Publisher Health

Entropy is often associated with disorder and chaos, but in biology it is related to energy efficiency and is closely linked to metabolism, the set of chemical reactions that sustain life. An international research team led by the Universities of Barcelona and Padua, with the participation of Göttingen University and the Universities Complutense and Francisco de Vitoria in Madrid, has now developed a novel methodology for the measurement of entropy production at the scale of a nanometer, meaning one-billionth of a meter. The new approach enabled the scientists to measure the heat flow, known as the entropy production rate, of single red blood cells. The research was published in Science.
Researchers used a new way to measure the heat flow from the active metabolic forces inside the red blood cells by quantifying the increasing entropy by simply observing the continuous and erratic fluctuations of the red blood cell membrane. To ensure that this approach works, the researchers also created more complex approaches, where small, micrometre-sized particles were glued to the membrane which could not only be used to measure the fluctuations of the membrane, but also to apply minuscule forces that are created by simply illuminating the particles with light. Such colloidal particles — small solid particles suspended in a fluid phase — can be seen as an excellent way to measure and also manipulate the motion of the living cells’ membrane. For their calculations using actual red blood cells, the researchers used experimental approaches based on direct optical manipulation of the membrane, but also optical sensing, and ultrafast live-imaging microscopy. The researchers at the University of Göttingen contributed by carrying out sensitive and precise experiments: “We developed an experiment that used photons, by which we mean light, to hold the cells so gently that the delicate heat flux was not perturbed by the light, but still strong enough to measure its effects,” says Professor Timo Betz, from the Biophysics Institute in Göttingen.
“Heat is a symptom of cell health, and this finding could open up new ways to determine tissue health,” explains lead researcher Professor Felix Ritort, Institute of Nanoscience and Nanotechnology, University of Barcelona. He adds: “Characterizing the entropy production in living systems is crucial for understanding the efficiency of energy conversion processes.”
There is great interest in measuring entropy production in physical and biological systems because they are relevant to so many other systems. “This breakthrough has far-reaching implications for our understanding of metabolism and energy transport in living systems,” says Betz. “In addition, these findings may prove useful for applications in health and medicine, or guide the way to develop new smart materials that exploit a controlled entropy production rate to create a response to small external stimuli.”

More than 70% of American Indian young adults aged 20-39 and 50% of American Indian teens have cholesterol levels or elevated fat in the blood that put them at risk for cardiovascular disease, suggests a study supported by the National Institutes of Health. In some cases, these levels — specifically high low-density lipoprotein (LDL) cholesterol, often thought of as “bad cholesterol,” — were linked to plaque buildup and cardiovascular events, such as heart attack and stroke.
The findings, published in the Journal of the American Heart Association, came from a 19-year-review of the Strong Heart Family Study, part of the Strong Heart Study — the largest study of cardiovascular health outcomes and risk factors among American Indian adults. Researchers followed more than 1,400 participants, ages 15-39, between 2001-2003 and 2020. At the beginning of the study, 55% of participants ages 15-19 had abnormal cholesterol levels, as did 74% of those ages 20-29, and 78% of those ages 30-39.
“We were surprised about the numbers, especially in adolescents,” said Jessica A. Reese, Ph.D., an epidemiologist in the Center for American Indian Health Research at the University of Oklahoma Health Sciences Center, Oklahoma City. “These findings show the importance of early screenings and interventions, especially for teens and young adults who may be more likely to have underlying cardiovascular risks, diabetes, or chronic liver disease.”
The researchers defined a person’s cholesterol as abnormal if they had either high total cholesterol; high LDL cholesterol or other types of “bad” cholesterol; moderately-high triglycerides; low HDL cholesterol, often thought of as “good cholesterol”; or if they had been prescribed cholesterol-lowering medication.
About 40% of study participants had high LDL levels (at least 100 mg/dL), while nearly 3% had very high levels (at least 160 mg/dL). However, less than 2% of participants with very high LDL cholesterol took cholesterol-lowering medication at the start of the study.
“This research supports efforts to identify ways, such as increased screenings and culturally relevant education, to improve heart health and support younger generations of Native Americans,” said Mona Puggal, M.P.H., an epidemiologist in the Division of Cardiovascular Sciences at the National Heart, Lung, and Blood Institute (NHLBI), part of NIH.
Heart disease is twice as high in American Indian adults compared to the general U.S. population. Abnormal cholesterol levels seen among participants in the current study were also twice as high as abnormal levels seen in the general population of U.S. teens and young adults. Researchers underscored the value of routine check-ins and screenings. All participants in this observational study were also notified about their lab work and imaging results after their physical exam and researchers encouraged them to take the results to their healthcare providers.

At the start of the study, 1,165 participants had ultrasounds of the carotid artery, an artery in the neck that carries blood from the heart to the brain. Approximately 61 (5%) showed signs of plaque or early plaque development. Plaque can prohibit blood flow to the heart or rupture when too much of it accumulates in an artery, and that can lead to a stroke or need for surgery.
About 5.5 years after the baseline measurements, 19 participants — about one-third of those with detectable plaque — had signs of their plaque getting worse. Among the 1,104 who did not have detectable plaque at the beginning, 109 (10%) had signs of it during the second check-in. Researchers linked high levels of LDL cholesterol, total cholesterol, and other non-HDL cholesterol to these outcomes.
By the end of the study, approximately 127 participants (9%) had experienced a heart attack, stroke, heart failure, or a related heart surgery or death. Participants who had diabetes and at least a few cardiovascular risks, such as having a large waistline, high blood sugar, high triglycerides, high blood pressure, or low levels of HDL cholesterol, were also more likely to have cardiovascular events.
To support early risk detection, researchers emphasized the importance of youth staying connected to health care providers.
“It’s important for everyone to work with their physician to annually check their blood cholesterol and blood sugar, which can support a healthy life later on,” said Ying Zhang, M.D., Ph.D., Director at the Center for American Indian Health Research at the University of Oklahoma Health Sciences Center. “It’s also vital that annual care is coordinated as youth mature from seeing pediatricians to adult health care providers.”
To learn more about cholesterol and heart health, visit: https://www.nhlbi.nih.gov/resources/cholesterol-your-heart-what-you-need-know-fact-sheet
This research was funded by NHLBI.

According to a new study, there is mounting evidence that nature can help humans address the time pressure of contemporary urban lifestyles by contributing to the regulation of human sense of time. A better understanding of the relationship between natural environments and human time perception can help design healthier living environments.
Time is a central dimension of present-day lifestyles and popular expressions such as “time is money” or “spending time” showcase the importance humans attribute to time. This is particularly true for people living in fast-paced urban environments who are often forced to regulate their daily dynamics according to the ticking clock rather than the rhythms of nature.
This emphasis on clock time is taking a toll on human cognitive processes and affects people’s well-being negatively, as evidenced by a growing number of people reporting a feeling of time scarcity. Could reconnecting with nature and its rhythms allow us to regain a healthier relationship with time?
“Time perception in humans is highly subjective and regulated by a complex interaction of factors related to attention, memory, emotions and physical status. As an example, time may seem like it is standing still while stuck in traffic on the way to meet a friend, and then it may fly by quickly while having fun together,” says Dr Ricardo Correia, Assistant Professor at the University of Turku, Finland. “Living in cities and everything it entails puts a strain on the processes that influence how we perceive time. In contrast, nature is known to have a restorative effect for humans and may help us to recover a more balanced sense of time.”
In a recent study, Ricardo Correia reviewed the scientific literature on the relationship between human temporal perception and natural environments and found that nature experiences contribute positively to at least two dimensions of human time perception: temporal duration and temporal perspective.
Temporal duration relates to how humans understand and experience the length and flow of time. Various studies suggest that people experience the same duration of time spent in urban or natural environments differently. Specifically, people tend to overestimate how long they have been in nature and thus time seems to last longer in natural environments. This may give people a sense of “gaining time” while experiencing nature and can help to balance feelings that time is always rushing by and is never enough, which are commonly associated with a perception of time scarcity.
There is also strong evidence that people’s temporal perspective changes between natural and urban environments. Temporal perspective reflects the human capacity to focus on the past, present or future and mentally “time-travel” between them. Some people have a tendency to reminisce about the past, for example, due to trauma or nostalgia, while others live in the present and seek to enjoy the moment. In addition, there are people who are goal-driven and thus tend to focus on the future. Too much emphasis on a single negative perspective is often associated with risky behaviours and can be indicative of poor mental well-being. Being in nature can help people to flow between different temporal frames and develop a more positive and balanced time perspective.
“Put together, the existing evidence strongly suggests that nature experiences play an important role in regulating and maintaining a healthy sense of time, and I think the impact of nature on human well-being should be better recognised” affirms Dr Ricardo Correia. “Furthermore, we lack detailed information about which elements of nature or nature experiences regulate our time perception the most. Developing a better understanding of these aspects can provide important information that helps us to design our cities and parks so that they boost our collective well-being.”

Researchers from the Broad Institute of MIT and Harvard, Harvard Medical School, and McLean Hospital have uncovered a strikingly similar suite of changes in gene activity in brain tissue from people with schizophrenia and from older adults. These changes suggest a common biological basis for the cognitive impairment often seen in people with schizophrenia and in the elderly.
In a study published in Nature, the team describes how they analyzed gene expression in more than a million individual cells from postmortem brain tissue from 191 people. They found that in individuals with schizophrenia and in older adults without schizophrenia, two brain cell types called astrocytes and neurons reduced their expression of genes that support the junctions between neurons called synapses, compared to healthy or younger people. They also discovered tightly synchronized gene expression changes in the two cell types: when neurons decreased the expression of certain genes related to synapses, astrocytes similarly changed expression of a distinct set of genes that support synapses.
The team called this coordinated set of changes the Synaptic Neuron and Astrocyte Program (SNAP). Even in healthy, young people, the expression of the SNAP genes always increased or decreased in a coordinated way in their neurons and astrocytes.
“Science often focuses on what genes each cell type expresses on its own,” said Steve McCarroll, a co-senior author on the study and an institute member at the Broad Institute. “But brain tissue from many people, and machine-learning analyses of those data, helped us recognize a larger system. These cell types are not acting as independent entities, but have really close coordination. The strength of those relationships took our breath away.”
Schizophrenia is well-known for causing hallucinations and delusion, which can be at least partly treated with medications. But it also causes debilitating cognitive decline, which has no effective treatments and is common in aging as well. The new findings suggest that the cognitive changes in both conditions might involve similar cellular and molecular alterations in the brain.
“To detect coordination between astrocytes and neurons in schizophrenia and aging, we needed to study tissue samples from a very large number of individuals,” said Sabina Berretta, a co-senior author of the study, an associate professor at Harvard Medical School, and a researcher in the field of psychiatric disorders. “Our gratitude goes to all donors who chose to donate their brain to research to help others suffering from brain disorders and to whom we’d like to dedicate this work.”
McCarroll is also director of genomic neurobiology for the Broad’s Stanley Center for Psychiatric Research and a professor at Harvard Medical School. Berretta also directs the Harvard Brain Tissue Resource Center (HBTRC), which provided tissue for the study. Emi Ling, a postdoctoral researcher in McCarroll’s lab, was the study’s first author.

SNAP insights
The brain works in large part because neurons connect with other neurons at synapses, where they pass signals to one another. The brain constantly forms new synapses and prunes old ones. Scientists think new synapses help our brains stay flexible, and studies — including previous efforts by scientists in McCarroll’s lab and international consortia — have shown that many genetic factors linked to schizophrenia involve genes that contribute to the function of synapses.
In the new study, McCarroll, Berretta, and colleagues used single-nucleus RNA sequencing, which measures gene expression in individual cells, to better understand how the brain naturally varies across individuals. They analyzed 1.2 million cells from94 people with schizophrenia and 97 without.
They found that when neurons boosted expression of genes that encode parts of synapses, astrocytes increased the expression of a distinct set of genes involved in synaptic function. These genes, which make up the SNAP program, included many previously identified risk factors for schizophrenia. The team’s analyses indicated that both neurons and astrocytes shape genetic vulnerability for the condition.
“Science has long known that neurons and synapses are important in risk for schizophrenia, but by framing the question a different way — asking what genes each cell type regulates dynamically — we found that astrocytes too are likely involved,” said Ling.
To their surprise, the researchers also found that SNAP varied greatly even among people without schizophrenia, suggesting that SNAP could be involved in cognitive differences in healthy humans. Much of this variation was explained by age; SNAP declined substantially in many — but not all — older individuals, including both people with and without schizophrenia.

With better understanding of SNAP, McCarroll says he hopes it might be possible to identify life factors that positively influence SNAP, and develop medicines that help stimulate SNAP, as a way to treat the cognitive impairments of schizophrenia or help people maintain their cognitive flexibility as they age.
In the meantime, McCarroll, Berretta, and their team are working to understand if these changes are present in other conditions such as bipolar disorder and depression. They also aim to uncover the extent to which SNAP appears in other brain areas, and how SNAP affects learning and cognitive flexibility.
Funding:
This work was supported by the Stanley Family Foundation, the Simons Collaboration on Plasticity and the Aging Brain, and the National Institute of Mental Health and the National Human Genome Research Institute at the National Institutes of Health.

There is perhaps no bodily function more essential for humans and other mammals than breathing. With each breath, we suffuse our bodies with oxygen-rich air that keeps our organs and tissues healthy and working properly — and without oxygen, we can survive mere minutes.
But sometimes, our breathing becomes restricted, whether due to infection, allergies, exercise, or some other cause, forcing us to take deep, gasping breaths to quickly draw in more air.
Now, researchers at Harvard Medical School have identified a previously unknown way in which the body counteracts restricted breathing — a new reflex of the vagus nerve that initiates deep breathing. Their work is published March 6 in Nature.
The research, conducted in mice, reveals a rare and mysterious cell type in the lungs that detects airway closure and relays the signal to the vagus nerve — the information highway that connects the brain to almost every major organ. After the signal reaches the brain, a gasping reflex is initiated that helps the animal compensate for the lack of air.
“Our airway sensations are some of our most vital and powerful for survival, but a lot of the neural pathways within the airways are poorly understood. We found a fundamental pathway for how the body monitors lung openness and the efficiency of the respiratory system to control breathing,” said lead author Michael Schappe, a research fellow in neurobiology at HMS.
Although the research remains to be confirmed in humans, these findings provide valuable insight into how the brain and body are connected to monitor and modulate respiration — and could offer a starting point for understanding what happens when respiration goes wrong.
The mystery of orphan neurons
Study senior author Stephen Liberles, professor of cell biology in the Blavatnik Institute at HMS, is broadly interested in how the brain and body work together to control various physiologic functions, including how the brain processes information from internal organs, senses infections such as influenza, and suppresses nausea.

As Schappe, Liberles, and their team began investigating the respiratory system, they realized there are many different types of neurons in the lungs, but little is known about what some of these neurons actually do.
“We were excited by the idea that these mysterious ‘orphan neurons’ could be involved in body-brain reflexes that have remained hidden and uncharacterized,” Liberles said.
In the 1860s, scientists discovered the Hering-Breuer reflex, which protects the lungs from over-inflation. This reflex occurs when neurons in the lungs detect that the airway is being stretched and quickly signal the body to exhale and breathe less deeply.
The researchers suspected that there might be a second, inverse respiratory reflex that occurs when neurons sense that the airway is getting restricted, lung volume is reduced, and the body needs to take in more air. The resulting sensation of breathlessness or air hunger, Liberles said, can be distressing, yet little is known about how it arises.
A reflex to guard against air hunger
To test whether such a reflex existed, Schappe led a series of experiments in mice that involved restricting their breathing and recording their physiologic reactions, as well as the response of neurons in their lungs. The team also used genetic tools to activate and deactivate the lung neurons to see how this activity or inactivity affected respiration.

When mice experienced airway closure, they reflexively gasped for air. The researchers noticed that a particular subgroup of vagal sensory neurons was more active during this gasping behavior. When the researchers deactivated the neurons, the mice no longer gasped for air in response to airway closure. When the neurons were activated, the animals gasped even in the absence of airway restriction.
This finding points to a dedicated reflex through the vagus nerve that gets activated by airway closure and leads to gasping, Liberles said.
Next, the researchers examined how these neurons prompt a gasping reflex. They observed that the neurons sit in the lining of the respiratory tract and have a distinct chandelier-shaped structure. Each “arm” of the neuron leads to a cluster of cells called neuroepithelial bodies, or NEBs, which, according to Liberles, “are very poorly studied and have been a mystery since they were first discovered in the lungs.”
Further experiments showed that NEBs were necessary for the gasping reflex, and sufficient to cause it. The team discovered that NEBs expressed a force-sensing protein called PIEZO2 that is also involved in sensing touch in the skin, and that disabling PIEZO2 eliminated the gasping reflex.
“We found an airway closure-activated reflex that is the companion of the Hering-Breuer reflex,” Liberles said. “This new reflex involves a very different neuron structure in the lungs and resolves the long-standing mystery of what NEBs are doing.”
More unknowns ahead
NEB cells have been linked to certain human diseases that cause decreased lung function, but it was unexpected to find a connection between NEBs and the pathway through the vagus nerve that senses a reduction in lung volume, Schappe said.
The findings, the researchers noted, highlight how much there is to learn about NEBs, including their role in disease.
Next, the researchers are interested in solving another mystery: PIEZO2 is classically known to be activated by stretch, not constriction, so they want to know how airway closure changes the lung forces around NEBs to activate the protein.
The team is also interested in studying the remaining orphan neurons in the lungs and airways to understand what they are sensing and whether they are involved in other undiscovered respiratory reflexes.
The study falls firmly in the realm of basic research, but it provides an important first step towards more fully understanding the respiratory system in humans, who have many of the same genes and cell types, including sensory receptors, as mice.
“We want to understand the functions of these neurons and what they control physiologically so that ultimately we can figure out how they translate into internal sensations experienced by humans,” Schappe said.

A research team has examined the link between adverse childhood experiences and the risk of mental health problems later in life, according to a study in JAMA Psychiatry. The researchers from Karolinska Institutet and University of Iceland have found that the risk of suffering from mental illness later in life among those experiencing significant adversity in childhood can be partly explained by factors shared by family members, such as genetics and environment.
Several previous studies have shown that people who have experienced various types of adverse childhood experiences have a higher risk of suffering from psychiatric illness later in life. Now, a new study from Karolinska Institutet, using a special type of twin research design, can confirm the link, show a clear dose-response relationship and at the same time broaden the picture. The researchers can now show that there are also significant genetic and environmental factors that play a role and contribute to mental illness.
The researchers used three different cohorts of the Swedish Twin Registry, comprising over 25,000 individuals. The twins’ responded to a large web-based questionnaire and answered questions about different types of adverse childhood experiences including family violence, emotional abuse or neglect, physical neglect, physical abuse, sexual abuse, rape and hate crime. In addition, information about adult psychiatric disorders was obtained from the Swedish Patient Registry.
“These are of course very difficult questions to answer, but this is the best data source we have access to,” says Hilda Björk Daníelsdóttir, a doctoral student at the University of Iceland and visiting doctoral student at the Institute of Environmental Medicine at Karolinska Institutet and the study’s first author.
By identifying twin pairs who reported different experiences of abuse while growing up in the same family and then following those who later received a psychiatric diagnosis, the researchers have been able to sort out how much of the increased risk is due to the abuse itself and how much is due to genetics and environment.
“Most previous studies on the mental health effects of childhood adversity have not been able to take these things into account. Now we can show that the increased risk of mental health problems after adverse childhood experiences can be partly explained by factors shared by family members, such as genetic factors or factors in the childhood environment,” says Hilda Björk Daníelsdóttir.
She argues that this finding should therefore lead to health care interventions addressing risk factors within the whole family, not just the affected child or children.
The more different types of childhood adversities individuals experienced, the higher the risk was of receiving a psychiatric diagnosis later in life. The researchers can also show that sexual abuse and rape in childhood as well as having experienced three or more types of adversities were the experiences most strongly linked to future mental health problems. This is something that is also important knowledge when treating vulnerable children and their families.
“I hope that our study can raise awareness of childhood circumstances as possible causes of psychiatric disorders in adulthood and how to best address them,’ says Hilda Björk Daníelsdóttir.
The research was funded by the European Research Council, the Icelandic Research Center and the EU’s Horizon 2020.

Some of our genes can be expressed or silenced depending on whether we inherited them from our mother or our father. The mechanism behind this phenomenon, known as genomic imprinting, is determined by DNA modifications during egg and sperm production. The Burga Lab at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences uncovered a novel gene regulation process, associated with the silencing of selfish genes, that could represent the first step in the evolution of imprinting. Their discovery, reported in Nature, could begin to solve the mystery of how and why imprinting first evolved. 
Alejandro Burga and his lab at IMBA, in collaboration with the lab of Eyal Ben-David at the Hebrew University, have reported the discovery of the first parent-of-origin effect in nematodes, in a study published in Nature on March 6th, 2024.  
In diploid organisms, one set of chromosomes is inherited from each parent. However, not all of the genes contained within will be expressed equally; instead, some may be silenced depending on whether they were inherited from the mother or the father. This phenomenon, known as genomic imprinting, depends on DNA methylation, an epigenetic signal that is erased and rewritten in every generation. Genomic imprinting arose independently in mammals and plants over 100 million years ago. However, how this mechanism evolved has, so far, remained largely a mystery. Key to solving this enigma is understanding how parent-of-origin effects, the substrate for the evolution of imprinting, evolved in the first place.  
Thirty years ago, Denise Barlow, a pioneer in the study of imprinting working at the IMP, also located at the Vienna BioCenter, hypothesized that imprinting could be evolutionarily related to genome defense mechanisms that silence parasitic DNA elements called selfish genetic elements. Selfish elements and the defense mechanisms against them participate in an arms race: each evolves further to outcompete the other. Although much has been discovered about selfish element silencing in the thirty years since Denise Barlow postulated her theory, a direct connection between germline defense mechanisms and the origin of parent-of-origin effects was missing. 
The findings by the Burga lab provide the first clear example of how parent-of-origin effects can originate from the host small RNA genome defense pathway. Their findings point to the potential evolutionary origin of imprinting. 
Curiosity paves the way for a new discovery 
Sometimes in science, curiosity and attention to surprising details can lead to unexpected paths and new discoveries. This was the case when first author Pinelopi Pliota was studying selfish genetic elements in a new nematode model organism called C. tropicalis, a close cousin of the more widely studied C. elegans. Pliota was investigating toxin-antidote elements (TAs), a type of selfish element that has evolved a fascinating mechanism to ensure its own inheritance: When a mother carries the TA, it will “poison” its eggs with a toxin that can only be countered by an antidote which is also present in the TA,” she explains, “this way, all descendants that don’t inherit the TA will either die or be developmentally delayed. 
To generate the mothers they were studying, the group always crossed a mother C. tropicalis carrying the TA with a father not carrying it. Pinelopi asked me if we had ever done these crossings the other way around explains Alejandro Burga, corresponding author of the publication. Her curiosity led to an interesting discovery: To our surprise, this reciprocal crossing produced mothers incapable of poisoning their eggs. All of a sudden, there was no effect at all, explains Pliota. Fascinated by this unexpected result, the team decided to study how inheriting the TA from the mother or the father could lead to different effects. We wanted to understand how this happens, what the molecular basis of this parent-of-origin effect is, says Burga. 

Inhibiting the inhibitor: maternal mRNA licenses toxin expression 
To figure out the mechanism of the observed parent-of-origin effect, the Burga group decided to study the main germline defense mechanism against selfish genetic elements, known as the piRNA pathway. In the piRNA pathway, a coordinated effort of different small RNA molecules and proteins silences the expression of selfish elements during germline development to ensure genome stability in reproduction. 
The group, collaborating with the lab of Julius Brennecke, also at IMBA, were able to identify the piRNA molecules and proteins involved in silencing the toxin-antidote element. However, all these factors alone didn’t explain the parent-of-origin-specific results they were observing. The researchers were missing a piece in this puzzle. 
Fortunately, the Burga group had one last trick up their sleeve: We knew from previous research that worms have evolved various ingenious ways to discriminate their own genes from foreign elements like a virus or a selfish element. Burga says.We realized that, in this case, the key missing element was maternal RNA which is loaded into eggs.  
They proved that, in maternal inheritance, the TA is accompanied by the toxin mRNA, which is expressed in the germline of the mother and loaded into the egg. The Burga group showed that this mRNA marks the TA as “own,” avoiding its silencing by the piRNA pathway. This process is called epigenetic licensing, and its balance with the piRNA pathway determines whether a gene is expressed or not. 
On the other hand, when the TA is inherited paternally, the lack of maternal mRNA means there is no licensing, leading to a strong repression of the toxin gene and very low levels of toxin being expressed. By default, the piRNA pathway will silence the toxin gene explains Burga. Unless there’s maternal mRNA that licenses it by repressing the piRNA pathway. This inhibition of the inhibitor is what causes the toxin gene to be active, and the eggs to be poisoned. 
Interestingly, this silencing pattern was observed to last for several generations, meaning that lack of licensing in one generation can even affect their great-grand-daughters. This is not the case in genomic imprinting, which gets reset in each generation. 

Explaining the evolution of imprinting 
The results from the Burga group cement the evolutionary link between parent-specific gene expression and host defence mechanisms, tracing the origins back to organisms that lack DNA methylation and canonical imprinting. Despite the differences between these processes in worms and mammals, the Burga group believes that the mechanism they described could represent an evolutionary first step for more advanced forms of inherited silencing. These more advanced forms of silencing ended up regulating the expression of the cell’s endogenous genes, leading to the evolution of genomic imprinting.

One of the fundamental goals of basic biology is understanding how diverse cell types work in concert to form tissues, organs, and organ systems. Recent efforts to catalog the different cell types in every tissue in our bodies are a step in the right direction, but only one piece of the puzzle. The great mystery of how those cells communicate with one another remains unsolved.
Now, a new paper in Nature describes uLIPSTIC, a tool capable of laying the groundwork for a dynamic map tracking the physical interactions between different cells — the elusive cellular interactome. The authors have been perfecting the technology since 2018 and the latest iteration can in principle allow researchers to directly observe any cell-to-cell interaction in vivo.
“With uLIPSTIC we can ask how cells work together, how they communicate, and what messages they transfer,” says Rockefeller’s Gabriel D. Victora. “That’s where biology resides.”
Kiss-and-run
Ever since single-cell mRNA sequencing came into its own, researchers have been scrambling to connect the dots and explain how diverse cells unite to form tissue. Several methods of cataloging cell-to-cell interactions have already emerged, but all have considerable shortcomings. Early efforts that involved direct observation under a microscope failed to retrieve interacting cells for further analysis; subsequent attempts leaned on advanced imaging techniques that intuit how cells might interact based on their structure and proximity to other cells. No approach captured true physical interactions and signal exchange between cell membranes.
Enter LIPSTIC, an innovative approach from the Victora lab that involved labeling cellular structures that touch when two cells make fleeting, “kiss-and-run” contact before parting ways. The labels ensured that, if one cell “kissed” another, it would leave a mark akin to a lipstick, enabling easy identification and quantification of physical interactions between cells.
Originally, the platform had narrow applications. Victora and colleagues designed LIPSTIC to record a very specific kind of cell-to-cell interaction between T cells and B cells, a major focus of their lab. Other researchers, however, began clamoring for a version of LIPSTIC that would work on other cellular interactions too. “We could have tailored a LIPSTIC for every type of interaction,” Victora says. “But why not try to make a universal version, instead?”
Mapping every interaction

In the original version of LIPSTIC, a “donor” cell uses an enzyme borrowed from bacteria to place a labeled peptide tag onto the surface of an “acceptor” cell upon contact — the biochemical equivalent of applying lipstick to one cell and looking for a kiss print on another. That method required knowing exactly how the “kiss” would occur, identifying molecules the donor cell uses to interact with recipient cells and painstakingly forcing the tags onto those molecules. But over time the team discovered that dousing the cells with a high volume of enzyme and its target would ensure that any interaction that one cell had with another cell would be tracked just as efficiently.
“If you cram partner cells with enough enzyme and target, you can make any any cell pair capable of LISPTIC labeling without needing to know in advance what molecules these cells will use for their interaction,” Victora says.
The result was a uLIPSTIC, a universal platform not bound by foreknowledge of molecules, ligands, or receptors. Scientists can now theoretically smear uLIPSTIC on any cell, without preconceived notions of how it would interact with its environment, and observe physical cell-to-cell interactions. To demonstrate the power of the platform, the team showed that uLIPSTIC could expand beyond LIPSTIC’s narrow repertoire of B cells and T cells to track how dendritic cells kickstart the body’s immune response against tumors and food allergens.
“The reception to uLIPSTIC has been great,” says Sandra Nakandakari-Higa, a PhD student in the Victora lab and lead author on the paper. “We’re already getting a lot of inquiries from other labs about how they can adapt our system to their models.”
The team hopes to eventually use uLIPSTIC to discover the receptor-ligand pairs key to cellular interactions, in an effort to better understand how cells unite into tissue at the molecular level. Eventually, the team envisions uLIPSTIC as a key tool in the effort to generate comprehensive atlases describing how cells interact to form tissue — a key to the long-awaited interactome.

Epigenetic changes play important roles in cancer, metabolic and aging-related diseases, but also during loss of resilience as they cause the genetic material to be incorrectly interpreted in affected cells. A major study by scientists at Helmholtz Munich published in Nature now provides important new insights into how complex epigenetic modification signatures regulate the genome. This study will pave the way for new treatments of diseases caused by faulty epigenetic machineries.
The Unresolved Mystery of Epigenetic Complexity
Our bodies are made up of hundreds of different cell types, each with its unique shape and function. The information on how to build an organism is stored in our DNA. However, while all our cells share the same DNA, they don’t all read it in the same way. So how does, for example, a liver or a brain cell know which instructions to follow? To make this possible, small chemical tags, so-called epigenetic modifications, are used. They act like flags and tell each cell which parts of the DNA to use and which ones to ignore.
Simple at first glance, this epigenetic regulation is much more complex, as there are many different modifications that can either be attached directly to our DNA or to so-called histone proteins. “Histones are small proteins around which our DNA is wrapped, and which thereby serve to package the genetic material,” says study leader Dr. Till Bartke, deputy director of the Institute of Functional Epigenetics (IFE) at Helmholtz Munich. “Depending on how the histones or the DNA are chemically modified, they can have different effects on the DNA and thereby control gene activity.” Together, epigenetic modifications form what scientists call the epigenetic code, allowing cells to switch genes on or off according to their specific needs.
However, how these epigenetic modifications work together has remained a big puzzle. Finding out how this epigenetic code works is the focus of the research at the Institute of Functional Epigenetics led by Prof. Robert Schneider: “Our understanding of the complex interaction between our DNA and epigenetic mechanisms has now taken an important step forward with this groundbreaking study from our institute.”
Cracking the Epigenetic Code in a Test Tube
To decipher the epigenetic code, Till Bartke and co-workers developed a creative way to examine how different combinations of epigenetic modifications work together. They reconstructed many of these modifications in a test tube and carried out experiments to study how they interact with the proteins in our cells, using a combination of sophisticated biochemical and mass spectrometric methods.

“Epigenetic modifications usually act in cooperation with so-called epigenetic reader proteins that recognize them and promote downstream effects” explains Dr. Andrey Tvardovskiy, post-doctoral researcher and one of the first authors of the study. “Uncovering how epigenetic readers interpret such complex modification signatures is therefore key to understanding how our genome functions and how its misregulation can lead to human diseases.” For the first time, the researchers could see how different combinations of modifications are “read” and translated by the protein machineries in our cells.
Decoding the Epigenetic Language with a Computer
Using newly developed AI approaches, they next set out to decode the language of epigenetic modifications. The researchers found that some constituents of the epigenetic code have a big impact, especially on stretches of the DNA that control gene activation, while others have a smaller effect. By putting together all this information, they managed to extract several fundamental rules of how our genetic material is organized and controlled inside our cells. These insights are highly relevant for many scientists across different fields and are anticipated to catalyze many future discoveries. To ensure that their findings are as widely available as possible, the researchers built a website called the ‘Modification Atlas of Regulation by Chromatin States’ (https://marcs.helmholtz-munich.de), that provides an intuitive interactive online resource to explore the results of their study.
Understanding Epigenetics to Treat Human Diseases
“Since epigenetic modifications play crucial roles in everything our bodies do, from growing and learning to staying healthy, things go wrong when the modifications are misplaced or misread. Often this causes diseases like cancer, developmental disorders, or mental disabilities” says Till Bartke. “But epigenetic changes also accumulate throughout life and are affected by the environment, nutrition, and lifestyle — this can contribute to diseases such as diabetes and lead to deleterious effects of aging.” By understanding how epigenetic modifications work and what goes wrong in diseases, researchers at the IFE aim to develop new ways to treat these diseases and tackle adaptation to a changing environment.
About the scientists
Dr. Till Bartke, Deputy Director of the Institute of Functional Epigenetics at Helmholtz Munich
Dr. Andrey Tvardovskiy, Postdoc at the Institute of Functional Epigenetics at Helmholtz Munich
Prof. Dr. Robert Schneider, Director of the Institute of Functional Epigenetics at Helmholtz Munich

Living in neighborhoods with more white residents and greater lifetime experiences of racial discrimination are linked to increased systemic inflammation during pregnancy among Black women, according to new research led by a team from Penn State. The study, published in the February issue of the journal Brain, Behavior, & Immunity — Health, found that these social-environmental factors were associated with higher levels of a protein that has been connected to chronic stress and an elevated risk of preterm birth. The findings shed light on the distinctive stressors that Black women face and how they may influence pregnancy outcomes, the researchers said.
“Understanding these unique stressors might give us a better shot at trying to intervene,” said Christopher Engeland, professor of biobehavioral health at Penn State and senior author of the paper. “We know that the preterm birth rate is almost two times higher in Black women compared to white women, but it’s not fully explained by established risk factors such as socioeconomic status. We wanted to look at stressors that are both unique to the experience of Black women and potentially related to preterm birth to see if those associations might yield information about this ongoing health problem and could account for some of the disparities in pregnancy outcomes.”
Babies born before full-term, or 37 weeks of pregnancy, are at greater risk for death, health complications and disabilities, according to the Centers for Disease Control and Prevention. However, preterm birth rates haven’t budged over the last 10 years, hovering between 9.6% and 10.5%. In 2022, 10.4% of babies were born early. Among Black women, the preterm birth rate was 14.6%.
Doctors and researchers don’t fully understand all the factors that contribute to preterm birth or the underlying mechanisms, the researchers said. However, inflammation may be an important piece of the puzzle. Generally, in late pregnancy, both pro-inflammatory cytokines and inflammation increase. This appears to be related to increased prostaglandin synthesis, which is important for inducing contractions, and the onset of labor, Engeland explained. Cytokines are small proteins that help manage inflammation in the body and can be a marker for inflammation. When systemic inflammation and pro-inflammatory cytokines are elevated more than normal, this is associated with a higher risk for preterm birth.
When disparities exist within a specific subgroup of individuals, the researchers said it can be informative to look within that subgroup to understand their unique experience and how that may drive the underlying differences in health outcomes. Among Black women, systemic inflammation tends to be higher overall, whether they are pregnant or not, the researchers said. Studies have begun to look at psychosocial and social-environmental factors linked to chronic stress to see if those factors might lead to higher inflammation in the body and, subsequently, risk for preterm birth.
For the current study, the research team was interested in investigating two factors — experiences of racial discrimination and perceived neighborhood racial composition — and determining if these factors predicted cytokine levels during pregnancy. The prospective study involved a cohort of 545 Black women who were between the ages of 18 and 45 years old and pregnant with only one fetus. They were recruited during their first prenatal visit to clinics in Columbus, Ohio, and Detroit, Michigan, metropolitan areas. Data were collected at three time points during their pregnancy: 8- to 18-weeks, 19- to 29-weeks and 30- to 36-weeks gestation. Participants were asked to complete surveys about their lifetime experiences of discrimination, perceived racial segregation, depressive symptoms and demographic characteristics. The researchers also took blood samples to monitor pro-inflammatory and anti-inflammatory cytokines.
The study found that reports of higher lifetime racial discrimination, higher levels of depressive symptoms early in pregnancy and living in neighborhoods with more white individuals were each associated with higher levels of the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF). They didn’t observe a relationship with any other cytokine.

“This particular cytokine has a distinctive relationship with stress. Aside from inflammation, it may be a biomarker of chronic stress and it may have something to do with the mechanism underlying preterm birth,” Engeland said. Higher MIF levels are associated with glucocorticoid resistance, which means that our bodies are more prone to mount a more robust inflammatory response, he explained. Previous studies have linked MIF to chronic stress and preterm birth, which suggests a potential role in adverse pregnancy outcomes.
The researchers said the study is one of the first to examine if and how neighborhood racial composition contributes to systemic inflammation during pregnancy in Black women. The relationship between MIF and neighborhood racial composition was present at all three timepoints and strongest in late pregnancy. MIF levels also appeared to increase in a stepwise fashion as neighborhood composition changed from mostly Black to some Black to mixed to mostly white neighborhoods.
“It suggests that there’s something about living in neighborhoods with a higher proportion of white individuals that’s eliciting stress for these African American women who are pregnant. This cytokine seems to be particularly sensitive to it,” said Molly Wright, a graduate student at Penn State and lead author of the study. “The fact that we saw this association across all timepoints suggests that this wasn’t a spurious finding.”
The findings point to the need to consider neighborhood context, racial discrimination and other distinctive chronic stressors that Black individuals frequently experience when considering factors that might influence preterm birth risk, according to the researchers. They plan to follow up this study by comparing gestational age at birth and MIF levels within the same cohort of women to determine any relationship to preterm birth.
Other authors on the paper are Carmen Giurgescu, professor and associate dean for research and principal investigator of the broader study, University of Central Florida College of Nursing; Dawn P. Misra, chair of the department of epidemiology and biostatistics, Michigan State University College of Human Medicine; and Jaime C. Slaughter-Acey, currently an associate professor of epidemiology at the University of North Carolina Gillings School of Global Public Health. At the time the research was conducted, Slaughter-Acey was affiliated with the University of Minnesota School of Public Health.
The National Institute on Minority Health and Health Disparities funded this work.