Publisher Health

About 283 million people worldwide suffer from alcohol use disorder, a debilitating health challenge for which limited therapeutic options are available. The cost to society is estimated at greater than $2 trillion annually.
“People try to rehabilitate, but it is very challenging,” said Yu Shin Kim, PhD, a neuroscience researcher at The University of Texas Health Science Center at San Antonio. “Headache is one of the severe withdrawal symptoms that pushes the rehabilitating patient back to alcohol, because people know that, after drinking, alcohol will actually reduce the headache. It becomes a vicious cycle. This is how they develop alcohol dependence.”
Kim, associate professor of oral and maxillofacial surgery in the health science center’s School of Dentistry, and colleagues found that a stress hormone called corticotropin-releasing factor (CRF) activates immune cells known as mast cells in the dura — the thin, transparent membrane under the skull.
Dura matter includes peripheral nerve fibers and peripheral blood vessels. CRF binds to a specific mast cell receptor called MrgprB2, Kim said. This is the central finding of the team’s study published Oct. 30 in the journal Neuron.
“After alcohol withdrawal, the CRF stress hormone is released from the hypothalamus, a brain region that controls many functions,” Kim said. “The CRF travels through peripheral blood vessels to dura matter, where it is released from the vessels and binds to MrgprB2. This signals the mast cells to degranulate, or open, and secrete chemical messengers that induce functions including blood vessel dilation (widening).
“This also activates peripheral nerve fibers extending from trigeminal ganglia neurons, which are sensory neurons. That is how these neurons are sensitized and a person has alcohol-withdrawal headache.”
It is this process that sends the pain signals.
Researchers knew that peripheral neural fibers must be related to vessel dilation that occurs with alcohol withdrawal. The lab’s new contribution is that CRF binds to the mast cell receptor MrgprB2, Kim said.
“MrgprB2 is a very specific receptor for mast cells. Only mast cells have these receptors,” Kim said.
This research may benefit further studies of various substance use disorder mechanisms including withdrawal, he said. It may be possible to develop a small-molecule drug therapy to inhibit the CRF and MrgprB2 interaction, resulting in fewer pain signals during alcohol withdrawal.

As little as 1 per cent reduction in deep sleep per year for people over 60 years of age translates into a 27 per cent increased risk of dementia, according to a study which suggests that enhancing or maintaining deep sleep, also known as slow wave sleep, in older years could stave off dementia.
The study, led by Associate Professor Matthew Pase, from the Monash School of Psychological Sciences and the Turner Institute for Brain and Mental Health in Melbourne, Australia, and published today in JAMA Neurology, looked at 346 participants, over 60 years of age, enrolled in the Framingham Heart Study who completed two overnight sleep studies in the time periods 1995 to 1998 and 2001 to 2003, with an average of five years between the two studies.
These participants were then carefully followed for dementia from the time of the second sleep study through to 2018. The researchers found, on average, that the amount of deep sleep declined between the two studies, indicating slow wave sleep loss with ageing. Over the next 17 years of follow-up, there were 52 cases of dementia. Even adjusting for age, sex, cohort, genetic factors, smoking status, sleeping medication use, antidepressant use, and anxiolytic use, each percentage decrease in deep sleep each year was associated with a 27 per cent increase in the risk of dementia.
“Slow-wave sleep, or deep sleep, supports the ageing brain in many ways, and we know that sleep augments the clearance of metabolic waste from the brain, including facilitating the clearance of proteins that aggregate in Alzheimer’s disease,” Associate Professor Pase said.
“However, to date we have been unsure of the role of slow-wave sleep in the development of dementia. Our findings suggest that slow wave sleep loss may be a modifiable dementia risk factor.”
Associate Professor Pase said that the Framingham Heart Study is a unique community-based cohort with repeated overnight polysomnographic (PSG) sleep studies and uninterrupted surveillance for incident dementia.
“We used these to examine how slow-wave sleep changed with ageing and whether changes in slow-wave sleep percentage were associated with the risk of later-life dementia up to 17 years later,” he said.
“We also examined whether genetic risk for Alzheimer’s Disease or brain volumes suggestive of early neurodegeneration were associated with a reduction in slow-wave sleep. We found that a genetic risk factor for Alzheimer’s disease, but not brain volume, was associated with accelerated declines in slow wave sleep.”

Indiana University School of Medicine researchers have identified multiple species of bacteria that, when present in the gut, are linked to an increased risk of developing severe malaria in humans and mice. Their findings, recently published in Nature Communications, could lead to the development of new approaches targeting gut bacteria to prevent severe malaria and associated deaths.
Malaria is a life-threatening infectious disease caused by parasites transmitted through the bite of infected mosquitoes. According to the World Health Organization’s latest World Malaria Report, an estimated 619,000 people died from malaria globally in 2021, with 76% of those deaths occurring in children age 5 or younger.
IU School of Medicine’s Nathan Schmidt, PhD, an associate professor of pediatrics with the Ryan White Center for Pediatric Infectious Disease and Global Health and the Herman B Wells Center for Pediatric Research, said previous efforts to combat the disease have led to several advancements in malaria treatment and prevention, including new vaccines and antimalarial drugs, insecticides to manage mosquito populations and improved health care processes. However, he said new developments are desperately needed because the gains made in decreasing malaria-related deaths between the early 2000s and late 2010s have plateaued over the last five years.
“This plateau highlights the need for novel approaches to prevent malaria-related fatalities,” said Schmidt, whose research lab is focused on investigating this global health crisis and its critical impact on children. “Presently, there are no approaches that target gut microbiota. Therefore, we believe that our approach represents an exciting opportunity.”
In a pivotal 2016 article published in PNAS, Schmidt and his colleagues made a groundbreaking discovery in their experimental models: the gut microbiota has the capability to influence the severity of malaria. This revelation ignited their determination to pinpoint the precise microorganisms, called “Bacteroides,” within the intestinal tract that orchestrate this effect.
In their latest study, the researchers found mice harboring particular species of Bacteroides were notably associated with an elevated risk of severe malaria. A similar correlation was also observed in the intestinal tracts of children afflicted with severe malaria.
Most of the Schmidt lab’s research has been conducted using mouse models of malaria. Thanks to collaboration with several colleagues in the field, the research team was able to extend its observations by studying approximately 50 children with malaria in Uganda. They plan to continue their clinical observations by working with a cohort of over 500 children with malaria.

In an exciting scientific breakthrough, a team of researchers led by Professor Yehuda Tzfati from the Institute of Life Science at the Hebrew University and Professor Klaus Kaestner from the University of Pennsylvania Perelman School of Medicine, has introduced the “Telomouse.” This discovery involves changing just one tiny building block in one gene of ordinary lab mice, Mus musculus, to make their telomeres (our chromosome caps) look much more like the telomeres in humans.
Telomeres hold a pivotal responsibility in safeguarding our genetic material and ensuring the orderly division of our cells. Maintaining their structural integrity and optimal length holds the potential to diminish the risk of cancer and facilitate a healthier aging process. However, a significant hurdle has emerged: conventional laboratory mice possess telomeres approximately five times longer than those in humans. This disparity has posed a formidable challenge in using mice models for comprehending the implications of telomeres for human aging and cancer.
In the development of the Telomouse model, researchers turned their attention to a distinct mouse species, M. spretus, notable for its inherently shorter telomeres. Within the genetic code of these mice, a subtle variation within a pivotal protein known as RTEL1 was identified. By transferring this genetic distinction into typical laboratory mice, they succeeded in producing a lineage of mice with human-length telomeres. These novel Telomice exhibit robust health and reproductive capabilities, making them an exceptional resource for in-depth investigations into the complex realms of aging and cancer.
This study illuminates the central role of RTEL1 as the arbiter of telomere length. A nuanced modification to this crucial protein has enabled scientists to fashion a mouse model that closely approximates the human telomere length.
During the reaseach, the researchers also achieved an invaluable breakthrough in our ability to measure the length of each single telomere, and particularly the shortest telomeres in the cell which are the ones to dictate the cellular function and fate. They developed a novel method for measuring the precise length of individual telomeres using a new generation of DNA sequencing called nanopore sequencing. This method, termed ‘NanoTelSeq’, enables evaluating the ‘telomeric health’ in samples from blood or other tissues of healthy individuals, as well as patients of cancers and aging diseases, and improve diagnosis, prognosis and treatment of these patients.
Professor Yehuda Tzfati, the principal investigator of this endeavor, posits, “The Telomouse model is promising to enrich our comprehension of the intricate nexus between telomeres, cancer and the aging process. I believe that NanoTelSeq will replace currently used methods, enable acurate evaluation of the telomere state in patients and healthy individuals, and reveal how it affects human health. Such insights will hopefully culminate in innovative strategies for combating cancer and fostering the well-being of aging individuals.”

In a new study, a group of researchers, led by Dr. Joshua Goldberg from the Hebrew University, describe a new kind of neurochemical wave in the brain. Their research, published in Nature Communications, unveils the existence of traveling waves of the neurochemical acetylcholine in the striatum, a region of the brain responsible for motivating actions and habitual behaviors.
The motivation to execute an action is widely thought to depend on the release of the another neurochemical, dopamine, in the striatum. Recent research has shown that dopamine is released in wave-like patterns within the striatum. The team led by Goldberg discovered that acetylcholine is also released in the striatum in wave-like patterns. It has long been thought that in order for the striatum to function properly a balance needs to be maintained between dopamine and acetylcholine release in the striatum, and that the disruption of this balance leads to movement disorders such as Parkinson’s disease. The new study proposes a mathematical mechanism by which simultaneous waves of acetylcholine and dopamine arise, which may represent how this balance is realized.
The research was conducted using state-of-the-art genetic tools and advanced imaging techniques, allowing the team to visualize the acetylcholine waves in awake, behaving animals. Additionally, imaging techniques were employed to observe the interaction between acetylcholine and dopamine in vitro. Through a rigorous mathematical analysis, using reaction-diffusion activator-inhibitor models and computer simulations, the team proposed a model that explains the formation of both acetylcholine (the activator) and dopamine (the inhibitor) traveling waves.
Key Highlights of the Study:
First description of acetylcholine waves: in the striatum of healthy behaving animals.
Local Dopamine Release is Triggered by individual non-dopamine neurons: The study demonstrated that electrical activation of a single acetylcholine-releasing neuron in the striatum is sufficient to induce local dopamine release in its proximity.
A novel model for how the two neurochemical waves arise simultaneously: The study proposes a novel mathematical model based on the known interaction between acetylcholine and dopamine in the striatum, that can give rise to the simultaneous generation of these waves.
Finally, the study provides strong testable predictions about the relationship between these two wave phenomena and the neural mechanism for their formation. The study also proposes that dopamine and acetylcholine axons (which are the very long appendages of the dopamine and acetylcholine neurons) interact directly and locally in the striatum, which is not how neurons are traditionally thought to interact.

Cardiovascular deaths from extreme heat in the U.S. may more than double by the middle of the century. Without reductions in greenhouse gas emissions, that number could even triple, according to new research published today in the American Heart Association’s flagship journal Circulation.
“Climate change and its many manifestations will play an increasingly important role on the health of communities around the world in the coming decades, ” said lead study author Sameed Khatana, M.D., M.P.H., assistant professor of medicine at the University of Pennsylvania and a staff cardiologist at the Philadelphia Veterans Affairs Medical Center, both in Philadelphia. “Climate change is also a health equity issue as it will impact certain individuals and populations to a disproportionate degree and may exacerbate preexisting health disparities in the U.S.”
How much and how quickly greenhouse gas emissions increase in the next decades will determine the health impacts of extreme heat. More aggressive policies to reduce greenhouse gas emissions have the potential to reduce the number of people who may experience the adverse health effects of extreme heat, according to Khatana.
Previously, the authors examined county-by-county data in the continental U.S. to demonstrate a link between a greater number of extreme heat days and an increase in cardiovascular deaths between 2008-2017. This data served as a benchmark for the analysis in this new study. Researchers used models for future greenhouse gas emissions and future socioeconomic and demographic makeup of the U.S. population to estimate the possible impact of extreme heat on cardiovascular deaths in the middle years of the current century (2036-2065). They estimated the excess number of cardiovascular deaths associated with extreme heat by comparing the predicted number of deaths for each county if no extreme heat occurred vs. if the projected number of heat days occurred.
The analysis found: Between 2008 and 2019, extreme heat was associated with 1,651 excess cardiovascular deaths per year. Even if currently proposed reductions in greenhouse gas emissions are fully implemented, excess cardiovascular deaths due to extreme heat are projected to be 162% higher in the middle of this century compared to the 2008-2019 baseline. However, if those greenhouse gas emissions reduction policies are not implemented, excess cardiovascular deaths due to extreme heat are projected to increase 233% in the coming decades. Depending on how aggressively policies to reduce greenhouse gas emissions are implemented, adults aged 65 and older are projected to have a 2.9 to 3.5 times greater increase in cardiovascular death due to extreme heat in comparison to adults ages 20-64. Non-Hispanic Black adults are projected to have a 3.8 to 4.6 times greater increase in cardiovascular death due to extreme heat compared with non-Hispanic white adults, depending on the degree to which greenhouse policies are implemented. Projected increases in deaths due to extreme heat were not significantly different among adults in other racial or ethnic groups, or between men and women.”The magnitude of the percent increase was surprising. This increase accounts for not only the known association between cardiovascular deaths and extreme heat, but it is also impacted by the population getting older and the proportionate increases in the number of people from other races and/or ethnicities in the U.S.,” Khatana said.
Both medical and environmental factors may influence the greater impact of extreme heat for people in these population groups, he said. Disparities in neighborhood and environmental factors are crucial factors to also consider.

A study in mice conducted by the University of Cordoba proves that exposure to contaminating mixtures of metals and drug residue increases damage to health, and evaluates the positive effects of a diet enriched in selenium to reduce this harm
People are exposed daily, through the environment and their diets, to external substances that can be harmful to their health. Metals and the residue of pharmaceuticals, for example, in high doses, contaminate water and food, creating mixtures where they can interact, with this increasing their individual toxicity.
Analyzing the effects of environmental pollution on organisms is essential to develop regulations establishing maximum doses of these pollutants for people. But, what about mixtures of pollutants? What happens when, even when faced with accepted doses, the different compounds interact with each other?
To understand the health effects of exposure to these “cocktails of contaminants,” a team from the Biochemistry and Molecular Biology Department at the University of Cordoba, comprised of Nieves Abril, Paula Huertas, María José Prieto and Juan Jurado, evaluated, in mice, the toxicity of a mixture of contaminants that is very common in the environment and that accumulates along the food chain: a combination of metals (arsenic, cadmium, mercury) and drugs (diclofenac, flumequine).
In order to determine how these compounds interacted with each other, “we studied the controlled exposure of mice to this mixture and analyzed how it affects the proteins in the liver; that is, how their liver proteostasis changes when ingesting these mixtures of contaminants for two weeks,” explained Professor Nieves Abril.
Their conclusion is negative: the cocktail effect creates synergy between these compounds, doing increased damage to health increase when the compounds act together.
“We used a massive protein detection technique (shotgun proteomic), which allowed us to compare how the proteins of the group exposed to the mixture of contaminants were altered compared to the control group,” April explained.

Cat hair could be the purr-fect way to catch criminals, according to researchers from the University of Leicester.
They have shown that a single cat hair contains DNA which could link a suspect and a crime-scene, or a victim.
Around 26 per cent of UK householders own a cat and with the average feline shedding thousands of hairs annually, it’s inevitable that once you leave, you’ll bear evidence of the furry resident. This is potentially useful in the forensic investigation of criminal activity.
While a human perpetrator may take pains not to leave their own DNA behind, transferred cat hair contains its own DNA that could provide a link between a suspect and a crime-scene, or a victim.
In a paper published in the journal Forensic Science International: Genetics earlier this month, researchers at the University of Leicester describe a sensitive method that can extract maximum DNA information from just one cat hair.
Emily Patterson, the lead author of the study and a Leicester PhD student, said: “Hair shed by your cat lacks the hair root, so it contains very little useable DNA. In practice we can only analyse mitochondrial DNA, which is passed from mothers to their offspring, and is shared among maternally related cats.”
This means that hair DNA cannot individually identify a cat, making it essential to maximise information in a forensic test.

Dendritic cells are immune cells that capture and present antigens to T cells, activating an immune response. Researchers from Okayama University have discovered that short-chain fatty acids produced by intestinal bacteria regulate a crucial step in this process, the extension of dendritic “arms.” This breakthrough finding could potentially lead to the development of disease prevention strategies involving beneficial bacteria and new drugs targeting the regulation of dendritic cell function.
Dendritic cells play a key role in the mammalian immune system. These cells are present throughout the human body and are known to capture foreign bodies, i.e., antigens, using extendable “arms” called dendrites. Once captured, dendritic cells present these substances to immune T cells, thereby initiating an immune response. Dendritic cells are responsive to their environment and capable of changing their morphology and other attributes dynamically. For instance, dendritic cells in the intestine’s mucosa (inner layer) capture harmful bacteria by extending their dendrites through the epithelium (outermost layer) and into the intestinal lumen (inner space). However, the exact mechanism through which they do is not clear.
In a study that was published in The FEBS Journal on August 30, 2023, a team of researchers led by Associate Professor Kazuyuki Furuta, Mr. Takuho Inamoto, Dr. Kazuya Ishikawa, and Dr. Chikara Kaito from the Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences at Okayama University, Japan found that short-chain fatty acids (SCFAs) produced by intestinal bacteria are responsible for initiating the extension of dendrites into the intestinal lumen by dendritic cells.
SCFAs are a group of fatty acids with six or fewer carbon atoms, found in high concentrations in the intestine. The research team found that SCFAs such as acetic, propionic, butyric and valeric acids induce dendrite elongation by inhibiting an enzyme called histone deacetylase. Inhibition of histone deacetylase leads to the reorganization of the actin cytoskeleton of dendritic cells, inducing morphological changes. To arrive at these findings, the team examined the effects of SCFAs on a dendritic cell line (DC2.4 cells) and mouse bone marrow-derived dendritic cells (BMDCs) in a laboratory setting.
“Ours is the first study to demonstrate that SCFAs induce dendrite elongation by inhibiting histone deacetylase. Moreover, dendritic cells activated by SCFAs exhibited more stronger immune responses, due to increased pathogen uptake,” explains Dr. Furuta.
Upon conducting further analyses, the team found that treating dendritic cells with valeric acid led to an increase in the uptake of soluble proteins, insoluble beads, and Staphylococcus aureus bacteria. In contrast, the treatment of BMDCs with valeric acid enhanced their antigen presentation ability. It was also observed that SCAFs activated dendrite elongation by stimulating a signaling pathway involved in reorganization of the actin cytoskeleton — forces responsible for cell movement and cell morphology. So, what are the implications of these findings? “Our findings may be leveraged to identify beneficial intestinal bacteria producing SCFAs to activate immune responses and aid in the prevention of diseases. In addition, the dendritic elongation mechanism we discovered can be used as a target to develop drugs regulate immune responses artificially,” remarks Dr. Furuta.
By revealing the exact mechanism through which SCFAs trigger dendritic elongation, this study has paved the way for new drugs that directly target dendritic cells. We cannot wait to see these new treatments unfold!

Organoids help researchers understand biological processes in health and in disease. It is, however, difficult to influence the way in which they organize themselves into complex tissues. Now a group led by Nikolaus Rajewsky has found a new way to do so. They report their work in Nature Methods.
They look like storm clouds that could fit on the head of a pin: Organoids are three-dimensional cell cultures that play a key role in medical and clinical research. This is thanks to their ability to replicate tissue structures and organ functions in the petri dish. Scientists can use organoids to understand how diseases occur, how organs develop, and how drugs work. Single-cell technologies allow researchers to drill down to the molecular level of the cells. With spatial transcriptomics, they can observe which genes in the organoids are active and where over time.
The miniature organs are usually derived from stem cells. These are cells that haven’t differentiated at all, or only minimally. They can become any kind of cell, such as heart or kidney cells, muscle cells, or neurons. To make stem cells differentiate, scientists “feed” them with growth factors and embed them in a nutrient solution. There, the cells bunch together in tiny clumps and begin functioning and interacting as if they were in a real tissue. Previously, it was almost impossible to control this process. But now researchers led by Professor Nikolaus Rajewsky, Director of the Berlin Institute for Medical Systems Biology of the Max Delbrück Center (MDC-BIMSB), have published a paper in Nature Methods describing the technology they used to both initiate and control the process, and observe it across time and space. “We combined spatial transcriptomics with optogenetics,” says lead author Dr. Ivano Legnini. “This allows us to both control gene expression in living cells and observe their behavior.”
Using light sensors to activate or block genes
In optogenetics, natural or artificial “light sensors” are inserted into cells. If light reaches the sensors, they activate or block genes in the cells, depending on how they’re programmed. Legnini installed these light sensors in stem cell-derived neuronal precursor cells that would come together to form neural organoids. He worked on this with the Organoid Technology Platform team led by Dr. Agnieszka Rybak-Wolf, and with the Systems Biology of Neural Tissue Differentiation Lab led by Dr. Robert Patrick Zinzen. The researchers wanted to find out how the nervous system develops in the human embryo. Molecules known as morphogens play a key role in the process. They signal to neuronal progenitors whether they should become neurons that function in the front of the brain or the rear part of the spinal cord for example. The combination of these molecules produces typical patterns of gene expression during development.
The researchers used light to activate a morphogen called Sonic Hedgehog. Their subsequent spatially resolved single-cell analyses showed that the cells responded by arranging themselves into stereotypically patterned organoids. The researchers created the light in two ways: using either a laser microscope or a digital micromirror device, which Rajewsky’s group developed in collaboration with Dr. Andrew Woehler. At the time, Dr. Woehler was leading the Systems Biology Imaging Platform at the Max Delbrück Center. Since November 2022, he has been leading the Janelia Experimental Technology facility at the Howard Hughes Medical Institute in Ashburn, Virginia, USA. The micromirror microscope is fitted with a chip holding several hundred thousand tiny mirrors. These can be programmed so the microscope can — unlike a laser, which only hits a single point — produce complex light patterns on a sample.
Accurate — with room for improvement
“Our method allows us to very accurately reproduce, in the petri dish, processes that are connected to gene expression in tissue,” says Legnini. In March this year, he began setting up his own working group at the Human Technopole in Milan, Italy. His plans for the group include improving the technology’s spatial and temporal resolution and making it usable for other organoids.
Rajewsky also wants to refine the method: “I’m really looking forward to working with optogenetics experts to further improve the technology and to apply it to clinically relevant human organoid models.”