But some scientists worry that the remarkable success of the first COVID-19 vaccines may work against updated versions, undermining the utility of an annual vaccination program. A similar problem plagues the annual flu vaccine campaign; immunity elicited by one year’s flu shots can interfere with immune responses in subsequent years, reducing the vaccines’ effectiveness.

A new study by researchers at Washington University School of Medicine in St. Louis helps to address this question. Unlike immunity to influenza virus, prior immunity to SARS-CoV-2, the virus that causes COVID-19, doesn’t inhibit later vaccine responses. Rather, it promotes the development of broadly inhibitory antibodies, the researchers report.

The study, available online in Nature, shows that people who were repeatedly vaccinated for COVID-19 — initially receiving shots aimed at the original variant, followed by boosters and updated vaccines targeting variants — generated antibodies capable of neutralizing a wide range of SARS-CoV-2 variants and even some distantly related coronaviruses. The findings suggest that periodic re-vaccination for COVID-19, far from hindering the body’s ability to recognize and respond to new variants, may instead cause people to gradually build up a stock of broadly neutralizing antibodies that protect them from emerging SARS-CoV-2 variants and some other coronavirus species as well, even ones that have not yet emerged to infect humans.

“The first vaccine an individual receives induces a strong primary immune response that shapes responses to subsequent infection and vaccination, an effect known as imprinting,” said senior author Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine. “In principle, imprinting can be positive, negative or neutral. In this case, we see strong imprinting that is positive, because it’s coupled to the development of cross-reactive neutralizing antibodies with remarkable breadth of activity.”

Imprinting is the natural result of how immunological memory works. A first vaccination triggers the development of memory immune cells. When people receive a second vaccination quite similar to the first, it reactivates memory cells elicited by the first vaccine. These memory cells dominate and shape the immune response to the subsequent vaccine.

In the case of the flu vaccine, imprinting has negative effects. Antibody-producing memory cells crowd out new antibody-producing cells, and people develop relatively few neutralizing antibodies against the strains in the newer vaccine. But in other cases, imprinting can be positive, by promoting the development of cross-reactive antibodies that neutralize strains in both the initial and subsequent vaccines.

To understand how imprinting influences the immune response to repeat COVID-19 vaccination, Diamond and colleagues including first author Chieh-Yu Liang, a graduate student, studied the antibodies from mice or people who had received a sequence of COVID-19 vaccines and boosters targeting first the original and then omicron variants. Some of the human participants also had been naturally infected with the virus that causes COVID-19.

The first question was the strength of the imprinting effect. The researchers measured how many of the participants’ neutralizing antibodies were specific for the original variant, the omicron variant or both. They found that very few people had developed any antibodies unique to omicron, a pattern indicative of strong imprinting by the initial vaccination. But they also found few antibodies unique to the original variant. The vast majority of neutralizing antibodies cross-reacted with both.

The next question was how far the cross-reactive effect extended. Cross-reactive antibodies, by definition, recognize a feature shared by two or more variants. Some features are shared only by similar variants, others by all SARS-CoV-2 variants or even all coronaviruses. To assess the breadth of the neutralizing antibodies, the researchers tested them against a panel of coronaviruses, including SARS-CoV-2 viruses from two omicron lineages; a coronavirus from pangolins; the SARS-1 virus that caused the 2002-03 SARS epidemic; and the Middle Eastern Respiratory Syndrome (MERS) virus. The antibodies neutralized all the viruses except MERS virus, which comes from a different branch of the coronavirus family tree than the others.

Further experiments revealed that this remarkable breadth was due to the combination of original and variant vaccines. People who received only the vaccines targeting the original SARS-CoV-2 variant developed some cross-reactive antibodies that neutralized the pangolin coronavirus and SARS-1 virus, but the levels were low. After boosting with an omicron vaccine, though, the cross-reactive neutralizing antibodies against the two coronavirus species increased.

Taken together, the findings suggest that regular re-vaccination with updated COVID-19 vaccines against variants might give people the tools to fight off not only the SARS-CoV-2 variants represented in the vaccines, but also other SARS-CoV-2 variants and related coronaviruses, possibly including ones that have not yet emerged.

“At the start of the COVID-19 pandemic, the world population was immunologically naïve, which is part of the reason the virus was able to spread so fast and do so much damage,” said Diamond, also a professor of molecular microbiology and of pathology & immunology. “We do not know for certain whether getting an updated COVID-19 vaccine every year would protect people against emerging coronaviruses, but it’s plausible. These data suggest that if these cross-reactive antibodies do not rapidly wane — we would need to follow their levels over time to know for certain — they may confer some or even substantial protection against a pandemic caused by a related coronavirus.”

The sweet taste receptor, expressed in taste bud cells, conveys sweetness from the mouth when it is activated. Earlier this month, a study in PLOS One, led by another Monell researcher, delved into how the sweet-taste receptor might be the first stop in a metabolic surveillance system for sugar. The receptor is also expressed in certain intestinal cells, where it may facilitate glucose absorption and assimilation, as part of this system.

The team found that stimulation and inhibition of TAS1R2-TAS1R3 demonstrates that it helps regulate glucose metabolism in humans and may have implications for managing such metabolic disorders as diabetes. Glucose is the primary type of sugar found in human blood, making it a key source of energy for cells.

“Our objective was to determine whether TAS1R2-TAS1R3 influences glucose metabolism in two directions,” said Monell Member Paul Breslin, PhD, Professor of Nutritional Sciences, Rutgers University, and senior author on the paper.

They showed that a TAS1R2-TAS1R3 agonist (sucralose, a zero-calorie sweetener) or a TAS1R2-TAS1R3 antagonist (lactisole, a sodium salt that inhibits sweet taste) mixed with a glucose meal acutely altered human glucose tolerance in different ways. Here, an agonist binds to a receptor and stimulates a cell and an antagonist binds to a receptor and prevents stimulation.

“The novelty of our findings is that the receptor we studied in this experiment impacts blood glucose and insulin during a glucose meal differently, depending on whether it is stimulated or inhibited,” said Breslin. This work provides further evidence that taste receptors help regulate metabolism and nutrient handling.

Plasma insulin levels were measured in study participants given an oral glucose tolerance test (OGTT), which follows blood sugar levels before and after a person drinks a liquid meal containing glucose. Participants’ ratings of perceived sucralose sweetness correlated with early increases in plasma glucose, as well as increases in plasma insulin levels when sucralose was added to the OGTT. The added sucralose tended to accelerate the release of insulin to the glucose load. On the other hand, participants’ sensitivity to lactisole-driven inhibition of sweetness was correlated with decreased plasma glucose levels. Lactisole also tended to slow insulin release.

“When glucose stimulates taste receptors before being absorbed into the body, signals are sent via the mouth and intestine to regulatory organs such as the pancreas. Perhaps, we could devise ways of using TAS1R2-TAS1R3 to help the body handle glucose better by anticipating when glucose will appear in the blood,” said Breslin. When the body senses glucose, it speeds up the absorption to deliver glucose to tissues that may need it and possibly also to prevent glucose from moving too far along the intestine, which may not be good for maintaining a healthy gut microbiome.

“This system is elegant in its simplicity,” said Breslin. The same taste receptor is all over the body — the mouth, gastrointestinal tract, pancreas, liver, and fat cells, with the last three being major metabolic regulatory tissues, all part of the body’s 24/7 metabolic watch.

Is there a relationship between a person’s health status and the activity of their TAS1R2-TAS1R3 receptors? Study authors say likely, suggesting that the degree of receptor activation exerts acute influences on plasma glucose and insulin levels and their timing of onset, which is important for metabolic health.

The team maintains that, in general, the current dietary habits of excessive consumption of food and beverages high in sucrose, high fructose corn syrup, and high-potency sweeteners could hyperstimulate TAS1R2-TAS1R3, contributing to the improper regulation of glucose in the blood. This could lead to a diagnosis of metabolic syndrome, a cluster of risk factors including elevated plasma glucose and insulin insensitivity (along with obesity, hypertension, and elevated plasma fats) that increases the risk of heart disease, stroke, and diabetes. The authors say that future studies should examine the effects of TAS1R2-TAS1R3 stimulation and inhibition in people who are at risk for metabolic syndrome to determine the therapeutic potential of manipulating TAS1R2-TAS1R3 for better metabolic control instead of worse.

“Studies like these — using Monell’s technical capability and deep expertise in the chemical senses — show that the sweet taste receptor TAS1R2-TAS1R3 helps to regulate glucose differently, depending on the sweetness of the food or beverage,” said Breslin. The team’s hope is to apply what they learned to make what we eat and drink healthier.

“A small metabolic change for the positive can add a lot more to the life and health of humans when compounded over decades and millions of people,” said Breslin.

Heatwaves, which we’ve increasingly seen around the globe in recent years, are also becoming more and more common in the Arctic. During a heatwave, not only the air but also the ocean grows warmer — the temperature is substantially higher than the seasonal mean value for at least five consecutive days. But how these short-term temperature fluctuations affect polar organisms remains largely unclear. To shed light on this aspect, a team led by Dr Klara Wolf (Universities of Hamburg and Konstanz) and Dr Björn Rost from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI) has now used experiments to investigate how single-cell algae, the phytoplankton, respondact to these extreme events. Given the phytoplankton’s role as the basis of the marine food web, changes in it could resonate throughout the entire Arctic ecosystem.

In incubation experiments at the AWIPEV Station in Svalbard, the researchers allowed natural phytoplankton communities from nearby Kongsfjorden to grow for 20 days under various conditions — normal and increased but constant temperatures (2° C, 6° C, 9° C). For comparison, they subjected the phytoplankton to repeated heatwaves of varying intensity (6° C, 9° C) , each lasting five days with a three-day cooling phase at the seasonal mean temperature (2° C) in between. Different types of samples were collected at defined intervals in order to characterise the physiological responses and any potential species shifts.

“Under stable temperatures, even an extreme increase of +7° C led to accelerated growth and higher productivity, with surprisingly small changes in the composition of species, even over weeks,” says Klara Wolf regarding the experiments’ outcomes. “In contrast, the effects of heatwaves are considerably more complex and don’t follow the same pattern. This implies that our knowledge about constant temperature increases cannot readily be applied to these short-term warm phases, which normally only last a few days.” One reason for the difference is apparently that not just the exposure to increased temperatures has a major impact on productivity, but also and especially the cooling phases after or between heatwaves — and very little is known about these effects.

“We’re only just starting to gain a mechanistic understanding of how heatwaves can impact the polar regions,” says AWI biologist Björn Rost. “Our study represents an important first step and shows which aspects of heatwaves and which phytoplankton-related processes we need to take a closer look at. In addition, our study shows that what we know about the processes and effects of constantly higher temperatures can’t simply be applied one-to-one.” In fact, scenarios involving fluctuating temperatures can produce a broad range of effects, which is why predicting their implications is more complicated than for continuous warming.

Accordingly, in order to develop better projections and models regarding how primary production and the Arctic ecosystem will change in response to climate change, it won’t suffice to investigate the effects of mean temperatures; the effects of temperature fluctuations need to receive more attention. While stable warming up to a certain temperature increases productivity, some heatwaves can decrease it, while others increase it. A better grasp of the effects of variable temperatures, especially the cooling phases, is therefore essential to improving forecasts on potential biodiversity changes. Investigations on phytoplankton are hereby most crucial, since changes at the basis of the food web can impact all higher trophic levels, all the way up to fisheries.

The study researchers and their enlisted volunteer “otter spotters” followed 196 radio-tagged southern sea otters off the coast of California to better understand how the threatened species uses tools in a rapidly changing environment. The research team from The University of Texas at Austin, University of California, Santa Cruz, Monterey Bay Aquarium and elsewhere monitored how the marine mammals used tools — such as rocks, shells and trash — to break open prey and identified links to the animals’ dietary patterns and dental health.

For the first time, researchers found that the use of tools among male and female otters led to a reduction in tooth injuries.

“Sea otters vary in how often they use tools,” said Chris Law, a postdoctoral researcher and an Early Career Provost Fellow at UT Austin who led the study while a graduate student at UC Santa Cruz. “The females are likely using tools to overcome their smaller body size and weaker biting ability in order to meet their calorie demands. Raising pups takes a lot of energy, and the females need to be efficient in their foraging. The study shows that tool use is an important behavior for survival.”

The study is published in Science.

In the southern sea otter’s range of coastal Central California, some of the preferred prey such as large abalone and sea urchins, are not difficult to break open. However, these food resources dwindle or disappeare in many areas. This leads otters to prey more often on crabs, clams, mussels and small marine snails whose hard shells can damage the otter’s teeth in the process of prying them open.

Tooth condition is important for survival because when an otter’s teeth become too worn or damaged, they could starve. Using tools helped individual otters to meet their calorie needs by branching out into different types of prey. The study found female otters had less tooth damage than male otters did.

Research shows that female otters are more likely to use tools, and in the study, those that did were able to access harder or larger prey than otters that did not use tools. In fact, females were able to consume prey that were up to 35% harder compared with that of males that used tools.

Female dolphins, chimps and bonobos are also known to use tools more than their male counterparts, probably for the same reasons. In these species, females tend to raise offspring, and they are often the ones that pass down tool-use behavior to offspring.

Listed as a threatened species under the U.S. Endangered Species Act, southern sea otters number only about 3,000 in California, where they play a critical role in marine ecosystems preying on sea urchins that feed on kelp forests.

Rita Mehta and Tim Tinker of the University of California, Santa Cruz; Jessica Fujii, Teri Nicholson and Michelle Staedler with the Monterey Bay Aquarium; Joseph Tomoleoni of the U.S. Geological Survey; and Colleen Young of the California Department of Fish and Wildlife were also authors on the paper. Chris Law was previously a postdoctoral scholar with University of Washington.

The research was funded by the U.S. National Science Foundation, Packard Foundation, Coastal Conservancy, U.S. Fish and Wildlife Service, Pacific Gas & Electric and Bureau of Ocean Energy Management.

AlphaFold2, an artificial intelligence system that predicts protein structures, has made it possible for scientists to identify and conjure an almost infinite number of drug candidates for the treatment of neuropsychiatric disorders. However recent studies have sown doubt about the accuracy of AlphaFold2 in modeling ligand binding sites, the areas on proteins where drugs attach and begin signaling inside cells to cause a therapeutic effect, as well as possible side effects.

In a new paper, Bryan Roth, MD, PhD, the Michael Hooker Distinguished Professor of Pharmacology and director of the NIMH Psychoactive Drug Screening Program at the University of North Carolina School of Medicine, and colleagues at UCSF, Stanford and Harvard determined that AlphaFold2 can yield accurate results for ligand binding structures, even when the technology has nothing to go off of. Their results were published in Science.

“Our results suggest that AF2 structures can be useful for drug discovery,” said Roth, senior author who holds a joint appointment at the UNC Eshelman School of Pharmacy. “With a nearly infinite number of possibilities to create drugs that hit their intended target to treat a disease, this sort of AI tool can be invaluable.”

AlphaFold2 and Prospective Modeling

Much like weather forecasting or stock market prediction, AlphaFold2 works by pulling from a massive database of known proteins to create models of protein structures. Then, it can simulate how different molecular compounds (like drug candidates) fit into the protein’s binding sites and produce wanted effects. Researchers can use the resulting combinations to better understand protein interactions and create new drug candidates.

To determine the accuracy of AlphaFold2, researchers had to compare the results of a retrospective study against that of a prospective study. A retrospective study involves researchers feeding the prediction software compounds they already know bind to the receptor. Whereas, a prospective study requires researchers to use the technology as a fresh slate, and then feed the AI platform information about compounds that may or may not interact with the receptor.

Researchers used two proteins, sigma-2 and 5-HT2A, for the study. These proteins, which belong to two different protein families, are important in cell communication and have been implicated in neuropsychiatric conditions such as Alzheimer’s disease and schizophrenia. The 5-HT2A serotonin receptor is also the main target for psychedelic drugs which show promise for treating a large number of neuropsychiatric disorders.

Roth and colleagues selected these proteins because AlphaFold2 had no prior information about sigma-2 and 5-HT2A or the compounds that might bind to them. Essentially, the technology was given two proteins for which it wasn’t trained on — essentially giving the researchers a “blank slate.”

First, researchers fed the AlphaFold system the protein structures for sigma-2 and 5-HT2A, creating a prediction model. Researchers then accessed physical models of the two proteins that were produced using complex microscopy and x-ray crystallography techniques. With a press of a button, as many as 1.6 billion potential drugs were targeted to the experimental models and AlphaFold2 models. Interestingly, every model had a different drug candidate outcome.

Successful Hit Rates

Despite the models having differing results, they show great promise for drug discovery. Researchers determined that the proportion of compounds that actually altered protein activity for each of the models were around 50% and 20% for the sigma-2 receptor and 5-HT2A receptors, respectively. A result greater than 5% is exceptional.

Out of the hundreds of millions of potential combinations, 54% of the drug-protein interactions using the sigma-2 AlphaFold2 protein models were successfully activated through a bound drug candidate. The experimental model for sigma-2 produced similar results with a success rate of 51%.

“This work would be impossible without collaborations among several leading experts at UCSF, Stanford, Harvard, and UNC-Chapel Hill,” Roth said. “Going forward we will test whether these results might be applicable to other therapeutic targets and target classes.”