The researchers found that Mic-628 works by attaching to CRY1, a protein that normally suppresses clock gene activity. This interaction encourages the formation of a larger molecular complex known as CLOCK-BMAL1-CRY1-Mic-628. Once formed, this complex switches on Per1 by acting at a specific DNA site called a “dual E-box.” Through this mechanism, Mic-628 shifts the timing of both the brain’s master clock located in the suprachiasmatic nucleus (SCN) and clocks in other organs, including the lungs. Notably, these clock shifts occurred together and did not depend on when the compound was given.

Faster Recovery From Jet Lag in Animal Tests

To test real-world relevance, the team used a mouse model designed to mimic jet lag by advancing the light-dark cycle by six hours (6-hour light-dark phase advance). Mice that received a single oral dose of Mic-628 adjusted to the new schedule much faster, taking four days instead of seven. Further mathematical analysis showed that this steady, one-direction shift forward is driven by a built-in feedback loop involving the PER1 protein, which helps stabilize the clock change.

Why Advancing the Clock Is So Difficult

Adjusting to earlier schedules, such as traveling east across time zones or working night shifts, requires the body clock to move forward. This type of adjustment is typically slower and more stressful for the body than delaying the clock. Common approaches like light exposure or melatonin depend heavily on precise timing and often produce uneven results. Because Mic-628 consistently advances the clock regardless of dosing time, it offers a fundamentally different drug-based approach to circadian reset.

What Comes Next for Mic-628

The researchers plan to continue studying Mic-628 to better understand its safety and effectiveness in additional animal studies and in humans. Since the compound reliably moves the body clock forward through a clearly defined biological pathway, it could become a model “smart drug” for addressing jet lag, sleep problems linked to shift work, and other disorders caused by circadian misalignment.

The findings were published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS).

The compound studied is called indole. It is produced by beneficial gut bacteria when they break down tryptophan, an amino acid found in foods like turkey and nuts. The results add to growing research focused on preventing metabolic dysfunction-associated steatotic liver disease (MASLD). This form of fatty liver disease affects both adults and children, but it often advances more quickly in children and is closely linked to diabetes.

“The prevalence of MASLD in children is about 30% in those with obesity and about 10% in children without obesity,” said Jed Friedman, Ph.D., director of the OU Health Harold Hamm Diabetes Center and professor of biochemistry and physiology in the OU College of Medicine. “Unfortunately, the risk is higher if a mother is obese or consumes a poor diet. The disease in children is silent and typically isn’t discovered until a parent seeks help for their child for liver-related symptoms.”

Testing the Role of the Microbiome

Friedman led the study alongside Karen Jonscher, Ph.D., associate professor of biochemistry and physiology in the OU College of Medicine. Their work was published in the journal eBioMedicine. The team set out to explore whether gut bacteria, known together as the microbiome, influence how fatty liver disease develops.

To investigate this, female mice were fed a high-fat, high-sugar (Western-style) diet throughout pregnancy and lactation. Some of the mice also received indole. After they were weaned, the offspring were placed on a standard diet and later switched to a Western-style diet to encourage the development of fatty liver disease.

“Because offspring inherit their microbiome from their mother, a poor maternal diet can shape the infant’s microbiome in harmful ways,” Friedman said.

Healthier Livers and Lasting Benefits

Offspring born to mothers that received indole showed multiple health advantages. They had healthier livers, gained less weight, maintained lower blood sugar levels, and developed smaller fat cells, even after being exposed to an unhealthy diet later in life. The researchers also observed activation of a protective gut pathway involving the acyl hydrocarbon receptor (AHR).

The study found no increase in harmful liver fats known as long-chain ceramides, while levels of beneficial very long-chain ceramides rose. In a key experiment, gut bacteria from the protected offspring were transferred to other mice that had not received indole. Those mice also experienced less liver damage, reinforcing the idea that the microbiome itself plays a central protective role.

Implications for Preventing Childhood MASLD

Although the research was conducted in animals and cannot yet be applied directly to humans, the findings point to new strategies for reducing the growing impact of MASLD through early prevention.

At present, weight loss is the only effective treatment option for pediatric MASLD once the disease is established, and there are no approved medications. “Anything we can do to improve the mother’s microbiome may help prevent the development of MASLD in the offspring,” Jonscher said. “That would be far better than trying to reverse the disease once it has already progressed.”

The study focuses on three major groups of calcifying plankton: coccolithophores, foraminifers, and pteropods. According to the authors, climate models often simplify or exclude these organisms, which can lead to an incomplete picture of how the ocean responds to climate change.

How Calcifying Plankton Shape the Carbon Cycle

When climate models leave out calcifying plankton, they may miss key steps in the global carbon cycle. These organisms build tiny shells made of calcium carbonate (CaCO₃), a substance that plays a central role in ocean chemistry. As plankton grow and die, they help move carbon from the atmosphere into deeper layers of the ocean.

This process, known as the ocean carbon pump, helps stabilize Earth’s climate over long periods of time. It also affects seawater chemistry and contributes to the formation of sediments that scientists use to study past climates.

“Plankton shells are tiny, but together they shape the chemistry of our oceans and the climate of our planet,” said Patrizia Ziveri, ICREA research professor at ICTA-UAB and lead author of the study. “By leaving them out of climate models, we risk overlooking fundamental processes that determine how the Earth system responds to climate change.”

The Missing Process of Shallow Dissolution

The researchers point out that much of the calcium carbonate produced by plankton does not sink all the way to the ocean floor. Instead, a significant portion dissolves in the upper ocean, a process known as “shallow dissolution.” This breakdown is driven by biological activity, including predation, clumping of particles, and microbial respiration.

Shallow dissolution changes ocean chemistry in important ways, yet it is largely missing from major Earth System Models (e.g. CMIP6) used in global climate assessments. Without accounting for this process, models may misjudge how carbon moves through the ocean and how the system responds to environmental stress.

Different Plankton Face Different Climate Threats

The study also emphasizes that not all calcifying plankton behave the same way. Each group has unique characteristics that influence where it lives, how it functions in marine ecosystems, and how vulnerable it is to climate change.

Coccolithophores are the largest producers of CaCO₃, but they are especially sensitive to ocean acidification because they lack specialized mechanisms to remove excess acidity from their cells. Foraminifers and pteropods do have such mechanisms, but they face other risks, including declining oxygen levels and rising ocean temperatures. Together, these organisms determine how carbon is stored and recycled in the ocean, and treating them as a single group can oversimplify the ocean’s response to climate pressures.

Improving Climate Models With Better Ocean Biology

The authors call for urgent efforts to measure how much calcium carbonate each plankton group produces, dissolves, and exports to deeper waters. They argue that incorporating these details into climate models would improve predictions of ocean and atmosphere interactions, long-term carbon storage, and the interpretation of sediment records used to reconstruct Earth’s climate history.

“If we ignore the ocean’s smallest organisms, we might miss important climate dynamics,” says Dr. Ziveri. “Integrating calcifying plankton into climate models could offer sharper predictions and deeper insights into how ecosystems and societies may be affected.”

The researchers conclude that closing these knowledge gaps is essential for building the next generation of climate models, ones that more accurately reflect the biological complexity of the oceans.

Both outbreaks had major consequences in the United States. The 2009 H1N1 flu pandemic led to 274,304 hospitalizations and 12,469 deaths. The COVID-19 pandemic has been even more devastating, with 1.2 million confirmed deaths reported so far.

Modeling the Spread Across Cities

The researchers aimed to understand how these pandemics traveled geographically in order to improve planning for future outbreaks. To do this, they combined detailed information about how each virus spreads with computer models that accounted for air travel, everyday commuting, and the possibility of superspreading events. Their analysis focused on more than three hundred metropolitan areas across the U.S.

Rapid Expansion Before Early Warnings

The simulations revealed that both pandemics were already circulating widely in most metro areas within just a few weeks. This widespread transmission often occurred before early case detection or government response measures were in place. Although H1N1 and COVID-19 followed different routes between locations, both relied on shared transmission hubs, including major metro areas such as New York and Atlanta. Air travel played a much larger role than commuting in driving this rapid spread. At the same time, unpredictable transmission patterns added significant uncertainty, making it difficult to anticipate where outbreaks would emerge in real time.

“The rapid and uncertain spread of the 2009 H1N1 flu and 2020 COVID-19 pandemics underscores the challenges for timely detection and control. Expanding wastewater surveillance coverage coupled with effective infection control could potentially slow the initial spread of future pandemics,” says the study’s senior author, Sen Pei, PhD, assistant professor of environmental health sciences at Columbia Mailman School.

Wastewater Surveillance and Pandemic Preparedness

Previous research has highlighted the value of wastewater surveillance as an early warning tool. This new study adds further support, showing that expanding wastewater monitoring could play an important role in improving pandemic preparedness and slowing early transmission.

Lessons Beyond H1N1 and COVID-19

In addition to reconstructing the spread of the last two pandemics, the researchers developed a flexible framework that can be used to study the early stages of other outbreaks. While human movement, especially air travel, is a major driver of pandemic spread, the team notes that other factors also influence how outbreaks unfold. These include population demographics, school calendars, winter holidays, and weather patterns.

The study’s first author is Renquan Zhang, Dalian University of Technology, Dalian, China. Additional authors include Rui Deng and Sitong Liu from Dalian University of Technology; Qing Yao and Jeffrey Shaman from Columbia University; Bryan T. Grenfell from Princeton; and Cécile Viboud from the National Institutes of Health.

For more than ten years, Jeffrey Shaman and colleagues, including Sen Pei, have worked to improve methods for tracking and simulating the spread of infectious diseases such as influenza and COVID-19. Their real-time forecasting tools estimate how quickly outbreaks grow, where they are likely to spread, and when they may peak, helping guide public health decision-making.