Although the exact molecule they identified in the worms has not yet been studied in humans, the new work helps scientists better understand the complex crosstalk between the gut and the brain. It also may shed light on why fasting — not eating for set periods of time — has benefits that are independent from the number of calories a person eats. The new study was published in Nature Communicationson August 11, 2024.

“We’ve found for the first time that fasting is conveying information to the brain beyond just caloric withdrawal,” says Scripps Research Professor of Neuroscience Supriya Srinivasan, PhD, the senior author of the new study. “These findings make me wonder whether there are molecules made in the guts of other animals, including mammals, that explain some of the health outcomes associated with fasting.”

Researchers have long known that the brain controls the production and breakdown of fats in humans, other mammals and model organisms such as C. elegans. In 2017, Srinivasan’s group identified FLP-7, a brain hormone that triggers fat burning in the roundworm’s gut. However, C. elegans do not have sensory nerves in their intestines, so scientists have struggled to pin down the reverse communication pathway: How does the gut signal the brain?

“We knew that altering the metabolic state of the gut could change the properties of neurons in the brain, but it was very mysterious how this actually happened,” says Srinivasan.

In the new work, Srinivasan and her colleagues removed more than 100 signaling molecules from C. elegans intestines, one at a time, and measured their impact on the brain’s production of FLP-7. They found one molecule that had a large effect on FLP-7: a form of insulin known as INS-7. In humans, insulin is most known as the hormone produced by the pancreas that control blood sugar levels. But this insulin molecule was instead being made by gut cells and also impacting fat metabolism via the brain.

“When we first found that this was an insulin, we thought it was paradoxical,” recalls Srinivasan. “Insulin is so well studied in mammals, and there was no precedent for an insulin molecule having this role.”

However, when the group probed how INS-7 was impacting FLP-7-producing brain cells, they found that it was not activating insulin receptors — as all previously discovered insulin molecules do — but by blocking the insulin receptor. In turn, this blockade set off a cascade of other molecular events that eventually made the brain cells stop producing FLP-7.

“INS-7 is basically a signal coming from the intestines that tells the brain not to burn any more fat stores right now because there’s no food coming in,” explains Srinivasan.

Studies have previously shown that periods of fasting can influence the body in a variety of ways, but the mechanisms of those changes have been unclear. The new study points toward one way that an empty gut can signal the brain, which could potentially lead to a variety of health impacts beyond fat.

The new results, Srinivasan says, help explain how the brain and digestive system communicate in both directions to control metabolism based on the availability of food. More research is needed to uncover which specific pathways are involved in new gut-to-brain signals in mammals. Compounds that mimic gut hormones — such as semaglutide, commonly known under brand names such as Ozempic, Wegovy and Rybelus — have recently emerged as popular ways to control obesity and diabetes, so new gut peptides could add to this drug class. Srinivasan is also planning experiments to probe how C. elegans gut cells are triggered to produce INS-7 during fasting and which types of brain cells are affected by the molecule.

This work was supported by funding from the National Institutes of Health (R01 DK124706 and R01 AG056648).

Specifically, viperins and argonautes, two proteins that are known to play important roles in the immune systems of all complex life — from insects to plants to humans — came from the Asgard archaea. Versions of these defense proteins are also present in bacteria, but the versions in complex life forms are most closely related to those in Asgard archaea, according to the new scientific study published in the journal Nature Communications.

This research bolsters the idea that all complex life, called eukaryotes, arose from a symbiotic relationship between bacteria and Asgard archaea.

“It adds more support to the fact that the Asgards are our microbial ancestors,” said Brett Baker, associate professor of integrative biology and marine science and senior author. “It says that not only did eukaryotes get all these rich structural proteins that we’ve seen before in Asgards, now it’s saying that even some of the defense systems in eukaryotes came from Asgards.”

The researchers identified for the first time a large arsenal of defense systems in archaea that were previously known only in bacteria.

When viperins detect foreign DNA, which might indicate a dangerous virus, they edit the DNA so that the cell can no longer make copies of the DNA, which stops the virus from spreading. When argonautes detect foreign DNA, they chop it up, also halting the virus. Additionally, in more complex organisms, argonautes can block the virus from making proteins in a process called RNA silencing.

“Viral infections are one of the evolutionary pressures that we have had since life began, and it is critical to always have some sort of defense,” said Pedro Leão, now an assistant professor at Radboud University in the Netherlands and a recent postdoctoral researcher in Baker’s lab. “When bacteria and archaea discovered tools that worked, they were passed down and are still part of our first line of defense.”

The researchers compared proteins involved in immunity across the tree of life and found many closely related ones. Then they used an AI tool called ColabFold to predict whether ones that had similar amino acid sequences also had similar three-dimensional shapes (aka structures). (It’s the shape of a protein that determines how it functions.) This showed that variations of the viperin protein probably maintained the same structure and function across the tree of life. They then created a kind of family tree, or phylogeny, of these sister amino acid sequences and structures that showed evolutionary relationships.

Finally, the researchers took viperins from Asgard archaea genomes, cloned them into bacteria (so the bacteria would express the proteins), challenged the bacteria with viruses, and showed that Asgard viperins do in fact provide some protection to the modified bacteria. They survived better than bacteria without the immune proteins.

“This research highlights the integral role cellular defenses must have played from the beginning of both prokaryotic and eukaryotic life,” said Emily Aguilar-Pine, a former undergraduate researcher who contributed to the project. “It also inspires questions about how our modern understanding of eukaryotic immunity can benefit from unraveling some of its most ancient origins.”

“It’s undeniable at this point that Asgard archaea contributed a lot to the complexity that we see in eukaryotes today,” Leão said. “So why wouldn’t they also be involved in the origin of the immune system? We have strong evidence now that this is true.”

Other authors, all from UT, are Mary Little, Kathryn Appler, Daphne Sahaya, Kathryn Currie, Ilya Finkelstein and Valerie De Anda.

This work was supported by the Simons and Moore foundations (via the Moore-Simons Project on the Origin of the Eukaryotic Cell) and The Welch Foundation.

“Extreme weather events disregard state and electric utilities’ boundaries, and so will the solution needed to mitigate the impact,” said study co-author Mareldi Ahumada-Paras, a postdoctoral scholar in energy science and engineering in the Stanford Doerr School of Sustainability.”Greater regional cooperation can benefit reliability under wide-spread stress conditions.”

The new abnormal

Across the West, electricity providers are struggling with three new realities. Demand and resource availability are becoming harder to predict because of factors ranging from more frequent and widespread weather extremes to the proliferation of rooftop solar installations to more frequent and widespread weather extremes. Rapid growth of renewable energy, such as wind and solar, along with energy storage options requires new operating and planning strategies for meeting demand. On top of these trends, a patchwork of state and federal clean energy goals creates different incentives that influence utilities’ operation and planning differently.

“New grid management approaches can capitalize on the opportunities created by our rapidly changing electricity system and address increasing stress from extreme heat, drought, and other climate-related events,” said study co-author Michael Mastrandrea, research director of the Climate and Energy Policy Program.

The study focuses on the power grid that stretches from the West Coast to the Great Plains and from western Canada to Baja California. In recent years, extreme heat events and severe droughts have put major demand stresses on the grid and reduced hydropower availability.

The researchers used power system optimization models to simulate grid operations under stress conditions based on those experienced during a 2022 California heat wave that saw record-breaking energy demand. Their simulations demonstrated that expanding the area of cooperation could reduce the risk of power outages by as much as 40%, reduce the amount of unserved energy — when electricity demand exceeds supply — by more than half, and increase reliability.

Policy and public opinion

The researchers refer to these estimates as “illustrative and directional” because incomplete information makes it hard to precisely simulate how those responsible for ensuring power system reliability within specific service territories will respond to stress conditions. Still, the results highlight how expanded cooperation among utilities can improve responses to local shortages and excesses, offer greater flexibility in managing unexpected disruptions and balancing supply and demand, and ensure reliable electricity supply during extreme weather events.

Expanded cooperation among utilities could also maximize the value of the region’s growing renewable energy portfolio, according to the researchers. Renewable power generation, such as wind and solar, can be variable since the wind doesn’t always blow and the sun only shines so many hours per day. Expanding cooperation across a larger geographic area can ensure that renewable power generation is used (or stored for later) when it is available. Critics of these sources are also likely to blame them for major power outages, according to the researchers, feeding a narrative that could sour public opinion and lead to policies slowing the adoption or expansion of clean energy.

“Our work shows how greater cooperation isn’t just about dollars and cents for utilities and their customers,” said study co-author Michael Wara, director of the Climate and Energy Policy Program at the Stanford Woods Institute for the Environment. “It’s about keeping the lights on as we confront the challenge of the energy transition and the growing impacts of climate change.”

Wara and Mastrandrea are also senior director for policy and director for policy, respectively, in the Stanford Doerr School of Sustainability’s Sustainability Accelerator.

The study, recently published online in the journal Neuron, describes team members’ focus on a region of the brain called the globus pallidus externus, which acts as a gatekeeper that regulates how we react to cocaine. They discovered that within the GPe, parvalbumin-positive neurons are crucial in controlling the response to cocaine by changing the activity neurons releasing the pleasure molecule dopamine.

“There are currently no effective therapeutics for dependence on psychostimulants such as cocaine, which, along with opioids, represent a substantial health burden,” said corresponding author Kevin Beier, UC Irvine associate professor of physiology and biophysics. “Our study deepens our understanding of the basic brain mechanisms that increase vulnerability to substance use disorder-related outcomes and provides a foundation for the development of new interventions.”

Findings in mice revealed that globus pallidus externus parvalbumin-positive cells, which indirectly influence the release of dopamine, become more excitable after being exposed to cocaine. This caused a drop in the expression of certain proteins that encode membrane channels that usually help keep the globus pallidus cell activity in check. Researchers found that carnosic acid, an isolate of rosemary extract, selectively binds to the affected channels, providing an avenue to reduce response to the drug in a relatively specific fashion.

“Only a subset of individuals are vulnerable to developing a substance use disorder, but we cannot yet identify who they are. If globus pallidus cell activity can effectively predict response to cocaine, it could be used to measure likely responses and thus serve as a biomarker for the most vulnerable,” Beier said. “Furthermore, it’s possible that carnosic acid could be given to those at high risk to reduce the response to cocaine.”

The next steps in this research include thoroughly assessing negative side effects of carnosic acid and determining the ideal dosage and timing. The team is also interested in testing its efficacy in reducing the desire for other drugs and in developing more potent and targeted variants.

In addition to UC Irvine researchers, scientists from the University of West Virginia and the University of Colorado participated in the study.

This work was supported by grants from the National Institutes of Health, One Mind, the Alzheimer’s Association, New Vision Research, BrightFocus Foundation, and the Brain & Behavior Research Foundation.

“Radiation exposure to the heart during lung cancer treatment can have very serious and immediate effects on a patient’s cardiovascular health,” said corresponding author Raymond Mak, MD, of the Department of Radiation Oncology at Brigham and Women’s Hospital. “We are hoping to inform not only oncologists and cardiologists, but also patients receiving radiation treatment, about the risks to the heart when treating lung cancer tumors with radiation.”

The emergence of artificial intelligence tools in health care has been groundbreaking and has the potential to positively reshape the continuum of care, including informing treatment plans for patients with cancer. Mass General Brigham, as one of the nation’s top integrated academic health systems and largest innovation enterprises, is leading the way in conducting rigorous research on new and emerging technologies to inform the responsible incorporation of AI into care delivery.

For patients receiving radiation therapy to treat non-small cell lung cancer (NSCLC), arrhythmias or irregular rhythms of the heart can be common. Because of the close proximity of the heart to the lungs and with NSCLC tumors being near or around the heart, the heart can receive collateral damage from radiation dose spillage meant to target the cancer tumors. Prior studies have found that this type of exposure to the heart is associated with general cardiac issues. However, this nuanced study demonstrated that the risk for different types of arrhythmias can vary significantly based on the pathophysiology and cardiac structures that are exposed to different levels of radiation.

In order to classify the types of arrhythmias that are associated with cardiac substructures receiving radiation, researchers conducted a retrospective analysis on 748 patients in Massachusetts, who were treated with radiation for locally advanced NSCLC. The arrhythmia subtypes cataloged included atrial fibrillation, atrial flutter, other supraventricular tachycardia, bradyarrhythmia, and ventricular tachyarrhythmia or asystole.

The team’s statistical analyses indicated that about one out of every six patients experienced at least one grade 3 arrhythmia with a median time of 2.0 years until the first arrhythmia. Grade 3 classifications are considered serious events that likely need intervention or require hospitalization. They also found that almost one-third of patients who experienced arrhythmias also suffered from major adverse cardiac events.

The arrhythmia classes outlined in the study did not entirely encompass the range of heart rhythm issues that are possible, but the authors note that these observations still create a better understanding of the possible pathophysiology pathways and potential avenues for minimizing cardiac toxicity after receiving radiation treatment. Their work also offers a predictive model for dose exposure and the type of expected arrhythmia.

For the future, the researchers believe that radiation oncologists should collaborate with cardiology experts to better understand the mechanisms of heart injuries and their connection to radiation treatment. In addition, they should take advantage of modern radiation treatment to actively sculpt radiation exposure away from the specific cardiac regions that are at high risk for causing arrhythmias. According to Mak, this study, alongside previous research, will help with surveillance, screening, and informing radiation oncologists on which parts of the heart to limit radiation exposure to, and in turn, mitigate complications.

“An interesting part of what we did was leverage artificial intelligence algorithms to segment structures like the pulmonary vein and parts of the conduction system to measure the radiation dose exposure in over 700 patients. This saved us many months of manual work,” said Mak. “So, not only does this work have potential clinical impact, but it also opens the door for using AI in radiation oncology research to streamline discovery and create larger datasets.”