Publisher Health

Researchers have established the protein p53 as critical for regulating sociability, repetitive behavior, and hippocampus-related learning and memory in mice, illuminating the relationship between the protein-coding gene TP53 and neurodevelopmental and conditions like autism spectrum disorder.
“This study shows for the first time that p53 is linked directly to autism-like behavior,” said Nien-Pei Tsai, an associate professor of molecular and integrative biology at the University of Illinois Urbana-Champaign and a researcher at the Beckman Institute for Advanced Science and Technology.
In living systems, genes act as a biological version of binary code, using the letters A, C, G, and T instead of ones and zeroes to spell out cellular marching orders. Some genes — called coding genes — instruct cells to create proteins with specific functions. For example, the gene TP53 instructs cells to create the protein p53; its job is to regulate how other genes are expressed.
In this study, Tsai and his colleagues lowered hippocampal p53 levels in mice, looking for changes in gene expressions related to behavior. They observed that the decreased p53 levels: Promoted repetitive behavior in mice. Reduced sociability in mice. Impaired hippocampus-dependent learning and memory, especially in male mice.The researchers also observed that p53 levels were elevated after a period of active communication between hippocampal neurons called long-term potentiation. Flexible neuron firing — known as plasticity — is related to positive learning and memory outcomes.
In a 2018 study, Tsai and his colleagues identified p53 as a key protein involved in the irregular brain cell activity seen in ASD and epilepsy. In future studies, they aim to explore how p53 coordinates the expression of those autism-linked genes to guide behavior.

Some substances in medicines, household items and the environment are known to affect prenatal child development. In a study published in Toxicological Sciences, researchers tested the effects of five drugs (including caffeine and the blood thinner warfarin) on the growth of zebrafish embryos. They found that all five had the same effect, impairing the migration of bone-forming cells which resulted in the onset of facial malformation. Zebrafish embryos grow quickly, are transparent and develop outside of the parent’s body, making them ideal for studying early development. A zebrafish-based system could be used to easily screen for potentially harmful substances, reducing animal testing on mammals and supporting parents-to-be when making choices for themselves and their baby.
Whether from birth or through events which happen in life, many people have differences in their facial appearance. Worldwide, over one-third of all congenital anomalies relate to the development of a child’s head or facial bones — their craniofacial features — a common example being having a cleft lip and/or palate. The exact cause of craniofacial differences is not fully understood, but researchers currently think that multiple factors may be involved. This includes genetics, the gestational parent’s environment, their diet, some illnesses and certain drugs or chemicals.
Teratogens are substances known to disturb the growth of an embryo or fetus; for example, pregnant people are advised to avoid alcohol and nicotine. Potential teratogens are typically screened for using animals such as rodents and rabbits. But researchers are looking for alternative methods which are quicker, cheaper and reduce the need for testing on mammals.
This is where zebrafish come in. These tiny, 2-5 centimeter freshwater fish grow very quickly, developing as much in a day as a human embryo would in a month. “Zebrafish embryos are transparent and grow outside the mother, so we can monitor the behavior of live cells as they develop,” said Toru Kawanishi, project assistant professor at the University of Tokyo’s Department of Biological Sciences at the time of the study. Within the past 10 years, several research projects have shown that zebrafish can effectively be used to check for teratogens. However, the exact mechanisms by which teratogens impair or alter typical embryonic development is still being investigated.
The team focused on a specific genetic marker for a group of cells involved in craniofacial development in both mammals and fish. In humans, these are known to become parts of the nose and jaw. “We manipulated the genome of zebrafish embryos and made bone-forming cells fluorescently visible in green. We then treated them with chemicals that are known to cause facial defects in human newborns, and tracked the trajectories of the bone-forming cells throughout embryonic stages,” explained Kawanishi.
The team tested five chemicals: valproic acid (used to treat neurological and psychiatric disorders), warfarin (an anticoagulant), salicylic acid (popular in skin ointments), caffeine and methotrexate (used in chemotherapy). They saw that, as expected, all the chemicals tested caused various degrees of craniofacial anomalies 96 hours after fertilization. However, they were surprised by the mechanism which caused this to happen and how quickly it started.
“Bone- and cartilage-forming cells in the head, called cranial neural crest cells (CNCCs), generally move a long distance from where they are first formed around the back of the neck, to their intended destinations such as the jaw or nose,” explained Kawanishi. “We were surprised that regardless of how each chemical acts on cells molecularly, impaired migration of bone-forming cells in early development was responsible for the onset of facial malformation for all the five chemicals. We could see signs of this within just 24 hours, at a point where zebrafish and mammalian embryos share very similar morphological and molecular characteristics.”
The results indicate the potential existence of a general mechanism by which teratogenic chemicals limit movement of CNCCs early on in embryos, causing the development of facial differences. The researchers extrapolate that facial differences caused by other substances might also follow the same mechanism. “We will aim to reveal the molecular mechanism underlying the impaired cell migration, to understand why different chemicals lead to the shared defects in cell migration,” said Kawanishi. The team proposes using this zebrafish-based system as another way to test for cross-species teratogens, so that parents and medical practitioners can be made aware to limit or avoid them.

Disturbances in sleep patterns and the internal biological clock are frequently associated with Parkinson’s disease. However, the link between biological rhythm and neuronal degeneration remains unclear. A team from the University of Geneva (UNIGE) investigated the destruction of neurons at different times of the day, using the fruit fly as a study model. The scientists discovered that the type of cellular stress involved in Parkinson’s disease was more deleterious to neurons when it occurred at night. This work can be read in the journal Nature Communications.
Parkinson’s disease is a progressive neurodegenerative disorder characterized by the destruction of certain neurons in the brain: dopamine neurons. The main symptoms of this disease are tremors, slowness of movement and muscular stiffness. Epidemiological studies show that other disorders may be associated, such as disturbances of the sleep and of the circadian cycle.
This cycle, defined by the alternate periods of wakefulness and sleep, lasts around 24 hours and constitutes the human body’s internal clock that regulates almost all its biological functions. In particular, the circadian clock controls the secretion of the ”sleep hormone”(melatonin) at the end of the day, variations in body temperature (lower in the early morning and higher during the day), and metabolism in periods of fasting (during sleep) or energy intake (during daytime meals).
Cause or consequence?
Disruptions in circadian and sleep rhythms can be observed years before the onset of motor symptoms in Parkinson’s patients. But does disruption of the circadian cycle contribute to the development of the disease, or is it a consequence?
This question is at the heart of work in the laboratory of Emi Nagoshi, associate professor in the Department of Genetics and Evolution at the UNIGE Faculty of Science. Her team uses the fruit fly as a study model for Parkinson’s disease and to dissect the mechanisms of dopamine neuron degeneration. Scientists can simulate the onset of the disease by exposing the flies for a few hours to a drug that induces oxidative stress, leading to the death of dopaminergic neurons in the following days.
Flies’ neurons are more sensitive at night
Despite being very different animals, the biological clocks of flies and humans are comparable. To determine whether the circadian cycle could influence the onset of Parkinson’s disease, flies were exposed to oxidative stress at six different times of the day and night.

Scientists at Nanyang Technological University, Singapore (NTU Singapore) have found how human cells distribute and maintain their cholesterol levels, aiding in research in neurodegenerative diseases such as Alzheimer’s disease, as well as cardiovascular diseases.
All the cells in the human body contain cholesterol, a waxy, fat-like substance and use it for vital body functions, such as building new cells, producing hormones, and even producing substances that help fight against pathogens.
Maintaining normal cholesterol levels within the central nervous system is essential for various processes, including the brain’s development and daily functions.
The cells in our body either produce cholesterol or acquire it through our diet and maintaining the appropriate levels and distribution of cholesterol within our cells is crucial, as failure to do so can lead to various diseases, including heart attacks and dementia.
Using a highly sensitive cholesterol probe in tests involving human cells, the team identified the key proteins involved in regulating and transporting cholesterol within cells, called OSBP1, ORP92, and gram domain-containing proteins 1 (GRAMD1s).
The study provides new insights into the precise mechanisms for maintaining cholesterol distribution within cells.
Lead author Associate Professor Yasunori Saheki, from NTU Singapore’s Lee Kong Chian School of Medicine (LKCMedicine), who led the study, said: “Our findings shed light on the critical mechanisms underlying cellular cholesterol distribution and their potential implications for various health conditions. This offers critical insights into the mechanisms underlying the maintenance of cellular cholesterol distribution. The study is of particular significance as disruptions in this process have been strongly associated with a wide range of neurodegenerative disorders, including Alzheimer’s disease.” Assoc Prof Saheki is also a cell biologist and a medical doctor.

A lack of sleep and reduced physical activity during pregnancy are linked to risk of preterm birth, according to new research led by the Stanford School of Medicine.
In the study, which will publish online Sept. 28 in npj Digital Medicine, the researchers collected data from devices worn by more than 1,000 women throughout pregnancy. With a machine learning algorithm, the scientists sifted through participants’ activity information to detect fine-grained changes in sleep and physical activity patterns.
“We showed that an artificial intelligence algorithm can build a ‘clock’ of physical activity and sleep during pregnancy, and can tell how far along a patient’s pregnancy is,” said senior study author Nima Aghaeepour, PhD, an associate professor of anesthesiology, perioperative and pain medicine and of pediatrics at Stanford Medicine. Normal pregnancy is characterized by progressive changes in sleep and physical activity as the pregnancy advances, he said. “But some patients don’t follow that clock.” When patients’ sleep and activity levels don’t change on a typical trajectory, the study showed, it’,s a warning sign for premature birth, he added.
The study’s lead author is Neal Ravindra, PhD, a former postdoctoral scholar at Stanford Medicine.
As the pregnancies progressed, sleep typically became more disrupted, and women became less physically active, the study showed. However, some women’s sleep and activity patterns changed on an accelerated timeline relative to how far along they were in their pregnancies. These individuals were more likely to deliver early, the study found.
“The people who look ‘very pregnant’ to the AI algorithm — but are not — end up being at significantly increased risk of preterm birth,” Aghaeepour said.
A struggle to prevent early deliveries
Premature birth, when a baby is born 3 or more weeks early, affects 10.5% of births in the United States; these rates are higher in some other parts of the world. Premature newborns can suffer many medical complications, including diseases of the eyes, lungs, brain and digestive system. Prematurity is the leading cause of death for children under age 5 around the world.

Compounds developed by University of Leicester Chemists aim to reveal the dual nature of formaldehyde, a chemical that is known to cause cancer but is also believed to play important roles in our biology.
The compounds are detailed in a new study in the journal Chemical Science and potentially allow scientists to study a chemical that is present in all living things but which has so far proven too volatile and too reactive to study with ease. The research has been supported by the Engineering and Physical Sciences Research Council (EPSRC), part of UK Research and Innovation (UKRI), the Wellcome Trust and Cancer Research UK.
Formaldehyde is prevalent in nature and also has a variety of uses such as a glue and a sterilising agent, famously used in artworks by Damien Hirst. It is also known to be a human toxin and carcinogen (has the potential to cause cancer) in high doses. Formaldehyde is also produced within our cells and it is present in animals and in plants. Scientists are seeing growing evidence that formaldehyde plays an important role in our biology despite its potential toxicity, giving it a dual nature much like the literary characters of Dr Jekyll and Mr Hyde.
However, studying formaldehyde inside a cell is challenging because of its volatility and reactivity. It is important to understand what makes the molecule toxic and carcinogenic as this could help scientists to find ways to prevent or treat those effects.
To probe its impact on our cells more accurately, a team at the University of Leicester with collaborators at the University of Oxford have developed a new library of compounds designed to release formaldehyde in cells in controlled amounts that can be used to more precisely to measure its effects. They are partly inspired by compounds used in the cosmetics industry that release low levels of formaldehyde over time.
Dr Richard Hopkinson from the University of Leicester Institute for Structural and Chemical Biology said: “The scientific community ideally needs ways to deliver formaldehyde in a quantifiable, controllable way that is reproducible. The problem is that formaldehyde’s high reactivity and volatility makes that really challenging.”
Formaldehyde is linked to a number of different types of cancer, particularly with nose and throat cancers from inhaling formaldehyde, but it is often difficult for scientists to draw a conclusive link between formaldehyde exposure and the onset of disease.
However, Dr Hopkinson notes that there is also emerging evidence suggesting that formaldehyde plays a role in our metabolism. “We are producing formaldehyde all the time inside us but it is a very reactive chemical and most things in biology are not that reactive.
“We think it might actually be an important nutrient, not just a toxin, but that having too much or even too little formaldehyde could tip us over the edge into disease. If we can work out exactly what formaldehyde is doing inside cells, hopefully we can begin to answer these important questions.

Actin filaments are dynamic protein-fibres in the cell built from single actin proteins. Many cellular functions, including cell movement, are regulated by constant filament assembly and disassembly. The disassembly phase is initiated by the release of a phosphate group from inside the filament, but the details of this process have puzzled scientists since decades. Researchers from the Max Planck Institute of Molecular Physiology in Dortmund and the Max Planck Institute of Biophysics in Frankfurt have joined forces to precisely identify a region in actin that functions as a “molecular backdoor” for phosphate to exit though. Using a wide variety of techniques, including cryogenic electron microscopy (cryo-EM) and molecular dynamics simulations, the scientists determined the mechanism of phosphate release from actin filaments in unprecedented molecular detail. They also described how a distorted backdoor enables the faster release of phosphate from an actin mutant linked to nemaline myopathy, a severe muscle disease. The study opens the door to further research on the dynamic actin-assembly cycle in cells and diseases related to defective actin organization.
The mysterious escape of phosphate
In eukaryotic cells, actin proteins join together (polymerize) into filaments that are part of the cell’s intricate supportive network, the cytoskeleton. The disassembly of old filaments is crucial for cell movement and is regulated by ATP hydrolysis — the reaction of ATP with water that cleaves a phosphate group and generates energy. Specifically, phosphate release from the filament core is the signal to the cell that the actin filament is old enough and can be dismantled into actin subunits. “The mechanism of phosphate release from actin filaments has remained enigmatic for decades,” says Wout Oosterheert, postdoc in the group of Stefan Raunser at the MPI Dortmund and first author of the publication.
The new results are built on previous research of Raunser’s group on actin that led to ground-breaking publications in 2015, 2018, and 2022 in the actin field. In the latter, the Raunser team determined high-resolution cryo-EM structures of actin filaments in three different states: bound to ATP, bound to ADP in the presence of the cleaved phosphate, and bound to ADP after release of the phosphate. However, in all structures, there was no opening or door in actin through which phosphate could escape from the filament. “Therefore, we surmised that there should be a backdoor that opens momentarily to release the phosphate, and then quickly closes again” says Raunser.
A multidisciplinary approach
MPI scientists have now tackled the problem from various angles. Since it was known that phosphate is released very rapidly from actin at the tip of the filament, called the barbed end, Raunser and his team determined its structure by cryo-EM. And indeed, only at the end of the filament, they found an open molecular backdoor, which explains the very fast phosphate release. However, it was still unclear how phosphate escapes from the actin subunits in the filament core. That’s where the expertise of Gerhard Hummer’s group from the MPI Frankfurt kicked in; they used the structural data from 2022 to perform molecular dynamics simulations and predict potential exit routes for the phosphate from the filament core. They then teamed up with the group of Peter Bieling (MPI Dortmund) to validate the possible routes by producing actin mutants potentially disrupting the molecular backdoor. They measured how fast they release the phosphate, and finally determined the high-resolution cryo-EM structures of the “fastest” candidates.
The mutational analysis revealed that the phosphate takes the same release route in the filament end and the filament core. The structures and interactions in the latter, however, need additional rearrangements that make it more difficult for the door to open. After phosphate cleavage, the backdoor remains predominantly closed (on average for 100 seconds) before opening for less than a second to let the phosphate leave. “This explains why we didn’t see an open backdoor arrangement in our cryo-EM data of 2022,” says Raunser.
The actin saga — To be continued…
One of the actin mutants analyzed, called N111S, is linked to the muscular disease nemaline myopathy and has therefore attracted the attention of the MPI scientists: the mutant always adopts an open backdoor and hence releases phosphate much faster than normal wild-type actin. “We propose that this ultrafast release may contribute to the pathophysiology in patients harboring this actin mutation,” says Oosterheert.
As a potential next step, the MPI scientists now want to uncover how phosphate release is controlled within the cell and what role the proteins that bind to actin play. In addition, their work now makes it possible to investigate other disease-related mutations in actin — an approach that may ultimately contribute to the development of new therapeutic strategies for these diseases.

In Parkinson’s disease, the cerebral cortex can take over tasks from a deeper part of the brain that has been damaged, where cells that make dopamine have been lost. The strength of compensation by the cerebral cortex determines how many symptoms people have. This is shown in a publication by Radboud university medical center. Patients can stimulate this compensation through sports, for example, and thus slow down the disease process.
It was already known that in Parkinson’s disease the cells in the brain that produce dopamine slowly disappear. This is why patients are given extra dopamine as medication. But only a limited link has been found between the loss of those cells, and the severity of symptoms in Parkinson’s. Even if all the cells have disappeared, one person experiences mild symptoms, while another has many more symptoms. Researchers at the Radboudumc looked into whether something else might be going on.
They discovered that the outer layer of the brain, the cerebral cortex, can compensate for the loss of the cells that make dopamine, thereby delaying the worsening of symptoms. It turns out that the severity of symptoms is clearly related to compensation by the cerebral cortex. The more active it is in taking over tasks, the milder the slowness of movement and the better the thinking. Doctors have long suspected that such a mechanism of compensation exists, but it has now been demonstrated for the first time.
Smoothness
The conclusions are based on a study in 353 people with Parkinson’s and 60 healthy volunteers. They all took a test while in an MRI scanner. The test was a kind of computer game, where participants had to make both easy and difficult choices, which demands a lot from the brain. The researchers could use the MRI scanner to identify brain regions that were active during the game. They expected that making difficult choices stimulates compensation, and that the deployment of compensation differs between people.
First, they saw that the brain structure that strongly depends on dopamine, the basal ganglia, is indeed damaged and shows much less activity in people with Parkinson’s than in healthy volunteers. The basal ganglia lie deep in the brain, below the cerebral cortex. This brain area allows people to move and think smoothly. Hence, damage in this area leads to slowness of movement and thinking in Parkinson’s.
Reinforcing compensation
It was also found that in people with Parkinson’s there is a very clear relationship between the severity of symptoms and activity in the cerebral cortex. PhD candidate Martin Johansson: ‘People with mild symptoms showed much more activity in the cerebral cortex, especially in areas that are involved in controlling movement. These areas were even more active than in healthy volunteers, which demonstrates their compensatory role. In patients with severe symptoms, on the contrary, the cerebral cortex was much less active than in healthy volunteers.’
This discovery offers new leads for treatment and lifestyle. ‘In parkinson’s we solve the dopamine deficiency with drugs. But with these new findings we are now going to look much more at how we can strengthen that compensation by the cerebral cortex’, says Rick Helmich, neurologist at Radboudumc. ‘We saw in a previous study that exercising three times a week helps against symptoms, and prevents shrinkage of the cerebral cortex. Thanks to the current study, we know why that cerebral cortex is so important.’

In lonely people, the boundary between real friends and favorite fictional characters gets blurred in the part of the brain that is active when thinking about others, a new study found.
Researchers scanned the brains of people who were fans of “Game of Thrones” while they thought about various characters in the show and about their real friends. All participants had taken a test measuring loneliness.
The difference between those who scored highest on loneliness and those who scored lowest was stark, said Dylan Wagner, co-author of the study and associate professor of psychology at The Ohio State University.
“There were clear boundaries between where real and fictional characters were represented in the brains of the least lonely participant in our study,” Wagner said.
“But the boundaries between real and some fictional people were nearly nonexistent for the loneliest participant.”
The results suggest that lonelier people may be thinking of their favorite fictional characters in the same way they would real friends, Wagner said.
Wagner conducted the study with Timothy Broom, a PhD graduate of Ohio State who is now a postdoctoral researcher at Columbia University. It was published recently in the journal Cerebral Cortex.

A team of researchers has uncovered a previously unknown compensatory mechanism found in liver disease. If Kupffer cells (KCs), a specific kind of immune cells found in the liver, become impaired by tissue scarring, immune cells originating in the bone marrow flow to the organ, where they form larger cell clusters to perform the same function. Researchers from the Cumming School of Medicine at the University of Calgary and Charité — Universitätsmedizin Berlin have observed for the first time how the liver preserves its bacterial filtration function even in the presence of disease. Their fundamental findings have been published in the journal Science.* They may contribute to developing new treatments for liver damage.
The liver is an amazing organ. The body’s central metabolic organ, it is responsible for both absorbing nutrients and breaking down toxins. It regulates the body’s fat and sugar metabolism and levels of minerals, vitamins, and hormones. Beyond that, the liver plays a lesser known but still vital role as the body’s central immunological organ. The liver is instrumental in keeping the human bloodstream free of pathogens — bacteria, viruses, and fungi. If sepsis, or blood poisoning, occurs, the liver filters out more than 90 percent of the foreign material involved.
This essential function of the organ is performed by a kind of specialized immune cell — macrophages known as Kupffer cells (KCs), which are named for German Baltic anatomist Karl Wilhelm von Kupffer. To perform their filtration function, Kupffer cells are located in the small blood vessels of the liver, the sinusoids, where they receive continuous signals from the hepatic cells themselves and those lining the blood vessels of the liver. In severe disease, especially chronic liver disease, damage to the liver causes a buildup of scar tissue known as fibrosis, which impairs the organ’s function. In the advanced stage of this tissue remodeling process, the area around the Kupffer cells also undergoes fateful changes — with consequences that were unknown until now.
A research team led by immunologist Dr. Paul Kubes, PhD, of the Cumming School of Medicine at the University of Calgary, partnered with colleagues at Charité to investigate this phenomenon. One of their primary aims was to improve treatment options in the future for patients with liver fibrosis. Chronic liver disease is rising sharply around the world. Heavy alcohol consumption and fatty liver disease are the main causes of liver fibrosis and its final stage, cirrhosis.
It is estimated that one in four people worldwide already have fatty liver disease caused by lifestyle factors such as excessive food intake, lack of exercise, and diseases including diabetes and metabolic disorders. Infections and genetic factors can also lead to liver fibrosis. Although there are already good models of liver disease, no one had yet been able to trace the development of liver fibrosis and the key filtration function at the same time.
Role of the immune system in liver fibrosis appears in new light
Now, the international team has done just that. Using an innovative microscopy technique that makes it possible to observe cellular functions in detail in a living organism and other microscopy techniques, the researchers closely studied the functioning of Kupffer cells in the animal model and in tissue samples taken from patients with liver cirrhosis. In the process, they identified a new cell type, which they call Kupffer cell-like syncytia. These are a kind of giant cells — larger, multinucleated clusters of cells formed out of immune cells originating in the bone marrow that have traveled to the scene in response.