Writing in the March 18, 2021 online issue of Science, they also note that their simulations suggest that the mutating virus dies out naturally more than three-quarters of the time without causing an epidemic.

“Our study was designed to answer the question of how long could SARS-CoV-2 have circulated in China before it was discovered,” said senior author Joel O. Wertheim, PhD, associate professor in the Division of Infectious Diseases and Global Public Health at UC San Diego School of Medicine.

“To answer this question, we combined three important pieces of information: a detailed understanding of how SARS-CoV-2 spread in Wuhan before the lockdown, the genetic diversity of the virus in China and reports of the earliest cases of COVID-19 in China. By combining these disparate lines of evidence, we were able to put an upper limit of mid-October 2019 for when SARS-CoV-2 started circulating in Hubei province.”

Cases of COVID-19 were first reported in late-December 2019 in Wuhan, located in the Hubei province of central China. The virus quickly spread beyond Hubei. Chinese authorities cordoned off the region and implemented mitigation measures nationwide. By April 2020, local transmission of the virus was under control but, by then, COVID-19 was pandemic with more than 100 countries reporting cases.

SARS-CoV-2 is a zoonotic coronavirus, believed to have jumped from an unknown animal host to humans. Numerous efforts have been made to identify when the virus first began spreading among humans, based on investigations of early-diagnosed cases of COVID-19. The first cluster of cases — and the earliest sequenced SARS-CoV-2 genomes — were associated with the Huanan Seafood Wholesale Market, but study authors say the market cluster is unlikely to have marked the beginning of the pandemic because the earliest documented COVID-19 cases had no connection to the market.

Regional newspaper reports suggest COVID-19 diagnoses in Hubei date back to at least November 17, 2019, suggesting the virus was already actively circulating when Chinese authorities enacted public health measures.

In the new study, researchers used molecular clock evolutionary analyses to try to home in on when the first, or index, case of SARS-CoV-2 occurred. “Molecular clock” is a term for a technique that uses the mutation rate of genes to deduce when two or more life forms diverged — in this case, when the common ancestor of all variants of SARS-CoV-2 existed, estimated in this study to as early as mid-November 2019.

Molecular dating of the most recent common ancestor is often taken to be synonymous with the index case of an emerging disease. However, said co-author Michael Worobey, PhD, professor of ecology and evolutionary biology at University of Arizona: “The index case can conceivably predate the common ancestor — the actual first case of this outbreak may have occurred days, weeks or even many months before the estimated common ancestor. Determining the length of that ‘phylogenetic fuse’ was at the heart of our investigation.”

Based on this work, the researchers estimate that the median number of persons infected with SARS-CoV-2 in China was less than one until November 4, 2019. Thirteen days later, it was four individuals, and just nine on December 1, 2019. The first hospitalizations in Wuhan with a condition later identified as COVID-19 occurred in mid-December.

Study authors used a variety of analytical tools to model how the SARS-CoV-2 virus may have behaved during the initial outbreak and early days of the pandemic when it was largely an unknown entity and the scope of the public health threat not yet fully realized.

These tools included epidemic simulations based on the virus’s known biology, such as its transmissibility and other factors. In just 29.7 percent of these simulations was the virus able to create self-sustaining epidemics. In the other 70.3 percent, the virus infected relatively few persons before dying out. The average failed epidemic ended just eight days after the index case.

“Typically, scientists use the viral genetic diversity to get the timing of when a virus started to spread,” said Wertheim. “Our study added a crucial layer on top of this approach by modeling how long the virus could have circulated before giving rise to the observed genetic diversity.

“Our approach yielded some surprising results. We saw that over two-thirds of the epidemics we attempted to simulate went extinct. That means that if we could go back in time and repeat 2019 one hundred times, two out of three times, COVID-19 would have fizzled out on its own without igniting a pandemic. This finding supports the notion that humans are constantly being bombarded with zoonotic pathogens.”

Wertheim noted that even as SARS-CoV-2 was circulating in China in the fall of 2019, the researchers’ model suggests it was doing so at low levels until at least December of that year.

“Given that, it’s hard to reconcile these low levels of virus in China with claims of infections in Europe and the U.S. at the same time,” Wertheim said. “I am quite skeptical of claims of COVID-19 outside China at that time.”

The original strain of SARS-CoV-2 became epidemic, the authors write, because it was widely dispersed, which favors persistence, and because it thrived in urban areas where transmission was easier. In simulated epidemics involving less dense rural communities, epidemics went extinct 94.5 to 99.6 percent of the time.

The virus has since mutated multiple times, with a number of variants becoming more transmissible.

“Pandemic surveillance wasn’t prepared for a virus like SARS-CoV-2,” Wertheim said. “We were looking for the next SARS or MERS, something that killed people at a high rate, but in hindsight, we see how a highly transmissible virus with a modest mortality rate can also lay the world low.”

Co-authors include: Jonathan Pekar and Niema Moshiri, UC San Diego; and Konrad Scheffler, Illumina, Inc.

Funding for this research came, in part, from the National Institutes of Health (grants AI135992, AI136056, T15LM011271), the Google Cloud COVID-19 Research Credits Program, the David and Lucile Packard Foundation, the University of Arizona and the National Science Foundation (grant 2028040).

In recent years, it was thought that the pace had slowed; one of the biggest challenges of putting more circuits and power on a smaller chip is managing heat.

A multidisciplinary group that includes Patrick E. Hopkins, a professor in the University of Virginia’s Department of Mechanical and Aerospace Engineering, and Will Dichtel, a professor in Northwestern University’s Department of Chemistry, is inventing a new class of material with the potential to keep chips cool as they keep shrinking in size — and to help Moore’s Law remain true. Their work was recently published in Nature Materials.

Electrical insulation materials that minimize electrical crosstalk in chips are called “low-k” dielectrics. This material type is the silent hero that makes all electronics possible by steering the current to eliminate signal erosion and interference; ideally, it can also pull damaging heat caused by electrical current away from the circuitry. The heat problem becomes exponential as the chip gets smaller because not only are there more transistors in a given area, which makes more heat in that same area, they are closer together, which makes it harder for heat to dissipate.

“Scientists have been in search of a low-k dielectric material that can handle the heat transfer and space issues inherent at much smaller scales,” Hopkins said. “Although we’ve come a long way, new breakthroughs are just not going to happen unless we combine disciplines. For this project we’ve used research and principles from several fields — mechanical engineering, chemistry, materials science, electrical engineering — to solve a really tough problem that none of us could work out on our own.”

Hopkins is one of the leaders of UVA Engineering’s Multifunctional Materials Integration initiative, which brings together researchers from multiple engineering disciplines to formulate materials with a wide array of functionalities.

“Seeing ‘my’ problem through someone else’s lens in a different field was not only fascinating, it also sparked ideas that ultimately brought advancement. I think we all had that experience,” said Ashutosh Giri, a former UVA Engineering senior scientist and Ph.D. student in Hopkins’ lab, the co-first author on the Nature Materials paper and a mechanical, industrial and systems engineering assistant professor at Rhode Island University.

“The heart of the project was when the chemical team realized the thermal functionality of their material, understanding a new dimension about their work, and when the mechanical and materials team understood the level of molecular engineering possible with chemistry,” Giri said.

“We’re taking sheets of polymer that are only one atom thick — we call this 2D — and controlling their properties by layering the sheets in a specific architecture,” Dichtel said.

“Our efforts on improving the methods to produce high-quality 2D polymer films enabled this collaborative work.”

The team is applying this new material class to try to meet the requirements of miniaturizing transistors on a dense chip, Dichtel said.

“This has enormous potential for use in the semiconductor industry, the industry that that manufactures chips. The material has both low electrical conductivity, or ‘low-k,’ and high heat transfer capability,” he said.

This combination of properties was recently identified by the International Roadmap for Semiconductors as a prerequisite for next-generation integrated circuits.

“For this project, we are focusing on the thermal properties of this new material class, which is fantastic, but even more exciting is that we are just scratching the surface,” said Austin Evans, a Ph.D. student in Dichtel’s lab at Northwestern and first co-author on the Nature Materials paper. “Developing new classes of materials with unique combinations of properties has amazing technological potential.

“We are already exploring this new class of materials for many applications, for instance, chemical sensing. We can use these materials to determine — ‘sense’ — what chemicals and how much of those chemicals are in the air. This has broad reaching implications. For instance, by knowing about the chemicals in the air, we can optimize food storage, transport, and distribution to reduce global food waste. As we continue exploring, we are likely to find even more traits unique to these new materials,” Evans said.

Researchers now think the region’s widespread loss of glacier ice helped set the stage for the quake.

In a recently published research article, scientists with the University of Alaska Fairbanks Geophysical Institute found that ice loss near Glacier Bay National Park has influenced the timing and location of earthquakes with a magnitude of 5.0 or greater in the area during the past century.

Scientists have known for decades that melting glaciers have caused earthquakes in otherwise tectonically stable regions, such as Canada’s interior and Scandinavia. In Alaska, this pattern has been harder to detect, as earthquakes are common in the southern part of the state.

Alaska has some of the world’s largest glaciers, which can be thousands of feet thick and cover hundreds of square miles. The ice’s weight causes the land beneath it to sink, and, when a glacier melts, the ground springs back like a sponge.

“There are two components to the uplift,” said Chris Rollins, the study’s lead author who conducted the research while at the Geophysical Institute. “There’s what’s called the ‘elastic effect,’ which is when the earth instantly springs back up after an ice mass is removed. Then there’s the prolonged effect from the mantle flowing back upwards under the vacated space.”

In the study, researchers link the expanding movement of the mantle with large earthquakes across Southeast Alaska, where glaciers have been melting for over 200 years. More than 1,200 cubic miles of ice have been lost.

Southern Alaska sits at the boundary between the continental North American plate and the Pacific Plate. They grind past each other at about two inches per year — roughly twice the rate of the San Andreas fault in California — resulting in frequent earthquakes.

The disappearance of glaciers, however, has also caused Southeast Alaska’s land to rise at about 1.5 inches per year.

Rollins ran models of earth movement and ice loss since 1770, finding a subtle but unmistakable correlation between earthquakes and earth rebound.

When they combined their maps of ice loss and shear stress with seismic records back to 1920, they found that most large quakes were correlated with the stress from long-term earth rebound.

Unexpectedly, the greatest amount of stress from ice loss occurred near the exact epicenter of the 1958 quake that caused the Lituya Bay tsunami.

While the melting of glaciers is not the direct cause of earthquakes, it likely modulates both the timing and severity of seismic events.

When the earth rebounds following a glacier’s retreat, it does so much like bread rising in an oven, spreading in all directions. This effectively unclamps strike-slip faults, such as the Fairweather in Southeast Alaska, and makes it easier for the two sides to slip past one another.

In the case of the 1958 quake, the postglacial rebound torqued the crust around the fault in a way that increased stress near the epicenter as well. Both this and the unclamping effect brought the fault closer to failure.

“The movement of plates is the main driver of seismicity, uplift and deformation in the area,” said Rollins. “But postglacial rebound adds to it, sort of like the de-icing on the cake. It makes it more likely for faults that are in the red zone to hit their stress limit and slip in an earthquake.”

One of the keys to having a healthy brain at any age is having a healthy blood-brain barrier, a complex interface of blood vessels that run through the brain. Researchers reviewed more than 150 articles to look at what happens to the blood-brain barrier as we age. Their findings were published March 15 in Nature Aging.

Whether the changes to the blood-brain barrier alters brain function, however, is still up for debate.

“It turns out very little is known how the blood-brain barrier ages,” said lead author William Banks, a gerontology researcher at the University of Washington School of Medicine, and a researcher with the Geriatrics Research Education and Clinical Center at the Veterans Affairs Puget Sound Health Care System. “It’s often hard to tell normal aging from early disease.”

The blood-brain barrier, discovered in the late 1800s, prevents the unregulated leakage of substances from blood into the brain. The brain is an especially sensitive organ and cannot tolerate direct exposure to many of the substances in the blood. Increasingly, scientists have realized that the blood-brain barrier also allows many substances into the brain in a regulated way to serve the nutritional needs of the brain. It also transports informational molecules from the blood to the brain and pumps toxins out of the brain. A malfunctioning blood-brain barrier can contribute to diseases such as multiple sclerosis, diabetes, and even Alzheimer’s disease.

Before scientists can understand how such malfunctioning can contribute to the diseases of aging, they need to understand how a healthy blood-brain barrier normally ages.

Research shows that healthy aging individuals have a very small leak in their blood-brain barrier. This leakage is associated with some measures of the benign forgetfulness of aging, considered by most scientists to be normal. But could this leak and the difficulties in recall be the early stages of Alzheimer’s disease?

When a person carries the ApoE4 allele, the strongest genetic risk of Alzheimer’s risk, researchers said there is an acceleration of most of the blood-brain barrier age-related changes.

People with ApoE4 have a hard time getting rid of amyloid beta peptide in their brains, which causes an accumulation of plaque. With healthy aging, the pumps in the blood-brain barrier work less efficiently in getting rid of the amyloid beta peptide. The pumps work even less well in people with Alzheimer’s disease.

Another key finding in the review is that as we age, two cells begin to change in the blood-brain barrier: pericytes and astrocytes.

Recent work suggests that the leak in the blood-brain barrier that occurs with Alzheimer’s may be due to an age-related loss of pericytes. Astrocytes, by contrast, seem to be overactive. Recent work suggests that preserving pericyte function by giving the factors that they secrete or even transplanting them could lead to a healthier blood-brain barrier.

Some research suggests that pericyte health can be preserved by some of the same interventions that extend lifespan, such as regular exercise, caloric restriction, and rapamycin.

Other findings raise the question of whether the brain’s source of nutrition and its grip on control of the immune and endocrine systems could deteriorate with aging. Another finding raises the possibility that the rate at which many drugs are taken up by the brain may explain why older folks sometimes have different sensitivities to drugs than their children or grandchildren.

It’s a bit mysterious how this happens, though, because ice crystals are orderly structures of molecules, while aerosols are often disorganized chunks. New research by Valeria Molinero, distinguished professor of chemistry, and Atanu K. Metya, now at the Indian Institute of Technology Patna, shows how crystals of organic molecules, a common component of aerosols, can get the job done.

The story is more than that, though — it’s a throwback to Cold War-era cloud seeding research and an investigation into a peculiar memory effect that sees ice form more readily on these crystals the second time around.

The research, funded by the Air Force Office of Scientific Research, is published in the Journal of the American Chemical Society.

Throwback to cloud seeding

Molinero’s research is focused on how ice forms, particularly the process of nucleation, which is the beginning of ice crystal formation. Under the right conditions, water molecules can nucleate ice on their own. But often some other material, called a nucleant, can help the process along.

After several studies on the ways that proteins can help form ice, Molinero and Metya turned their attention to organic ice nucleants (as used here, “organic” means organic compounds containing carbon) because they are similar to the ice-producing proteins and are found in airborne aerosols.

But a review of the scientific literature found that the papers discussing ice nucleation by organic compounds came from the 1950s and 1960s, with very little follow-up work after that until very recently.

“That made me really curious,” Molinero says, “because there is a lot of interest now on organic aerosols and whether and how they promote the formation of ice in clouds, but all this new literature seemed dissociated from these early fundamental studies of organic ice nucleants.”

Additional research revealed that the early work on organic ice nucleants was related to the study of cloud seeding, a post-war line of research into how particles (primarily silver iodide) could be introduced into the atmosphere to encourage cloud formation and precipitation. Scientists explored the properties of organic compounds as ice nucleants to see if they might be cost-effective alternatives to silver iodide.

But cloud seeding research collapsed in the 1970s after political pressures and fears of weather modification led to a ban on the practice in warfare. Funding and interest in organic ice nucleants dried up until recently, when climate research spurred a renewed interest in the chemistry of ice formation in the atmosphere.

“There has been a growing interest in ice nucleation by organic aerosols in the last few years, but no connection to these old studies on organic crystals,” Molinero says. “So, I thought it was time to “rescue” them into the modern literature.”

Going all classic

Phloroglucinol is one of the organic nucleants studied in the mid-20^th century. It showed promise for controlling fog, but less for cloud seeding. Molinero and Metya revisited phloroglucinol as it proved potent at ice nucleation in the lab.

One question to answer is whether phloroglucinol nucleates ice through classical or non-classical processes. When ice nucleates on its own, without any surfaces or other molecules, the only hurdle to overcome is forming a stable crystallite of ice (only about 500 molecules in size under some conditions) that other molecules can build on to grow an ice crystal. That’s classical nucleation.

Non-classical nucleation, involving a nucleant surface, occurs when a layer of water molecules assembles on the surface on which other water molecules can organize into a crystal lattice. The hurdle to overcome in non-classical nucleation is the formation of the monolayer.

Which applies to phloroglucinol? In the 1960s, researcher L.F. Evans concluded that it was non-classical. “I am still amazed he was able to deduce the existence of a monolayer and infer the mechanism was non-classical from experiments of freezing as a function of temperature alone!” Molinero says. But Molinero and Metya, using molecular simulations of how ice forms, found that it’s more complicated.

“We find that the step that really decides whether water transforms to ice or not is not the formation of the monolayer but the growth of an ice crystallite on top,” Molinero says. “That makes ice formation by organics classical although no less fascinating.”

Holding on to memories of ice

The researchers also used their simulation methods to investigate an interesting memory effect previously observed with organic and other nucleants. When ice is formed, melted and formed again using these nucleants, the second round of crystallization is more effective than the first. It’s assumed that the ice melts completely between crystallizations, and researchers have posed several potential explanations.

Molinero and Metya found that the memory effect isn’t due to the ice changing the nucleant surface, nor to the monolayer of water persisting on the nucleant surface after melting. Instead, their simulations supported an explanation where crevices in the nucleant can hold on to small amounts of ice that melt at higher temperatures than the rest of the ice in the experiment. If these crevices are adjacent to one of the nucleant crystal surfaces that’s good at forming ice, then it’s off to the races when the second round of freezing begins.

Something in the air

Other mysteries still remain — the mid-century studies of organic crystals found that at high pressures, around 1500 times atmospheric pressure, that the crystals are as efficient at organizing water molecules into ice as an ice crystal itself. Why? That’s the focus of Molinero’s next experiments.

More immediately, though, phloroglucinol is a naturally-occurring compound in the atmosphere, so anything that researchers can learn about it and other organic nucleants can help explain the ability of aerosols to nucleate ice and regulate the formation of clouds and precipitation.

“It would be important to investigate whether small crystallites of these crystalline ice nucleants are responsible for the baffling ice nucleation ability of otherwise amorphous organic aerosols,” Molinero says.

The filamentary structure of hydrogen gas in which galaxies form, known as the cosmic web, is one of the major predictions of the model of the Big Bang and of galaxy formation. Until now, all that was known about the web was limited to a few specific regions, particularly in the direction of quasars, whose powerful radiation acts like car headlights, revealing gas clouds along the line of sight. However, these regions are poorly representative of the whole network of filaments where most galaxies, including our own, were born. Direct observation of the faint light emitted by the gas making up the filaments was a holy grail which has now been attained by an international team headed by Roland Bacon, CNRS researcher at the Centre de Recherche Astrophysique de Lyon (CNRS/Université Lyon 1/ENS de Lyon).

The team took the bold step of pointing ESO’s Very Large Telescope, equipped with the MUSE instrument coupled to the telescope’s adaptive optics system, at a single region of the sky for over 140 hours. Together, the two instruments form one of the most powerful systems in the world. The region selected forms part of the Hubble Ultra-Deep Field, which was until now the deepest image of the cosmos ever obtained. However, Hubble has now been surpassed, since 40% of the galaxies discovered by MUSE have no counterpart in the Hubble images.

After meticulous planning, it took eight months to carry out this exceptional observing campaign. This was followed by a year of data processing and analysis, which for the first time revealed light from the hydrogen filaments, as well as images of several filaments as they were one to two billion years after the Big Bang, a key period for understanding how galaxies formed from the gas in the cosmic web. However, the biggest surprise for the team was when simulations showed that the light from the gas came from a hitherto invisible population of billions of dwarf galaxies spawning a host of stars (3). Although these galaxies are too faint to be detected individually with current instruments, their existence will have major consequences for galaxy formation models, with implications that scientists are only just beginning to explore.

Notes:

(1) MUSE, which stands for Multi Unit Spectroscopic Explorer, is a 3D spectrograph designed to explore the distant Universe. The construction of the instrument was led by the Centre de Recherche Astrophysique de Lyon (CNRS/Université Claude Bernard-Lyon 1/ENS de Lyon).

(2) Other French laboratories involved: Laboratoire d’Astrophysique de Marseille (CNRS/Aix-Marseille Université/CNES), Institut de Recherche en Astrophysique et Planétologie (CNRS/Université Toulouse III — Paul Sabatier/CNES).

(3) Until now, theory predicted that the light came from the diffuse cosmic ultraviolet background radiation (very weak background radiation produced by all the galaxies and stars) which, by heating the gas in the filaments, causes them to glow.

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Hanna, who is in the Institute’s Molecular Genetics Department, explains that much of what is known about mammalian embryonic development today comes either from observing the process in non-mammals like frogs or fish that lay transparent eggs, or by obtaining static images from dissected mouse embryos and adding them together. The idea of growing early embryos outside the uterus has been around since before the 1930s, he adds, but experiments based on these proposals had limited success and the embryos tended to be abnormal.

Hanna’s team decided to renew that effort in order to advance the research in his lab, which focuses on the way the development program is enacted in embryonic stem cells. Over seven years, through trial and error, fine-tuning and double-checking, his team came up with a two-step process in which they were able to grow normally developing mouse embryos outside the uterus for six days — around a third of their 20-day gestation — by which time the embryos already had a well-defined body plan and visible organs. “To us, that is the most mysterious and the most interesting part of embryonic development, and we can now observe it and experiment with it in amazing detail,” say Hanna.

The research was led by Alejandro Aguilera-Castrejon, Dr. Bernardo Oldak, the late Dr. Rada Massarwa and Dr. Noa Novershtern in Hanna’s lab and Dr. Itay Maza, a former student of Hanna’s now in the Rambam Health Care Campus of the Technion — Israel Institute of Technology.

For the first step, which lasted around two days, the researchers started with several-day old mouse embryos — right after they would have implanted in the uterus. At this stage the embryos were balls consisting of 250 identical stem cells. These were placed on a special growth medium in a laboratory dish and the team got the balls to attach to this medium as they would to the uterine wall. With this step, they succeeded in duplicating the first stage of embryonic development, in which the embryo doubles and triples in size, as it differentiates into three layers: inner, middle and outer.

Beyond two days, as the embryos entered the next developmental stage — the formation of organs from each of the layers — they needed additional conditions. For this second step, the scientists placed the embryos in a nutrient solution in tiny beakers, setting the beakers on rollers that kept the solutions in motion and continually mixed. That mixing seems to have helped keep the embryos, which were growing without maternal blood flow to the placenta, bathed in the nutrients. In addition to carefully regulating the nutrients in the beakers, the team learned in further experiments to closely control the gases, oxygen and carbon dioxide — not just the amounts, but the gas pressure as well.

To check whether the developmental processes they were observing throughout the two steps were normal, the team conducted careful comparisons with embryos removed from pregnant mice in the relevant time period, showing that both the separation into layers and the organ formation were all but identical in the two groups. In subsequent experiments, they inserted into the embryos genes that labeled the growing organs in fluorescent colors. The success of this attempt suggested that further experiments with this system involving various genetic and other manipulations should produce reliable results. “We think you can inject genes or other elements into the cells, alter the conditions or infect the embryo with a virus, and the system we demonstrated will give you results consistent with development inside a mouse uterus,” says Hanna.

“If you give an embryo the right conditions, its genetic code will function like a pre-set line of dominos, arranged to fall one after the other,” he adds. “Our aim was to recreate those conditions, and now we can watch, in real time, as each domino hits the next one in line.” Among other things, explains Hanna, the method will lower the cost and speed up the process of research in the field of developmental biology, as well as reducing the need for lab animals.

In fact, the next step in Hanna’s lab will be to see if they can skip the step of removing embryos from pregnant mice. He and his team intend to try to create artificial embryos made from stem cells for use in this research. Among other things, they hope to put their new method to work to answer such questions as why so many pregnancies fail to implant, why the window for implantation is so short, how stem cells gradually lose their “stemness” as differentiation progresses and what conditions in gestation may later lead to developmental disorders.

Video: https://www.youtube.com/watch?v=tNb2npuiF3Q