of immunotherapy," says Joseph Sun, an immunologist in the Sloan Kettering Institute. "The more we can understand what drives these cells, the better we can program them to fight disease."

Despite a name straight from a Tarantino movie, natural killer (NK) cells are your allies when it comes to fighting infections and cancer. If T cells are like a team of specialist doctors in an emergency room, NK cells are the paramedics: They arrive first on the scene and perform damage control until reinforcements arrive.

Part of our innate immune system, which dispatches these first responders, NK cells are primed from birth to recognize and respond to danger. Learning what fuels NK cells is an active area of research in immunology, with important clinical implications.

"There's a lot of interest right now in NK cells as a potential target of immunotherapy," says Joseph Sun, an immunologist in the Sloan Kettering Institute. "The more we can understand what drives these cells, the better we can program them to fight disease."

First in Line

Previous work from researchers at MSK and elsewhere has shown that T cells rely on aerobic glycolysis to carry out their protective functions. But whether NK cells depend on this form of metabolism to power their own activities was not known.

Because Dr. Sun and his colleagues studied NK cells in animals instead of a dish, they could establish what type of metabolism NK cells use and compare it to T cells in a natural setting. They found that NK cells ramp up aerobic glycolysis about five days prior to when T cells respond with their own glycolytic surge.

"This fits with the idea that NK cells are innate immune cells that are really critical for mounting a rapid response," Dr. Sheppard says.

The findings are relevant to ongoing efforts to use NK cells as immunotherapy in people with cancer and other conditions. In particular, they have implications for using NK cells as a form of cell therapy -- when cells are grown outside a patient and then infused back into the patient's blood.

"If you're growing these cells in a dish and you push them to divide too rapidly, they may not have as much potential to undergo aerobic glycolysis when you put them into a patient," Dr. Sheppard says.

The takeaway for researchers designing clinical trials is this: They must find a balance between encouraging NK cells to multiply and preserving their stamina. These NK cells are the paramedics of our immune system, so it's important to keep them speedy and responsive.