“This is the first study to describe the transfer of mobile genetic elements between maternal and infant microbiomes,” says senior study author Ramnik Xavier of the Broad Institute of MIT and Harvard. “Our study also, for the first time, integrated gut microbiome and metabolomic profiles from both mothers and infants and discovered links between gut metabolites, bacteria and breastmilk substrates. This investigation represents a unique perspective into the co-development of infant gut microbiomes and metabolomes under the influence of known maternal and dietary factors.”

Gut bacteria promote the maturation of the immune system in part through the production of microbial metabolites. The development of the infant gut microbiome follows predictable patterns, starting with transmission of microbes from the mother at birth. In addition to immune system maturation, microbial metabolites also influence early cognitive development. The perinatal period represents a critical window for cognitive and immune system development, promoted by maternal and infant gut microbiota and their metabolites. Nevertheless, the co-development of microbiomes and metabolomes during the perinatal period and the determinants of this process are not well understood.

To address this knowledge gap, Xavier and his colleagues tracked the co-development of microbiomes and metabolomes from late pregnancy to one year of age using longitudinal multi-omics data from a cohort of 70 mother-infant dyads. They discovered large-scale mother-to-infant interspecies transfer of mobile genetic elements, frequently involving genes associated with diet-related adaptations. Infant gut metabolomes were less diverse than maternal metabolomes but featured hundreds of unique metabolites and microbe-metabolite associations not detected in mothers. Metabolomes and serum cytokine signatures of infants who received regular, but not extensively hydrolyzed, formula were distinct from those of exclusively breastfed infants.

“The infant gut harbored thousands of unique metabolites, many of which were likely modified from breastmilk substrates by gut bacteria,” says Tommi Vatanen, co-first author on the study along with Karolina Jabbar, both of the Broad Institute of MIT and Harvard. “Many of these metabolites likely impact immune system and cognitive development.”

Pregnancy was associated with an increase in steroid compounds, including gonadal hormone derivatives and intermediates of bile acid biosynthesis, several of which were independently linked to impaired glucose tolerance. Although infant gut metabolomes were less diverse than maternal metabolomes, the researchers detected more than 2,500 infant-unique metabolomic features. Moreover, they identified numerous infant-specific associations of bacterial species and fecal metabolites, including neurotransmitters and immune modulators.

“We were surprised to find that maternal gut bacteria that were rarely observed in infants contributed to the infant gut microbiome structure,” says Xavier “We also found evidence that prophages — dormant bacteriophages, or viruses that reside on bacterial genomes — contribute to the exchange of mobile genetic elements between maternal and infant microbiomes.”

The authors say that the maternal microbiome may shape the infant gut microbiome through horizontal gene transfer, apart from classical vertical transmission of strains and species. Moreover, the identification of distinctive metabolomic profiles and microbe-metabolite interactions in the infant gut constitutes a platform for further study of microbial contributions to infant development.

One study limitation was that the researchers did not consider changes in diet and lifestyle between pregnancy and the postpartum period, which may have affected microbiome and metabolome alterations. In future studies, they plan to further explore linkages between bacteria and metabolites and investigate strain-specific bacterial metabolic output using isolated bacteria in vitro.

“Taken together, our integrative analysis expands the concept of vertical transmission of the gut microbiome and provides new insights into the development of maternal and infant microbiomes and metabolomes during late pregnancy and early life,” Xavier says.

This work was funded by the National Institutes of Health, the Juvenile Diabetes Research Foundation, the Center for Microbiome Informatics and Therapeutics, and the Wallenberg Foundations. Xavier is co-founder of Jnana Therapeutics and Celsius Therapeutics, Board Director at MoonLake Immunotherapeutics, and consultant to Nestlé; these organizations had no role in the study. All other authors declare no competing interests.

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“We studied a behavior in which larval zebrafish must remember past displacements to accurately maintain their location in space because, for instance, water flow can sweep them into dangerous areas of their natural environment,” says senior author Misha Ahrens of the Janelia Research Campus, Howard Hughes Medical Institute. “Yet it is unknown whether they explicitly track their location over long timescales and use memorized positional information to return to their earlier location — a behavior we term positional homeostasis. Such capabilities can be ethologically critical because larval zebrafish swim intermittently and are moved by currents during rest.”

Many animals keep track of where they are in their environment. They use self-location information for many important behaviors, such as efficiently returning to safe locations after visiting unknown and potentially dangerous areas, revisiting food-rich areas, and avoiding foraging in food-poor areas. While self-location is represented in the hippocampal formation, it is unknown how such representations arise, whether they exist in more ancient brain regions, and by what pathways they control locomotion.

“Such circuits have been difficult to pinpoint because neuroscience typically relies on recordings from cells in preselected brain regions that cover a small fraction of all neurons in the brain,” says first author En Yang of the Janelia Research Campus, Howard Hughes Medical Institute.

In the new study, the researchers set out to identify complete navigational circuits in larval zebrafish, from motion integrators to premotor centers, by exhaustively imaging and analyzing the entire brain at cellular resolution during a behavior that relies on self-localization. Access to more than 100,000 neurons per animal revealed brain regions that were previously unknown to be involved in self-localization, leading to the discovery of a multiregional hindbrain circuit mediating a transformation from velocity, through displacement memory, to behavior.

“Our results reveal a neural system for self-localization and associated behavior in the vertebrate hindbrain and provide a circuit-level, representational, and control-theoretic understanding of its function. The system functions in a closed-loop with dynamic environments, and the environment-brain-behavior loop encompasses integration, neural representations of self-location, and motor control,” Ahrens says. “These results demonstrate the need to consider brains at the holistic level and to unify systems neuroscience concepts — such as self-localization and motor control — that are often studied separately.”

Whole-brain functional imaging revealed not only the existence of positional homeostasis in larval zebrafish, but also how the brain identifies and corrects changes in zebrafish location. The underlying circuit computes self-location in the dorsal brainstem by integrating visual information to form a memory of past displacements as the animal actively or passively changes its location. This self-location representation is read out by the inferior olive as a long-lasting positional error signal, reflecting the difference between the fish’s original and current position. This signal is transformed into locomotor output that corrects for accumulated displacements over the course of many seconds.

The authors say this multiregional circuit has potential anatomical and functional homologues in mammals and may interact with other known representations of self-location. Moreover, this work connects self-localization and olivocerebellar motor control and establishes the vertebrate hindbrain as a neural control center for goal-directed navigational behavior.

“Our results on location memory and positional homeostasis resonate with the idea that evolutionarily ancient brain regions contribute centrally to higher-order behaviors,” Ahrens says. “The idea that cognitive processes are widely distributed across the nervous system aligns with the evolutionary proposition that complex behaviors emerged, in part, by building new circuits on top of ancient brain structures that perform related computations. Brain-wide surveys of neural activity may thus be critical for determining the mechanisms of distributed cognitive function.”

This work was supported by the Howard Hughes Medical Institute and by the Simons Foundation.

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“We know that AMD starts in the outer blood-retina barrier,” said Kapil Bharti, Ph.D., who heads the NEI Section on Ocular and Stem Cell Translational Research. “However, mechanisms of AMD initiation and progression to advanced dry and wet stages remain poorly understood due to the lack of physiologically relevant human models.”

The outer blood-retina barrier consists of the retinal pigment epithelium (RPE), separated by Bruch’s membrane from the blood-vessel rich choriocapillaris. Bruch’s membrane regulates the exchange of nutrients and waste between the choriocapillaris and the RPE. In AMD, lipoprotein deposits called drusen form outside Bruch’s membrane, impeding its function. Over time, the RPE break down leading to photoreceptor degeneration and vision loss.

Bharti and colleagues combined three immature choroidal cell types in a hydrogel: pericytes and endothelial cells, which are key components of capillaries; and fibroblasts, which give tissues structure. The scientists then printed the gel on a biodegradable scaffold. Within days, the cells began to mature into a dense capillary network.

On day nine, the scientists seeded retinal pigment epithelial cells on the flip side of the scaffold. The printed tissue reached full maturity on day 42. Tissue analyses and genetic and functional testing showed that the printed tissue looked and behaved similarly to native outer blood-retina barrier. Under induced stress, printed tissue exhibited patterns of early AMD such as drusen deposits underneath the RPE and progression to late dry stage AMD, where tissue degradation was observed. Low oxygen induced wet AMD-like appearance, with hyperproliferation of choroidal vessels that migrated into the sub-RPE zone. Anti-VEGF drugs, used to treat AMD suppressed this vessel overgrowth and migration and restored tissue morphology.

“By printing cells, we’re facilitating the exchange of cellular cues that are necessary for normal outer blood-retina barrier anatomy,” said Bharti. “For example, presence of RPE cells induces gene expression changes in fibroblasts that contribute to the formation of Bruch’s membrane — something that was suggested many years ago but wasn’t proven until our model.”

Among the technical challenges that Bharti’s team addressed were generating a suitable biodegradable scaffold and achieving a consistent printing pattern through the development of a temperature-sensitive hydrogel that achieved distinct rows when cold but that dissolved when the gel warmed. Good row consistency enabled a more precise system of quantifying tissue structures. They also optimized the cell mixture ratio of pericytes, endothelial cells, and fibroblasts.

Co-author Marc Ferrer, Ph.D., director of the 3D Tissue Bioprinting Laboratory at NIH’s National Center for Advancing Translational Sciences, and his team provided expertise for the biofabrication of the outer blood-retina barrier tissues “in-a-well,” along with analytical measurements to enable drug screening.

“Our collaborative efforts have resulted in very relevant retina tissue models of degenerative eye diseases,” Ferrer said. “Such tissue models have many potential uses in translational applications, including therapeutics development.”

Bharti and collaborators are using printed blood-retina barrier models to study AMD, and they are experimenting with adding additional cell types to the printing process, such as immune cells, to better recapitulate native tissue.

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“To effectively prevent all tipping risks, the global mean temperature increase would need to be limited to no more than one degree — we are currently already at about 1.2 degrees,” Jonathan Donges, Co-Lead of the FutureLab on Earth Resilience in the Anthropocene at PIK adds. “The latest IPCC report is showing that we’re most likely on a path to temporarily overshoot the 1.5 degrees Celsius temperature threshold.”

Emergence of at least one tipping event increases with rising peak temperatures

To arrive at these results, the scientists, together with co-authors from the Earth Commission — a group of leading scientists convened by Future Earth — used different global warming overshoot scenarios with peak temperatures from two to four degrees and applied these to a set of four interacting tipping elements: the Greenland Ice Sheet, the West Antarctic Ice Sheet, the Atlantic Meridional Overturning Circulation AMOC, and the Amazon rainforest. The researchers applied a risk analysis approach based on millions of model simulations to reflect the uncertainties in relevant parameters such as the uncertainty in critical temperature thresholds as well as interaction strengths and interaction structure. Such an amount of simulations would be computationally too expensive to do based on fully coupled Earth System Model simulations. For the different overshoot scenarios, the research team then analyzed the risk of crossing critical thresholds and the potential for triggering cascading interactions between the four elements, depending on the magnitude and duration of the overshoot as well as the warming remaining on the long-term.

“We found that the risk for the emergence of at least one tipping event increases with rising peak temperatures — already at a peak temperature of three degrees Celsius, more than one third of all simulations showed a tipping event even when overshoot durations were limited strongly. At four degrees Celsius peak temperature, this risk extends to more than half of all simulations,” explains Nico Wunderling.

Tipping mechanisms under warming overshoots

“Especially the Greenland and the West Antarctic ice sheet are at risk of tipping even for small overshoots, underlining that they are among the most vulnerable tipping elements. While it would take a long time for the ice loss to fully unfold, the temperature levels at which such changes are triggered could already be reached soon,” says Ricarda Winkelmann, Earth Commissioner and Co-Lead of the FutureLab on Earth Resilience in the Anthropocene. “Our action in the coming years can thus decide the future trajectory of the ice sheets for centuries or even millennia to come.” The other two tipping elements considered in the study, the AMOC and Amazon rainforest, have higher critical temperature thresholds. Yet, they would react much faster once the tipping process has started. Therefore, it is much more difficult to stop their tipping process once initiated by a temporary global warming overshoot.

Current mitigation policies are expected to lead to 2-3.6 degrees Celsius of global warming by the end of this century. “This is not enough. Even though a temporary temperature overshoot would definitely be better than reaching a peak temperature and remaining there, some of the overshoot impacts may lead to irreversible damages in a high climate risk zone and this is why low-temperature overshoots are key here,” explains Jonathan Donges. Ricarda Winkelmann adds: “Every tenth of a degree counts. We must do what we can to limit global warming as quickly as possible.”

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To better understand the magnitude of the gun violence crisis and put it in perspective, researchers at Brown University and the University of Pennsylvania compared the risk of firearm-related death for young adult men living in the most violent areas in four major U.S. cities with the risks of combat death and injury faced by U.S. military personnel who served in Afghanistan and Iraq during active periods of war.

The results were mixed: The study, published in JAMA Network Open, found that young men from zip codes with the most firearm violence in Chicago and Philadelphia faced a notably higher risk of firearm-related death than U.S. military personnel deployed to wartime service in Afghanistan and Iraq. But the opposite was true in two other cities: The most violent areas in New York and Los Angeles were associated with much less risk for young men than those in the two wars.

In all zip codes studied, risks were overwhelmingly borne by young men from minority racial and ethnic groups, the study found.

“These results are an urgent wake-up call for understanding, appreciating and responding to the risks and attendant traumas faced by this demographic of young men,” said Brandon del Pozo, an assistant professor of medicine (research) at Brown’s Warren Alpert Medical School and an assistant professor of health services, policy and practice (research) at the University’s School of Public Health.

Del Pozo conducts research at the intersection of public health, public safety and justice, focusing on substance use, the overdose crisis, and violence. His recently released book, “The Police and the State: Security, Social Cooperation, and the Public Good,” is based on his academic research as well as his 23 years of experience as a police officer in New York City and as chief of police of Burlington, Vermont.

“Working as a police officer, I witnessed the toll of gun violence, and how disruptive it was for families and communities,” del Pozo said. “It stood out to me that the burden was not distributed evenly by geography or demographic. Some communities felt the brunt of gun violence much more acutely than others. By analyzing publicly available data on firearm fatalities in cities and in war, we sought to place that burden in sharp relief.”

At the same time, del Pozo said, he and the other study authors were responding to oft-repeated inflammatory claims about gun violence in American cities.

“We often hear opposing claims about gun violence that fall along partisan lines: One is that big cities are war zones that require a severe crackdown on crime, and the other is that our fears about homicides are greatly exaggerated and don’t require drastic action,” del Pozo said. “We wanted to use data to explore these claims — and it turns out both are wrong. While most city residents are relatively safe from gun violence, the risks are more severe than war for some demographics.”

Illustrating the magnitude of the firearm crisis

To conduct their analysis, the researchers obtained information on all fatal and nonfatal shootings of 18- to 29-year-old men recorded as crimes in 2020 and 2021 in Chicago; Los Angeles; New York; and Philadelphia — the four largest U.S. cities for which public data on those who were shot were available. For New York, Chicago and Philadelphia, they used shooting death and injury data sets made public by each city; for Los Angeles, they extracted firearm death and injury data from a larger public data set of recorded crimes. Data were aggregated to the zip code level and linked to corresponding demographic characteristics from the U.S. Census Bureau’s 2019 American Community Survey.

The researchers acquired wartime combat-related mortality and injury counts for the conflicts in Iraq and Afghanistan from peer-reviewed analyses of U.S. military data covering the years 2001 to 2014 for the war in Afghanistan and 2003 to 2009 for the war in Iraq, both of which were periods of active combat. Because there is limited data about the risks of serving in different military units at different times during the Afghanistan and Iraq wars, the researchers considered the mortality and injury data of a single, de-identified Army brigade combat team engaged in combat during a 15-month period of the Iraq War that involved notably above-average combat death and injury rates at a time considered to be the height of the conflict.

The analysis included 129,826 young men residing in the four cities considered in the study.

The researchers found that compared to the risk of combat death faced by U.S. soldiers who were deployed to Afghanistan, the more dangerous of the two wars, young men living in the most violent zip code of Chicago (2,585 individuals) had a 3.23 times higher average risk of firearm-related homicide, and those in Philadelphia (2,448 people) faced a 1.9 times higher average risk of firearm-related homicide. Singling out the elevated dangers faced by the U.S. Army combat brigade in Iraq, the young men studied in Chicago still faced notably greater risks, and the ones faced in Philadelphia were comparable.

However, these findings were not observed in the most violent zip codes of Los Angeles and New York, where young men faced a 70% to 91% lower risk than soldiers in the Afghanistan war across fatal and nonfatal categories.

When the researchers looked at the demographics of the young men in the zip codes studied, they determined that the risk of violent death and injury observed in the zip codes studied was almost entirely borne by individuals from minority racial and ethnic groups: Black and Hispanic males represented 96.2% of those who were fatally shot and 97.3% of those who experienced nonfatal injury across all four cities.

In the study, the researchers make the point that the risk of firearm death is not the only thing that young men living in violent U.S. zip codes have in common with young men at war.

“Exposure to combat has been associated with stress-inducing hypervigilance and elevated rates of homelessness, alcohol use, mental illness and substance use, which, in turn, are associated with a steep discounting of future rewards,” they write. “Our findings — which show that young men in some of the communities we studied were subject to annual firearm homicide and violent injury rates in excess of 3.0% and as high as 5.8% — lend support to the hypothesis that beyond the deaths and injuries of firearm violence, ongoing exposure to these violent events and their risks are a significant contributor to other health problems and risk behaviors in many U.S. communities.”

Del Pozo added that the health risks are likely even higher for people in cities, because they need to face their “battles” every day over a lifetime, as opposed to military personnel in a tour of duty in Afghanistan, which typically lasted 12 months. The study results, del Pozo said, help illustrate the magnitude of the firearms crisis, a necessary understanding to municipalities seeking to formulate an effective public health response.

“The findings suggest that urban health strategies should prioritize violence reduction and take a trauma-informed approach to addressing the health needs of these communities,” del Pozo said.

Other Brown contributors included Dr. Michael J. Mello, a physician and researcher at the Warren Alpert Medical School and the Injury Prevention Center at Rhode Island Hospital.

The study was supported by the National Institute on Drug Abuse (K01DA056654) and the National Institute of General Medical Sciences (P20GM139664).

Imaging light in deep tissues is extremely difficult because as light travels into tissue, much of it is either absorbed or scattered. The MIT team overcame that obstacle by designing a sensor that converts light into a magnetic signal that can be detected by MRI (magnetic resonance imaging).

This type of sensor could be used to map light emitted by optical fibers implanted in the brain, such as the fibers used to stimulate neurons during optogenetic experiments. With further development, it could also prove useful for monitoring patients who receive light-based therapies for cancer, the researchers say.

“We can image the distribution of light in tissue, and that’s important because people who use light to stimulate tissue or to measure from tissue often don’t quite know where the light is going, where they’re stimulating, or where the light is coming from. Our tool can be used to address those unknowns,” says Alan Jasanoff, an MIT professor of biological engineering, brain and cognitive sciences, and nuclear science and engineering.

Jasanoff, who is also an associate investigator at MIT’s McGovern Institute for Brain Research, is the senior author of the study, which appears today in Nature Biomedical Engineering. Jacob Simon PhD ’21 and MIT postdoc Miriam Schwalm are the paper’s lead authors, and Johannes Morstein and Dirk Trauner of New York University are also authors of the paper.

A light-sensitive probe

Scientists have been using light to study living cells for hundreds of years, dating back to the late 1500s, when the light microscope was invented. This kind of microscopy allows researchers to peer inside cells and thin slices of tissue, but not deep inside an organism.

“One of the persistent problems in using light, especially in the life sciences, is that it doesn’t do a very good job penetrating many materials,” Jasanoff says. “Biological materials absorb light and scatter light, and the combination of those things prevents us from using most types of optical imaging for anything that involves focusing in deep tissue.”

To overcome that limitation, Jasanoff and his students decided to design a sensor that could transform light into a magnetic signal.

“We wanted to create a magnetic sensor that responds to light locally, and therefore is not subject to absorbance or scattering. Then this light detector can be imaged using MRI,” he says.

Jasanoff’s lab has previously developed MRI probes that can interact with a variety of molecules in the brain, including dopamine and calcium. When these probes bind to their targets, it affects the sensors’ magnetic interactions with the surrounding tissue, dimming or brightening the MRI signal.

To make a light-sensitive MRI probe, the researchers decided to encase magnetic particles in a nanoparticle called a liposome. The liposomes used in this study are made from specialized light-sensitive lipids that Trauner had previously developed. When these lipids are exposed to a certain wavelength of light, the liposomes become more permeable to water, or “leaky.” This allows the magnetic particles inside to interact with water and generate a signal detectable by MRI.

The particles, which the researchers called liposomal nanoparticle reporters (LisNR), can switch from permeable to impermeable depending on the type of light they’re exposed to. In this study, the researchers created particles that become leaky when exposed to ultraviolet light, and then become impermeable again when exposed to blue light. The researchers also showed that the particles could respond to other wavelengths of light.

“This paper shows a novel sensor to enable photon detection with MRI through the brain. This illuminating work introduces a new avenue to bridge photon and proton-driven neuroimaging studies,” says Xin Yu, an assistant professor radiology at Harvard Medical School, who was not involved in the study.

Mapping light

The researchers tested the sensors in the brains of rats — specifically, in a part of the brain called the striatum, which is involved in planning movement and responding to reward. After injecting the particles throughout the striatum, the researchers were able to map the distribution of light from an optical fiber implanted nearby.

The fiber they used is similar to those used for optogenetic stimulation, so this kind of sensing could be useful to researchers who perform optogenetic experiments in the brain, Jasanoff says.

“We don’t expect that everybody doing optogenetics will use this for every experiment — it’s more something that you would do once in a while, to see whether a paradigm that you’re using is really producing the profile of light that you think it should be,” Jasanoff says.

In the future, this type of sensor could also be useful for monitoring patients receiving treatments that involve light, such as photodynamic therapy, which uses light from a laser or LED to kill cancer cells.

The researchers are now working on similar probes that could be used to detect light emitted by luciferases, a family of glowing proteins that are often used in biological experiments. These proteins can be used to reveal whether a particular gene is activated or not, but currently they can only be imaged in superficial tissue or cells grown in a lab dish.

Jasanoff also hopes to use the strategy used for the LisNR sensor to design MRI probes that can detect stimuli other than light, such as neurochemicals or other molecules found in the brain.

“We think that the principle that we use to construct these sensors is quite broad and can be used for other purposes too,” he says.

The research was funded by the National Institutes of Health, the G. Harold and Leyla Y. Mathers Foundation, a Friends of the McGovern Fellowship from the McGovern Institute for Brain Research, the MIT Neurobiological Engineering Training Program, and a Marie Curie Individual Fellowship from the European Commission.

The team, which includes researchers from the University of York and the British Museum, analysed the remains of 1,226 pottery vessels from 156 hunter-gatherer sites across nine countries in Northern and Eastern Europe. They combined radiocarbon dating, together with data on the production and decoration of ceramic vessels, and analysis of the remains of food found inside the pots.

Their findings, published in the journal Nature Human Behaviour, suggest that pottery-making spread rapidly westwards from 5,900 BCE onwards and took only 300-400 years to advance over 3,000 km, equivalent to 250 km in a single generation.

Professor Oliver Craig, from the University of York’s Department of Archaeology, said: “Our analysis of the ways pots were designed and decorated as well as new radiocarbon dates suggests that knowledge of pottery spread through a process of cultural transmission.

“By this we mean that the activity spread by the exchange of ideas between groups of hunter-gatherers living nearby, rather than through migration of people or an expanding population as we see for other key changes in human history such as the introduction of agriculture.”

“That methods of pottery-making spread so far and so fast through the passing on of ideas is quite surprising. Specific knowledge may have been shared through marriages or at centres of aggregation, specific points in the landscape where groups of hunter-gatherers came together perhaps at certain times of the year.”

By studying traces of organic materials left in the pots, the team demonstrated that the pottery was used for cooking, so the ideas of pottery-making may have been spread through shared culinary traditions.

Carl Heron, from the British Museum, said: “We found evidence that the vessels were used for cooking a wide range of animals, fish and plants, and this variety suggests that the drivers for making the pottery were not in response to a particular need, such as detoxifying plants or processing fish, as has previously been suggested.

“We also found patterns suggesting that pottery use was transmitted along with knowledge of their manufacture and decoration. These can be seen as culinary traditions that were rapidly transmitted with the artefacts themselves.”

The world’s earliest pottery containers come from East Asia and may have spread rapidly eastwards through Siberia, before being taken up by hunter-gatherer societies across Northern Europe, long before the arrival of farming.

This research is funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme.

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