Chronic inflammation causes a reduction in NAD+

NAD+ (nicotinamide adenine dinucleotide), a key metabolite central to an efficient and healthy metabolism, declines with age. This previously unexplained phenomena is associated with numerous age-related diseases and has spawned the development of many nutritional supplements aimed at restoring NAD+ to more youthful levels. Publishing in Nature Metabolism, researchers at the Buck Institute have identified chronic inflammation as a driver of NAD+ decline. They show that an increasing burden of senescent cells, which is also implicated in the aging process, causes the degradation of NAD via the activation of CD38 (cyclic ADP ribose hydrolase) a protein that is found on the cell membranes both inside and on the surface of many immune cells.

“We are very excited to link two phenomena which have been separately associated with aging and age-related disease,” said Eric Verdin, MD, Buck Institute President and CEO and senior author of the paper. “The fact that NAD+ decline and chronic inflammation are intertwined provides a more holistic, systemic approach to aging and the discovery of CD38 macrophages as the mediator of the link between the two gives us a new target for therapeutic interventions.”

The faucet or the sink? Or both?

Scientists have been aware that NAD+ levels decrease with age but Verdin says what hasn’t been clear is whether the decline stems from decreased production of NAD+, a problem with the “faucet,” or from its degradation, an issue akin to a “leaky sink”. “Our data suggests that, at least in some cases, the issue stems from the leaky sink,” he said, “Ultimately I think supplementation will be part of the equation, but filling the sink without dealing with the leak will be insufficient to address the problem.” Verdin says preliminary data suggests that blocking CD38 activity in older animals restores NAD+ levels in specific tissues.

Unique Buck collaboration drives the research

The research, led by Anthony J. Covarrubias, Ph.D., a postdoctoral fellow in the Verdin lab, also involved Buck professor Judith Campisi and her laboratory, which is recognized internationally for pioneering work in the field of cellular senescence. Experiments were done in mice and involved metabolic tissue from visceral white fat and the liver which were examined during aging and acute responses to inflammation. The work was validated in primary human macrophages. “Our initial hypothesis was that CD38 activation would be driven by inflammation,” Covarrubias said, “But we found that in this case, the activation occurred with both acute and age-related inflammation. That was a surprise.”

Inflammaging: Cellular senescence and the SASP

Senescent cells, which stop dividing in response to DNA damage, spew a multitude of pro-inflammatory proteins, called the senescence-associated secretory phenotype or SASP. Evolution selected cellular senescence as a protective measure against cancer; but as senescent cells accumulate in tissues over the course of a lifetime, the SASP drives low grade chronic inflammation which is associated with age-related disease, including late life cancer. “These inflammatory proteins in the SASP induce macrophages to proliferate, express CD38 and degrade NAD+. It’s a maladaptive process,” said Covarrubias, “But drugs that target the SASP or CD38 may offer us another way to deal with the decline of NAD+.”

NAD: Essential for life

NAD+ is found in every cell; it promotes cellular energy production and supports cellular metabolism. NAD is also critical for the activity of sirtuins which have global anti-aging properties. Comparing our cellular metabolism to a cash economy, Verdin describes NAD+ as the armored trucks that transfer money between institutions. “Money is the fuel. If you can’t transport the money, then the whole economy comes to a halt. It all comes crashing down. That’s how important NAD+ is to our cellular health and we look forward to applying this discovery to our efforts to stem the ravages of age-related disease.”

Zebra Finches Recognize the Calls of Over 40 Fellow Finches

Their ability to distinguish between individuals is strong evidence for fast mapping, a learning tool generally thought to belong only to humans.

Fast mapping, the ability to rapidly learn an association between two things after very little exposure, is a key tool responsible for the vast repertoire of human language. It’s the reason we can recognize voices from another room and why newborns prefer to listen to their mothers read them The Cat in the Hat over other women. While fast mapping is generally thought of as a human ability, zebra finches can also distinguish dozens of other finches’ vocalizations, doing so with very little exposure and retaining those memories for at least a month, researchers report today (November 13) in Science Advances.

“The reason that this study is groundbreaking is because zebra finches are the very first vocally learning species aside from ourselves with any evidence that fast mapping takes place,” Samantha Carouso-Peck, a behavioral neuroscientist at Cornell University who researches social influences on vocal learning in zebra finches but was not involved in the current work, tells The Scientist.

Prior to the new study, evidence of fast mapping in nonhumans had been suggested for only a single nonhuman animal: Rico the border collie. Rico is capable of distinguishing the name of more than 200 individual objects and can infer the meaning of a new word after hearing it only once. Whether this is truly evidence of fast mapping, however, has been debated among scientists who believe that only species capable of language, specifically humans, can be said to truly fast map. 

To test zebra finches’ ability to recognize individual calls, and the number of exposures they need to do so, researchers at the University of California, Berkeley, designed a five-day “learning ladder.” Birds were initially trained on a small set of call data that became increasingly larger over several days. 

On the first day of testing, each bird in the training arena went through a series of trials during which they heard brief clips of either a song or a distance call used by birds to locate their group when it is out of sight. These two distinct vocalizations were chosen because they are thought to have the most variation between individuals. Nineteen birds were trained on songs, while another 19 heard only distance calls. The vocalizations were parsed, so that one set led to a food reward, while the other set didn’t.

In the team’s experiments, birds in an arena learned to distinguish between vocalizations that came with a reward (Re Vocalizer) and those that did not (NoRe Vocalizer). When birds recognized a call they had heard before, they allowed the clip to play fully, which activated a food reward. When they did not, they hit a button to skip ahead to the next trial. In this way, scientists were able to show that individual finches can remember an average of 42 other vocalizers.

In that first test, each finch only needed to discriminate between two individuals’ vocalizations, one that provided a food reward and one that did not. By pecking a key, the finch would start the sound file. It could then either peck the key again to start a new trial or listen to the entire clip to receive a food reward. Repeating this process over several trials, the finches learned to associate vocalizations that led to a reward from the ones that did not and to quickly skip vocalizations that weren’t rewarding.

Each successive day, sounds from additional individuals were added to the training set. While finches were originally trained to discriminate between one pair of individuals, by day two it jumped to four pairs, and then eight on days three through five, for a total of 16 different individuals’ vocalizations. The researchers began evaluating the finches’ performance only on days four and five, when each bird had been exposed at least once to each possible vocalizer. 

To be certain the finches weren’t simply memorizing the sound files, each bird providing the vocalization was recorded 10 different times. “We were pulling randomly from a large library of calls that we have, so the calls were all different every time,” Frederic Theunissen, an auditory scientist at the University of California, Berkeley, tells The Scientist. “Not only are they different vocalizers, but they heard different renditions from the same vocalizer.”

Even with this added layer of complexity, Theunissen says he was “really impressed” by how well the finches performed. All 19 finches trained using song files were able to discriminate between the vocalizers they recognized based on their individual signatures and those they did not, and the same was true for 18 of the finches trained using distance calls. 

Beyond their ability to recognize other birds based on their calls, the team was also struck by how quickly the finches were able make the distinctions. The majority of birds could hear as few as 10 exposures to an individual and memorize their signature, while some required fewer than five, strong evidence for fast mapping in the species.

“We didn’t expect the birds to be so good at this,” Theunissen tells The Scientist. “We thought this was going to be interesting, but the fact that the number of vocalizers is so high, and that they can do this so quickly, was really quite astonishing.” 

In the study, the team decided to create what Theunissen calls “an impossible task” to test the limits of the finches’ performance. He created a new set of stimuli that included both songs and distance calls from 56 distinct vocalizers. Only four randomly-selected birds went through this mega-task, but on average, they were able to remember 42 individual vocalizers. 

A month later, he tested the recall of two of the four birds by running them through the same, 56-vocalizer test and found that they were still able to distinguish between individuals—they had retained their memories of the individual calls. Both the speed of their learning and their retention over time, Theunissen says, “point towards these really remarkable abilities that these birds have in terms of making auditory memories.”

Because these birds are so social, living gregariously in colonies of more than 100 individuals, it isn’t unexpected that zebra finches could discriminate between dozens of individuals, says Sarah Woolley, a neuroethologist at McGill University who studies the neurological basis for social behavior in songbirds. “We’ve always been pretty sure that birds could do that, zebra finches included,” Woolley says. “But no one had really demonstrated it, certainly not to the degree that they do in this paper.”

While the results are “very interesting evidence” that zebra finches are capable of fast mapping, Carouso-Peck says that more work on a larger sampling of birds is needed “before we can make weightier claims about what they’re capable of.” For example, one of the criticisms of the previous work with Rico the border collie is that fast mapping is a tool for learning language, and therefore only species capable of language truly do it. While Carouso-Peck says she doesn’t necessarily agree, as a next step she would like to see if finches are also capable of fast mapping verbally. For example, how many times must young zebra finches hear their father’s song before they can reproduce it for themselves?

“Language is something which we humans tend to hold up as our great crowning achievement, something that we are capable of which absolutely no [other] species is capable of,” Caruso-Peck tells The Scientist. “Over the last few decades, we’ve had to change the goalposts for what is language in order to maintain that high and mighty position.” 

K. Yu et al., “High-capacity auditory memory for vocal communication in a social songbird,” Science Advances, doi:10.1126/sciadv.abe0440, 2020.

Scientists Use Human Genes to Make Monkey Brains Bigger

Scientists introduced a human gene, ARHGAP11B, into monkey fetuses.
The gene caused an increase in the size of the monkey brains, including folding similar to that of human brains.
The study poses some serious ethical questions on genetic engineering.

In an experiment that could portend a real-life Planet of the Apes situation, scientists spliced human genes into the fetus of a monkey to substantially increase the size of the primate’s brain. And it worked.

Researchers from Germany’s Max Planck Institute of Molecular Cell Biology and Genetics in Germany and Japan’s Central Institute for Experimental Animals introduced a specifically human gene, ARHGAP11B, into the fetus of a common marmoset monkey, causing the enlargement of its brain’s neocortex. The scientists reported their findings in Science.This content is imported from {embed-name}. You may be able to find the same content in another format, or you may be able to find more information, at their web site.

The neocortex is the newest part of the brain to evolve. It’s in the name—“neo” meaning new, and “cortex” meaning, well, the bark of a tree. This outer shell makes up more than 75 percent of the human brain and is responsible for many of the perks and quirks that make us uniquely human, including reasoning and complex language.

Not long after our hominid ancestors branched off the evolutionary tree of our current chimpanzee cousins, their brains underwent a rapid expansion, nearly tripling in size over a span of 3 million years. Hominids’ brains grew so fast that they became cramped in the slowly evolving craniums, causing the distinctly human folding of the neocortex into wrinkles.

Scientists believe this was the result of a number of evolutionary factors, but the expression of ARGHAP11B, something unique to hominids, may have given a boost to the brains of our ancestors, and close-but-now-extinct relatives, the Neanderthals and Denisovans.

Previous studies have shown that ARHGAP11B, when unnaturally expressed in mice and ferrets, also caused an enlargement of the neocortex. However, this was the first time the gene was used in a non-human primate and with typical human levels of expression, further suggesting the gene played a key role in our evolution.

ARGHAP11B arose in our ancestors some 5 million years ago when a happy little accident was made copying the everyday gene ARGHAP11A. In an evolutionary mistake, a single substitution of one nucleotide base (the molecules that encode DNA) with another led to the loss of 55 nucleotides from ARHGAP11B. Like a computer reading an incorrect line of code, the mutation caused the neuron-producing cells of the brain to make more of themselves for longer periods of time, resulting in a larger neocortex.

A slice of the brain of a 101 day-old marmoset monkey showing the growth and folding of its neocortex.

“We found indeed that the neocortex of the common marmoset brain was enlarged and the brain surface folded,” Michael Heide, the lead author of the study, said in a press release. “Its cortical plate was also thicker than normal.” He continued:

“Furthermore, we could see increased numbers of basal radial glia progenitors in the outer subventricular zone and increased numbers of upper-layer neurons, the neuron type that increases in primate evolution.”

The scientists call these human-monkey hybrids “transgenic non-human primates,” which may be enough to ring the alarm of any doomsdayer. It certainly raises a lot of ethical questions when doing experiments on primates, let alone when introducing human genes into other animals.

Pompeii dig reveals ‘almost perfect’ remains of a master and his slave

bodies of a master and his slave in situ at a villa on the outskirts of Pompeii
Archaeologists have unearthed two exceptionally well-preserved victims of the eruption of Vesuvius in AD79

The almost perfectly preserved remains of two men have been unearthed in an extraordinary discovery in the ancient Roman city of Pompeii.

The bodies of what are thought to be a wealthy man and his slave, believed to have died as they were fleeing the catastrophic eruption of Mount Vesuvius in AD79, were found during excavations at a villa in the outskirts of the city, Pompeii archaeological park officials said yesterday.

Massimo Osanna, the park’s director, said the find was “truly exceptional”, while culture minister Dario Franceschini said it underlined the importance of Pompeii as a place for study and research.

The two men, lying close together, are believed to have escaped the initial phase of the eruption when the city was blanketed in volcanic ash and pumice, only to then be killed by a blast that happened the following day.

Their remains, for which casts have been created, were discovered in the same location where a stable containing the remains of three harnessed horses were unearthed in 2017.

Experts said the younger man, who was probably aged between 18 and 25, had several compressed vertebrae, which led them to believe that he was a manual labourer or slave. He is thought to have been wearing a pleated tunic, possibly made of wool.

The elder man, aged between 30 and 40, had a stronger bone structure, particularly around his chest area, and was also wearing a tunic. They were found lying in what would have been the corridor of the villa.

Park officials said that further digging over the coming months might reveal where the men were heading and determine the roles they played in the elegant villa.

It is the latest in a series of fascinating discoveries that excavations at Pompeii have yielded in recent years.

The bodies of two women and three children were discovered huddled together in the room of a villa in the Regio V area in October 2018. A week before, the same villa revealed a charcoal inscription that suggested Vesuvius erupted in October AD79, and not in August of that year as previously thought.

The remains of a man, who was also believed to have survived the first part of the explosion, were found in May 2018. His legs and torso were protruding from a large stone block but, rather than being decapitated by it, archaeologists believe he was killed by the lethal gases of the eruption’s later stages. The victim, believed to have been in his mid-30s, was also found with a small sack of 20 silver and two bronze coins, the equivalent of about €500 in today’s money.

The latest dig, part of a €1m project, is continuing despite the coronavirus pandemic. The park, which is currently closed to tourists, usually attracts four million people a year.

The Pompeii ruins were discovered in the 16th century, with the first excavations beginning in 1748. Over 1,500 of the estimated 2,000 victims have been found over the centuries.

Simple Invention Helps You Sober Up by Exhaling Alcohol

Above: Olivia Sobczyk, co-author and researcher at Toronto’s University Health Network, demonstrating how the ClearMate Device is used.
Image: University Health Network

Scientists in Canada say they’ve found a new way to treat potentially life-threatening alcohol intoxication—by helping people literally breathe out the alcohol in their system. Their device, which is designed to allow people to hyperventilate safely, was found to speed up the clearance of alcohol from healthy volunteers three times faster in a small pilot study.

Usually, toxins like alcohol are largely broken down by the liver. The liver can take a lot of punishment, but the rate that it metabolizes alcohol is constant, meaning you can’t speed up the process in times when the amount of alcohol in your body is enough to be fatal or seriously harmful. Most times, all doctors can do when someone is passed out is to make sure their breathing and body functions are stable until the liver can finish its job.

But the lungs also play a small role in naturally eliminating alcohol from our body, something that you’ve probably noticed if you’ve ever smelled booze on someone’s breath. This happens when blood saturated with alcohol reaches the lungs to be replenished with fresh oxygen. Some of the alcohol in the blood, along with carbon dioxide, is then exhaled.

This process can be sped up through hyperventilation, or the act of rapidly breathing. The trouble is, when we hyperventilate, we also lose too much carbon dioxide. To stop this from happening, our body has evolved to make us seriously uncomfortable or even lose consciousness when we hyperventilate for too long (this is why someone visibly panicking might faint).

According to study author and inventor Joseph Fisher, the device has found a way to interrupt this trigger while still keeping the person safe. The patient is outfitted with a gas mask, which connects to a supply of oxygen and carbon dioxide. The mixture of gases they breathe in causes them to hyperventilate, while the device then feeds them back enough carbon dioxide that the body doesn’t involuntarily freak out.

“With each breath, it is designed to allow the normal amount of carbon dioxide to escape and any excess is returned on the very next breath,” Fisher, an anesthesiologist and senior researcher at University Health Network in Toronto, said in an email. “This is all done in a simple way by a mechanical valve so it is foolproof—without needing electronics or computers.”

To test out the device, Fisher and his team recruited five healthy volunteers and told them to get mildly intoxicated (the beverage of choice was usually 250 milliliters of 80-proof vodka mixed with 500 milliliters of water). In a series of experiments conducted over two days, they were monitored as they both sobered up naturally and by using the device for up to a half hour. Their level of alcohol was measured via breathalyzer and through blood samples taken throughout the experiment. Compared to the natural method, the volunteers appeared to sober up three times faster while using the breathing device.

The team’s findings were published in Scientific Reports on Thursday.

Though the study’s sample is very small, meaning its results should be viewed with some caution, the device itself isn’t untested. Just last year, the company Fisher cofounded, Thornhill Medical, won marketing approval from the Food and Drug Administration for the device (branded as ClearMate) to be used in emergency rooms in the U.S. as a treatment for carbon monoxide poisoning. Fisher says the same device could be used to treat both conditions as well as others in the future, including more toxic forms of alcohol poisoning, such as in people who have consumed windshield-washer fluid (methanol) or bootleg booze (polyethelene glycol).

According to Fisher, the basic fact that our lungs help remove alcohol from our bodies has been known for nearly a century. But he’s not sure why no one up until now has thought to try exploiting this process.

“The method is so simple and obvious that even looking at it, no one recognizes its potential,” he said. “Hiding in plain sight. I don’t know how else to explain it.”

While this device can be safely used by someone with alcohol poisoning who is conscious, it may hold even more promise for people who are passed out, while still being safe to operate for health care workers. “The greater the alcohol concentration in the blood, the more effective the method is,” Fisher said. “If the patient is unconscious, a tube can be placed in the lungs to protect the patient’s breathing, and the method can then be applied manually.”

Japan’s creepy robot wolf scares away crop-raiding deer, bears

A Japanese town has deployed robot wolves in the hopes of scaring away bears and other wildlife that can damage crops — or potentially injure residents. 

The robot, simply named “Monster Wolf,” is being tested in a town called Takikawa, located on the Hokkaido island in Northern Japan. 

As reported by JAPANkyo, the ‘scarecrow’ has been created by Ohta Seiki and measures roughly 24-inches long, sporting a furry body, four legs, red, glowing eyes, and inbuilt speakers. 

Motion-based infrared sensors are embedded in the wolf, and when triggered, Monster Wolf will scream out one of 40 different sounds, including howls and growls.

According to the publication, the wolf can also be set to howl at particular intervals — and since being tested in a botanical garden in Sapporo last year, incidents of animals such as deer destroying the park’s foliage has decreased by 90%. 

When it comes to tests in Takikawa, the purchase of the wolves was prompted by an increase in bear sightings and dozens of attacks, as well as two that proved fatal. Following an emergency meeting of local officials, the two Monster Wolf robots were set to safeguard the town. 

No bears have been encountered since they arrived. 

Thanks to Pete C for bringing this to the It’s Interesting community.

Study finds evidence of neurobiological mechanism for hallucinations and delusions

A new study from researchers at Columbia University Vagelos College of Physicians and Surgeons has found evidence of a potential neurobiological mechanism for hallucinations and delusions that fits within the hierarchical model of psychosis and can explain their clinical presentation.

The study was published in eLife.

Columbia researchers Kenneth Wengler, Ph.D., a Postdoctoral Research Fellow and Guillermo Horga, MD, Ph.D., Florence Irving Associate Professor of Psychiatry, investigated the neurobiological mechanisms of two symptoms of schizophrenia: hallucinations and delusions. These two symptoms form the syndrome of psychosis, an immensely disabling psychiatric condition where patients lose their ability for reality testing.

“Typically, patients with more severe hallucinations also have more severe delusions, and these two symptoms respond similarly to antipsychotic medications. But this is not always the case; some patients have very prominent hallucinations but less severe delusions and vice versa,” says Wengler. “This suggests that these symptoms may share a common neurobiological mechanism while simultaneously depending on symptom-specific pathways.”

Some experts in the field believe that a hierarchical perceptual-inference model can explain the mechanisms behind psychosis. Wengler explains, “In its simplest form, the hierarchical model has two levels to the hierarchy: low and high. The low level makes inferences about basic features of stimuli and the high level makes inferences about their causes. An intuitive example of this is inferring the weather. In this scenario, you must decide if you are going to take an umbrella with you when you leave the house. The stimulus in this scenario is what you see when you look out the window; let’s say it’s cloudy. The context in this scenario is what you expect the weather to be like on a given day in the city you are in; let’s say you are in Seattle. Although it is not currently raining, because it’s cloudy and you are in a city where it often rains, you may decide to take an umbrella with you. The hierarchical model of psychosis frames hallucinations as resulting from dysfunction at the lower levels of the hierarchy and delusions as resulting from dysfunction at the higher levels of the hierarchy. Critically, these levels of inference are distinct but interconnected, so a dysfunction at one level would likely propagate upwards or downwards to other levels, therefore explaining why these symptoms tend to co-occur.”

To investigate the neurobiological mechanisms of hallucinations and delusions within the framework of the hierarchical model, the researchers used functional magnetic resonance imaging to measure intrinsic neural timescales throughout the brain. These neural timescales reflect how long information is integrated in a given brain region. Most importantly, these neural timescales are organized hierarchically, making it a fitting measure to test the hierarchical model of psychosis.

The researchers collected data from 127 patients with schizophrenia from various online databases and determined how an individual’s neural timescales related to their hallucination and delusion severities together. They found that neural timescales in the lower levels of the hierarchy tended to be longer in patients with more severe hallucinations, while neural timescales in the higher levels tended to be longer in patients with more severe delusions. These results provide the first direct evidence of a potential neurobiological mechanism for hallucinations and delusions that fits within the hierarchical model of psychosis and can explain their clinical presentation. The common neurobiological mechanism for both symptoms could result in increased neural timescales, but the symptom-specific pathways are the level of the hierarchy at which the neural timescales are increased.

“Our findings open the door for the development of treatments to target specific symptoms of psychosis depending on an individual subject’s symptom profile, in line with the current push for individualized medicine,” says Horga.

The paper is titled “Distinct Hierarchical Alterations of Intrinsic Neural Timescales Account for Different Manifestations of Psychosis.”

People who eat chili pepper may live longer

Individuals who consume chili pepper may live longer and may have a significantly reduced risk of dying from cardiovascular disease or cancer, according to preliminary research to be presented at the American Heart Association’s Scientific Sessions 2020.

Previous studies have found eating chili pepper has an anti-inflammatory, antioxidant, anticancer and blood-glucose regulating effect due to capsaicin, which gives chili pepper its characteristic mild to intense spice when eaten. To analyze the effects of chili pepper on all-cause and cardiovascular disease mortality, researchers screened 4,729 studies from five leading global health databases (Ovid, Cochrane, Medline, Embase and Scopus). Their final analysis includes four large studies that included health outcomes for participants with data on chili pepper consumption.

The health and dietary records of more than 570,000 individuals in the United States, Italy, China and Iran were used to compare the outcomes of those who consumed chili pepper to those who rarely or never ate chili pepper. Compared to individuals who rarely or never ate chili pepper, the analysis found that people who ate chili pepper had:

  • a 26% relative reduction in cardiovascular mortality;
  • a 23% relative reduction in cancer mortality; and
  • a 25% relative reduction in all-cause mortality.

“We were surprised to find that in these previously published studies, regular consumption of chili pepper was associated with an overall risk-reduction of all cause, CVD and cancer mortality. It highlights that dietary factors may play an important role in overall health,” said senior author Bo Xu, M.D., cardiologist at the Cleveland Clinic’s Heart, Vascular & Thoracic Institute in Cleveland, Ohio. “The exact reasons and mechanisms that might explain our findings, though, are currently unknown. Therefore, it is impossible to conclusively say that eating more chili pepper can prolong life and reduce deaths, especially from cardiovascular factors or cancer. More research, especially evidence from randomized controlled studies, is needed to confirm these preliminary findings.”

Dr. Xu said that there are several limitations to this type of study. The four studies reviewed included limited specific health data on individuals or other factors that may have influenced the findings. Researcher also noted that the amount and type of chili pepper consumed was variable among the studies, making it difficult to draw conclusions about exactly how much, how often and which type of chili pepper consumption may be associated with health benefits. The researchers are continuing to analyze their data and hope to publish the full paper soon.

Mobile phone data indicates that restaurants could account for most COVID-19 infections in US cities

In cities worldwide, coronavirus outbreaks have been linked to restaurants, cafes and gyms. Now, a new model using mobile-phone data to map people’s movements suggests that these venues could account for most COVID-19 infections in US cities.

The model, published in Nature today, also reveals how reducing occupancy in venues can significantly cut the number of infections.

The model “has concrete pointers as to what may be cost-effective measures to contain the spread of the disease, while at the same time, limiting the damage to the economy”, says Thiemo Fetzer, an economist at the University of Warwick in Coventry. “This is the policy sweet spot.”

Mobility data

To predict how people’s movements might affect viral transmission, the research team input anonymized location data from mobile-phone apps into a simple epidemiological model that estimated how quickly the disease spreads. The location data, collected by SafeGraph, a company based in Denver, Colorado, came from 10 of the largest US cities, including Chicago, Illinois; New York; and Philadelphia, Pennsylvania. It mapped how people moved in and out of 57,000 neighbourhoods to points of interest, such as restaurants, churches, gyms, hotels, car dealers and sporting-goods stores for 2 months starting in March.

When the team compared the model’s number of infections in Chicago neighbourhoods between 8 March and 15 April with the number of infections officially recorded in those neighbourhoods a month later, they found that the model had accurately predicted confirmed case numbers.

“We are able to faithfully estimate the contact network between 100 million people for every hour of the day. That is the secret ingredient we have,” says Leskovec.

Venue hot spots

The team then used the model to simulate different scenarios, such as reopening some venues while keeping others closed. They found that opening restaurants at full capacity led to the largest increase in infections, followed by gyms, cafes and hotels and motels. If Chicago had reopened restaurants on 1 May, there would have been nearly 600,000 additional infections that month, while Opening gyms would have produced 149,000 extra infections. If all venues were open, the model predicts that there would have been 3.3 million additional cases.

But capping occupancy for all venues at 30% would reduce the number of additional infections to 1.1 million, the model estimated. If occupancy was capped at 20%, new infections would be reduced by more than 80% to about 650,000 cases.

“The study highlights how real-time big data on population mobility offers the potential to predict transmission dynamics at unprecedented levels of spatial granularity,” says Neil Ferguson, an epidemiologist at Imperial College London.

The mobility data also suggest why people from poorer neighbourhoods are more likely to get COVID-19: because they are less able to work from home, and the stores they visit for essential supplies are often more crowded than in other areas. The average grocery store in poorer neighbourhoods had 59% more hourly visitors per square foot, and visitors stayed on average 17% longer than at stores outside those areas. Leskovec says that people living in these areas probably have limited options to visit less crowded stores, and as a result, a shopping trip is twice as risky as it is for someone from a wealthier area.

But Christopher Dye, an epidemiologist at the University of Oxford, says these mobility patterns need to be validated with real-world data. “It is an epidemiological hypothesis that remains to be tested. But it is a hypothesis that is well worth testing,” he says.

Global trend

Broadly speaking, Fetzer says, the modelling study corroborates much of what has been learnt from contact-tracing studies worldwide, which have identified restaurants, gyms, choir practices, nursing homes and other crowded indoor venues as locations of superspreader events, where many people are infected at one time.

Last month, Fetzer published a report showing how a UK government programme called Eat Out to Help Out, in which restaurant meals were subsidized during August, led to a huge surge in restaurant visits and accounted for up to 17% of new COVID-19 infections that month.

But restaurants might not be hot spots everywhere. Contact-tracing data from Germany has found that restaurants were not the primary source of infection in that country, says Moritz Kraemer, who models infectious diseases at the University of Oxford, UK. That might be because it can be difficult to identify the source of an infection using contact-tracing data. Although the model’s prediction of overall infection rates in cities was validated with real-world data, Kraemer says more detailed contact-tracing data will be required to test whether the model correctly identified the actual location of infections.

Leskovec says that all models have some amount of error. But as many of its predictions align with observational data, he adds, there is no reason to think that it wouldn’t work at smaller scales.

If the model is found to accurately predict the risk of visiting specific locations, health officials could use it to fine-tune social-distancing policies, says Ferguson.doi:

Researchers identify melatonin as possible COVID-19 treatment

Results from a new Cleveland Clinic-led study suggest that melatonin, a hormone that regulates the sleep-wake cycle and is commonly used as an over-the-counter sleep aid, may be a viable treatment option for COVID-19.

As COVID-19 continues to spread throughout the world, particularly with cases rising during what some have termed the “fall surge,” repurposing drugs already approved by the U.S. Food and Drug Administration for new therapeutic purposes continues to be the most efficient and cost-effective approach to treat or prevent the disease. According to the findings published today in PLOS Biology, a novel artificial intelligence platform developed by Lerner Research Institute researchers to identify possible drugs for COVID-19 repurposing has revealed melatonin as a promising candidate.

Analysis of patient data from Cleveland Clinic’s COVID-19 registry also revealed that melatonin usage was associated with a nearly 30 percent reduced likelihood of testing positive for SARS-CoV-2 (the virus that causes COVID-19) after adjusting for age, race, smoking history and various disease comorbidities. Notably, the reduced likelihood of testing positive for the virus increased from 30 to 52 percent for African Americans when adjusted for the same variables.

“It is very important to note these findings do not suggest people should start to take melatonin without consulting their physician,” said Feixiong Cheng, Ph.D., assistant staff in Cleveland Clinic’s Genomic Medicine Institute and lead author on the study. “Large-scale observational studies and randomized controlled trials are critical to validate the clinical benefit of melatonin for patients with COVID-19, but we are excited about the associations put forth in this study and the opportunity to further explore them.”

Here, the researchers harnessed network medicine methodologies and large-scale electronic health records from Cleveland Clinic patients to identify clinical manifestations and pathologies common between COVID-19 and other diseases. Specifically, they measured the proximity between host genes/proteins and those well-associated with 64 other diseases across several disease categories (malignant cancer and autoimmune, cardiovascular, metabolic, neurological and pulmonary diseases), where closer proximity indicates a higher likelihood of pathological associations between the diseases.

They found, for example, that proteins associated with respiratory distress syndrome and sepsis, two main causes of death in patients with severe COVID-19, were highly connected with multiple SARS-CoV-2 proteins. “This signals to us, then,” explained Dr. Cheng, “that a drug already approved to treat these respiratory conditions may have some utility in also treating COVID-19 by acting on those shared biological targets.”

Overall, they determined that autoimmune (e.g., inflammatory bowel disease), pulmonary (e.g., chronic obstructive pulmonary disease and pulmonary fibrosis) and neurological (e.g., depression and attention-deficit hyperactivity disorder) diseases showed significant network proximity to SARS-CoV-2 genes/proteins and identified 34 drugs as repurposing candidates, melatonin chief among them.

“Recent studies suggest that COVID-19 is a systematic disease impacting multiple cell types, tissues and organs, so knowledge of the complex interplays between the virus and other diseases is key to understanding COVID-19-related complications and identifying repurposable drugs,” said Dr. Cheng. “Our study provides a powerful, integrative network medicine strategy to predict disease manifestations associated with COVID-19 and facilitate the search for an effective treatment.”

More information: Yadi Zhou et al. A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19, PLOS Biology (2020). DOI: 10.1371/journal.pbio.3000970