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.”

Sabre teeth, those iconic elongated upper canine teeth, have long fascinated both scientists and the general public, notably because they have appeared several times in the fossil record, including two particularly well-known lineages of sabre-toothed tigers: the felids (the family of our domestic cats, lions, tigers, etc.) and the nimravids (a completely extinct family). However, the process by which these lineages acquired their elongated upper canines remains rather unclear.

Narimane Chatar, lead author of the study, who completed her doctorate at the EDDy Lab at the University of Liège and is now a post-doctoral fellow at UC Berkeley in the United States, has led an ambitious study to uncover the secrets of sabre tooth evolution. Using state-of-the-art 3D scanners and analytical methods, the team meticulously collected and analysed data from a diverse set of current and extinct species. “We quantified the shape of 99 mandibles and 91 skulls, from different eras and continents, giving us a better understanding of the evolution of these animals,” explains Dr Chatar. “Unlocking the secrets of sabre tooth evolution not only enriches our understanding of the Earth’s past, but also documents the mechanisms leading to evolutionary convergence,” says Professor Valentin Fischer, Director of the EDDyLab at ULiège.

The study revealed some surprising results. The first is that rather than contrasting two distinct cranial morphologies in species with elongated upper canines and those with short teeth, there is instead a continuum of form linking the smallest present-day cats and their extinct sabre-toothed counterparts. “From a morphological point of view, the skull of a present-day small cat is just as strange and modified as that of a large sabre-toothed felid,” says Dr Margot Michaud, a researcher at the University of French Guyana in Cayenne. These are therefore the two extremes of a continuum of forms that feline predators have seen evolve over geological time. “Our study suggests that what we often think of as examples of evolutionary patterns in textbooks are actually simplified for educational purposes. However, when we immerse ourselves in statistical analyses, we discover much more complex scenarios in these cases, as suggested by the results of our convergence tests,” explains Davide Tamagnini, post-doctoral researcher at the University of Rome La Sapienza.

The second surprise concerns the path taken by evolution to produce sabre-toothed species. In fact, the team’s work has revealed that sabre-toothed species show faster rates of morphological evolution at the start of their evolutionary history than species with shorter canines. “Among other fascinating discoveries, we have shown that craniomandibular integration in sabre-toothed species is reduced, facilitating greater adaptability and diversification in the jaw and cranial morphology,” points out Margot Michaud. Thus, rapid morphological diversification and a fairly plastic skull have been identified as two key components that facilitated the emergence of elongated upper canines in both felids and nimravids. “As a result, there appears to be a common recipe for evolving into sabre-toothed feline-like predators,” says Dr Chatar.

Finally, the team’s research highlighted the decline of sabre-toothed forms as well as the broader trends of feline-like predators over the course of their evolutionary history. Despite the relatively recent extinction of sabre-toothed forms ‘only’ a few thousand years ago, feline predators have in fact been in decline since the Miocene epoch (between -23 and -5 million years ago). “Some of these feline predators, particularly the sabre-toothed species, rapidly occupied fairly specialised niches, which made them more susceptible to extinction,” explains Dr Tamagnini. This phenomenon, known as ‘ratchet’ or macroevolutionary ratchet, has been proposed as a potential driver for the decline of certain groups, where evolution favours the loss of early generalised forms, leading to the emergence of more specialised, but also more vulnerable, forms later in the history of the lineage.

“Predators have their own evolutionary pathways and risks of extinction. Studying how ancient predators prospered and declined provides us with information about the possible futures of our ecosystems,” concludes Professor Fischer.