After 25 years, researchers uncover genetic cause of rare neurological disease

Spinocerebellar ataxia 4 is a devastating progressive movement disease that can begin as early as the late teens. Now, a multinational research team led by University of Utah researchers has conclusively identified the genetic difference that causes the disease, bringing answers to families and opening the door to future treatments.

Some families call it a trial of faith. Others just call it a curse. The progressive neurological disease known as spinocerebellar ataxia 4 (SCA4) is a rare condition, but its effects on patients and their families can be severe. For most people, the first sign is difficulty walking and balancing, which gets worse as time progresses. The symptoms usually start in a person's forties or fifties but can begin as early as the late teens. There is no known cure. And, until now, there was no known cause.

Now, after 25 years of uncertainty, a multinational study led by Stefan Pulst, M.D., Dr. med., professor and chair of neurology, and K. Pattie Figueroa, a project manager in neurology, both in the Spencer Fox Eccles School of Medicine at University of Utah, has conclusively identified the genetic difference that causes SCA4, bringing answers to families and opening the door to future treatments. Their results are published in the peer-reviewed journal Nature Genetics.

Solving a genetic enigma

SCA4's pattern of inheritance had long made it clear that the disease was genetic, and previous research had located the gene responsible to a specific region of one chromosome. But that region proved extraordinarily difficult for researchers to analyze: full of repeated segments that look like parts of other chromosomes, and with an unusual chemical makeup that makes most genetic tests fail.

To pinpoint the change that causes SCA4, Figueroa and Pulst, along with the rest of the research team, used a recently developed advanced sequencing technology. By comparing DNA from affected and unaffected people from several Utah families, they found that in SCA4 patients, a section in a gene called ZFHX3 is much longer than it should be, containing an extra-long string of repetitive DNA.

Isolated human cells that have the extra-long version of ZFHX3 show signs of being sick -- they don't seem able to recycle proteins as well as they should, and some of them contain clumps of stuck-together protein.

"This mutation is a toxic expanded repeat and we think that it actually jams up how a cell deals with unfolded or misfolded proteins," says Pulst, the last author on the study. Healthy cells need to constantly break down non-functional proteins. Using cells from SCA4 patients, the group showed that the SCA4-causing mutation gums up the works of cells' protein-recycling machinery in a way that could poison nerve cells.

Hope for the future

Intriguingly, something similar seems to be happening in another form of ataxia, SCA2, which also interferes with protein recycling. The researchers are currently testing a potential therapy for SCA2 in clinical trials, and the similarities between the two conditions raise the possibility that the treatment might benefit patients with SCA4 as well.

Finding the genetic change that leads to SCA4 is essential to develop better treatments, Pulst says. "The only step to really improve the life of patients with inherited disease is to find out what the primary cause is. We now can attack the effects of this mutation potentially at multiple levels."

But while treatments will take a long time to develop, simply knowing the cause of the disease can be incredibly valuable for families affected by SCA4, says Figueroa, the first author on the study. People in affected families can learn whether they have the disease-causing genetic change or not, which can help inform life decisions such as family planning. "They can come and get tested and they can have an answer, for better or for worse," Figueroa says.

The researchers emphasize that their discoveries would not have been possible without the generosity of SCA4 patients and their families, whose sharing of family records and biological samples allowed them to compare the DNA of affected and unaffected individuals. "Different branches of the family opened up not just their homes but their history to us," Figueroa says. Family records were complete enough that the researchers were able to trace the origins of the disease in Utah back through history to a pioneer couple who moved to Salt Lake Valley in the 1840s.

Since meeting so many families with the disease, studying SCA4 has become a personal quest, Figueroa adds. "I've been working on SCA4 directly since 2010 when the first family approached me, and once you go to their homes and get to know them, they're no longer the number on the DNA vial. These are people you see every day… You can't walk away. This is not just science. This is somebody's life."

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Parkinson's Disease: New theory on the disease's origins and spread

The nose or the gut? For the past two decades, the scientific community has debated the wellspring of the toxic proteins at the source of Parkinson's disease. In 2003, a German pathologist, Heiko Braak, MD, first proposed that the disease begins outside the brain. More recently, Per Borghammer, MD, with Aarhus University Hospital in Denmark, and his colleagues argue that the disease is the result of processes that start in either the brain's smell center (brain-first) or the body's intestinal tract (body-first).

A new hypothesis paper appearing in the Journal of Parkinson's Disease on World Parkinson's Day unites the brain- and body-first models with some of the likely causes of the disease-environmental toxicants that are either inhaled or ingested. The authors of the new study, who include Borghammer, argue that inhalation of certain pesticides, common dry cleaning chemicals, and air pollution predispose to a brain-first model of the disease. Other ingested toxicants, such as tainted food and contaminated drinking water, lead to body-first model of the disease.

"In both the brain-first and body-first scenarios the pathology arises in structures in the body closely connected to the outside world," said Ray Dorsey, MD, a professor of Neurology at the University of Rochester Medical Center and co-author of the piece. "Here we propose that Parkinson's is a systemic disease and that its initial roots likely begin in the nose and in the gut and are tied to environmental factors increasingly recognized as major contributors, if not causes, of the disease. This further reinforces the idea that Parkinson's, the world's fastest growing brain disease, may be fueled by toxicants and is therefore largely preventable."

Different pathways to the brain, different forms of disease

A misfolded protein called alpha-synuclein has been in scientists' sights for the last 25 years as one of the driving forces behind Parkinson's. Over time, the protein accumulates in the brain in clumps, called Lewy bodies, and causes progressive dysfunction and death of many types of nerve cells, including those in the dopamine-producing regions of the brain that control motor function. When first proposed, Braak thought that an unidentified pathogen, such as a virus, may be responsible for the disease.

The new piece argues that toxins encountered in the environment, specifically the dry cleaning and degreasing chemicals trichloroethylene (TCE) and perchloroethylene (PCE), the weed killer paraquat, and air pollution, could be common causes for the formation of toxic alpha-synuclein. TCE and PCE contaminates thousands of former industrial, commercial, and military sites, most notably the Marine Corps base Camp Lejeune, and paraquat is one of the most widely used herbicides in the US, despite being banned for safety concerns in more than 30 countries, including the European Union and China. Air pollution was at toxic levels in nineteenth century London when James Parkinson, whose 269th birthday is celebrated today, first described the condition.

The nose and the gut are lined with a soft permeable tissue, and both have well established connections to the brain. In the brain-first model, the chemicals are inhaled and may enter the brain via the nerve responsible for smell. From the brain's smell center, alpha-synuclein spreads to other parts of the brain principally on one side, including regions with concentrations of dopamine-producing neurons. The death of these cells is a hallmark of Parkinson's disease. The disease may cause asymmetric tremor and slowness in movement and, a slower rate of progression after diagnosis, and only much later, significant cognitive impairment or dementia.

When ingested, the chemicals pass through the lining of the gastrointestinal tract. Initial alpha-synuclein pathology may begin in the gut's own nervous system from where it can spread to both sides of the brain and spinal cord. This body-first pathway is often associated with Lewy body dementia, a disease in the same family as Parkinson's, which is characterized by early constipation and sleep disturbance, followed by more symmetric slowing in movements and earlier dementia, as the disease spreads through both brain hemispheres.

New models to understand and study brain diseases

"These environmental toxicants are widespread and not everyone has Parkinson's disease," said Dorsey. "The timing, dose, and duration of exposure and interactions with genetic and other environmental factors are probably key to determining who ultimately develops Parkinson's. In most instances, these exposures likely occurred years or decades before symptoms develop."

Pointing to a growing body of research linking environmental exposure to Parkinson's disease, the authors believe the new models may enable the scientific community to connect specific exposures to specific forms of the disease. This effort will be aided by increasing public awareness of the adverse health effects of many chemicals in our environment. The authors conclude that their hypothesis "may explain many of the mysteries of Parkinson's disease and open the door toward the ultimate goal-prevention."

In addition to Parkinson's, these models of environmental exposure may advance understanding of how toxicants contribute to other brain disorders, including autism in children, ALS in adults, and Alzheimer's in seniors. Dorsey and his colleagues at the University of Rochester have organized a symposium on the Brain and the Environment in Washington, DC, on May 20 that will examine the role toxicants in our food, water, and air are playing in all these brain diseases.

Read more at Science Daily

Discovery of how limiting damage from an asthma attack could stop disease

Scientists at King's College London have discovered a new cause for asthma that sparks hope for treatment that could prevent the life-threatening disease.

Most current asthma treatments stem from the idea that it is an inflammatory disease. Yet, the life-threatening feature of asthma is the attack or the constriction of airways, making breathing difficult. The new study, published today in Science, shows for the first time that many features of an asthma attack -- inflammation, mucus secretion, and damage to the airway barrier that prevents infections -- result from this mechanical constriction in a mouse model.

The findings suggest that blocking a process that normally causes epithelial cell death could prevent the damage, inflammation, and mucus that result from an asthma attack.

Professor Jody Rosenblatt from King's College London said: "Our discovery is the culmination of more than ten years work. As cell biologists who watch processes, we could see that the physical constriction of an asthma attack causes widespread destruction of the airway barrier. Without this barrier, asthma sufferers are far more likely to get long-term inflammation, wound healing, and infections that cause more attacks. By understanding this fundamental mechanism, we are now in a better position to prevent all these events."

In the UK, 5.4 million people have asthma and can suffer from symptoms such as wheezing, coughing, feeling breathlessness and a tight chest. Triggers such as pollen or dust can make asthma symptoms worse and can lead to a life-threatening asthma attack.

Despite the disease commonality, the causes of asthma are still not understood. Current medications treat the consequences of an asthma attack by opening the airways, calming inflammation, and breaking up the sticky mucus which clogs the airway, which help control asthma, but do not prevent it.

The answer to stopping asthma symptoms may lie in cell extrusion, a process the researchers discovered that drives most epithelial cell death. Scientists used mouse lung models and human airway tissue to discover that when the airways contract, known as bronchoconstriction, the epithelial cells that line the airway get squeezed out to later die.

Because bronchoconstriction causes so many cell extrusions, it damages the airway barrier which causes inflammation and excess mucus.

In previous studies, the scientists found that the chemical compound gadolinium can block extrusion. In this study, they found it could work in mice to prevent the excess extrusion that causes damage and inflammation after an asthma attack. The authors note that gadolinium has not been tested in humans and has not been deemed to be safe or efficacious.

Professor Rosenblatt said: "This constriction and destruction of the airways causes the post-attack inflammation and excess mucus secretion that makes it difficult for people with asthma to breathe.

"Current therapies do not prevent this destruction -- an inhaler such as Albuterol opens the airways, which is critical to breathing but, dishearteningly, we found it does not prevent the damage and the symptoms that follow an attack. Fortunately, we found that we can use an inexpensive compound, gadolinium which is frequently used for MRI imaging, to stop the airway damage in mice models as well as the ensuing inflammation and mucus secretion. Preventing this damage could then prevent the build-up of musculature that cause future attacks."

Professor Chris Brightling from the University of Leicester and one of the co-authors of the study said: "In the last decade there has been tremendous progress in therapies for asthma particularly directed towards airway inflammation. However, there remains ongoing symptoms and attacks in many people with asthma. This study identifies a new process known as epithelial extrusion whereby damage to the lining of the airway occurs as a consequence of mechanical constriction and can drive many of the key features of asthma. Better understanding of this process is likely to lead to new therapies for asthma."

Dr Samantha Walker, Director of Research and Innovation at Asthma + Lung UK, said: "Only two per cent of public health funding is allocated to developing new treatments for the 12 million people living with lung conditions in the UK so new research that can help in the treatment or prevention of asthma is good news.

"This research using an experimental mouse model shows that constricting the airways leads to damage to the lung lining and inflammation, like that seen in asthma. It is this constriction and resulting damage that makes it difficult for people with asthma to breathe.

"Current medications for asthma work by treating the inflammation, but this isn't effective for everyone. Treatments aim to prevent future asthma attacks and improve asthma control by taking inhalers every day, but we know that ~31 per cent of people with asthma don't have treatment options that work for them, putting them at risk of potentially life-threatening asthma attacks.

"This discovery opens important new doors to explore possible new treatment options desperately needed for people with asthma rather than focusing solely on inflammation."

The discovery of the mechanics behind cell extrusion could underlie other inflammatory diseases that also feature constriction such as cramping of the gut and inflammatory bowel disease.

Read more at Science Daily

Overeating and starving both damage the liver: Cavefish provide new insight into fatty liver disease

Fatty liver, which can lead to liver damage and disease, can occur from both overeating and starvation. Now, new research shows how naturally starvation-resistant cavefish, unlike other animals, are able to protect their liver and remain healthy. The findings have implications for understanding and potentially addressing liver conditions in humans.

Researchers from the Stowers Institute for Medical Research in collaboration with Universite Libre de Bruxelles in Belgium and Iowa State University compared cavefish to other animals more susceptible to starvation, and identified a gene responsible for the development of starvation-induced fatty liver.

The study, published in Life Science Alliance on March 11, 2024, led by co-first authors Ansa Cobham, Ph.D., in the lab of Associate Investigator Nicolas Rohner, Ph.D., and Macarena Pozo-Morales, Ph.D., in the lab of Assistant Professor Sumeet Pal Singh, Ph.D., also showed that this evolutionarily conserved gene can be targeted by an existing drug candidate to protect against liver damage.

"This same approach can be applied to what we see in overconsumption," Rohner said.

"In Western societies where, often, too many calories and not enough exercise is a problem, this new understanding may lead to prevention or potential treatment of fatty liver disease."

"We have discovered for the first time an organism -- cavefish -- that can avoid fatty liver under starvation conditions," said Cobham.

"Fatty liver can result in complications like liver cirrhosis and liver failure. This study helps us understand more about the biology underlying these diseases in humans."

Cavefish are cousins of the Mexican tetra river fish that flooded into underground caves over 100,000 years ago.

The researchers show that in the absence of food, cavefish at early developmental stages not only survive much longer than their river fish counterparts, but also do not accumulate liver fat.

"This was the first time we clearly showed that the mechanism for this resistance is accomplished by not accumulating excess fat in the liver," said Rohner.

The accumulation of fat in liver cells leads to organ damage and atrophy or wasting away.

The researchers compared gene expression levels between cavefish, river fish, zebrafish, and even fruit flies, identifying a gene that is activated during prolonged periods of starvation in all but cavefish.

"Expression levels of this gene are reduced in cavefish, which is a good indicator that if we are able to target this gene in humans, we may be able to treat or manage human metabolic diseases such as Type 2 diabetes and obesity," said Cobham.

The team's findings indicate that the starvation-induced gene not only regulates fatty liver disease, but its mechanism has also been conserved from fruit flies to fish to humans, or approximately 400 million years of animal evolution.

Inhibiting this gene's protein in zebrafish and river fish larvae and deleting the gene in fruit flies resulted in less liver fat and larger livers indicating this protects the liver from damage and atrophy.

Read more at Science Daily

Researchers identify gene involved in neuronal vulnerability in Alzheimer's disease

Early stages of neurodegenerative disorders are characterized by the accumulation of proteins in discrete populations of brain cells and degeneration of these cells. For most diseases, this selective vulnerability pattern is unexplained, yet it could yield major insight into pathological mechanisms. Alzheimer's disease (AD), the world-leading cause of dementia, is defined by the appearance of two hallmark pathological lesions, amyloid plaques (extracellular aggregates of Aβ peptides) and neurofibrillary tangles (intracellular aggregates of hyperphosphorylated tau, or NFTs). While plaques are widespread in the neocortex and hippocampus, NFTs follow a well-defined regional pattern that starts in principal neurons from the entorhinal cortex.

In a new study from Boston University Chobanian & Avedisian School of Medicine, researchers have identified a gene they believe may lead to the degeneration of the neurons that are most vulnerable to AD.

"We are trying to understand why certain neurons in the brain are particularly vulnerable during the earliest stages of AD. Why they accumulate and degenerate very early is unknown. We believe elucidating this vulnerability would allow for a new therapeutic avenue for AD," said corresponding author Jean-Pierre Roussarie, PhD, assistant professor of anatomy & neurobiology at the school.

In collaboration with leading computational genomic experts from Rice University, the BU researchers along with co-corresponding author, Patricia Rodriguez-Rodriguez, PhD, from Karolinska Institute, used cutting-edge analysis tools with machine learning to identify the gene DEK as possibly responsible for vulnerability of entorhinal cortex neurons.

They injected viruses into the entorhinal cortex of experimental models and neurons grown in the lab to manipulate levels of the DEK gene.

When they reduced the levels of the DEK gene, vulnerable neurons started to accumulate tau and to degenerate.

According to the researchers, preventing these neurons from degeneration by targeting DEK or proteins that collaborate with DEK, would prevent patients from developing memories loss and would curtail the disease before it spreads to larger areas of the brain.

"Given that entorhinal cortex neurons are necessary for the formation of new memories and since they are so vulnerable and the first to die, this explains why the first symptom of AD is the inability to form new memories," said Roussarie.

The researchers believe these findings are the first step in understanding how these fragile neurons die, yet they hope to uncover additional genes to fully understand what leads to the death of critical memory-forming neurons.

Read more at Science Daily

Researchers 3D-print functional human brain tissue

A team of University of Wisconsin-Madison scientists has developed the first 3D-printed brain tissue that can grow and function like typical brain tissue.

It's an achievement with important implications for scientists studying the brain and working on treatments for a broad range of neurological and neurodevelopmental disorders, such as Alzheimer's and Parkinson's disease.

"This could be a hugely powerful model to help us understand how brain cells and parts of the brain communicate in humans," says Su-Chun Zhang, professor of neuroscience and neurology at UW-Madison's Waisman Center.

"It could change the way we look at stem cell biology, neuroscience, and the pathogenesis of many neurological and psychiatric disorders."

Printing methods have limited the success of previous attempts to print brain tissue, according to Zhang and Yuanwei Yan, a scientist in Zhang's lab.

The group behind the new 3D-printing process described their method today in the journal Cell Stem Cell.

Instead of using the traditional 3D-printing approach, stacking layers vertically, the researchers went horizontally.

They situated brain cells, neurons grown from induced pluripotent stem cells, in a softer "bio-ink" gel than previous attempts had employed.

"The tissue still has enough structure to hold together but it is soft enough to allow the neurons to grow into each other and start talking to each other," Zhang says.

The cells are laid next to each other like pencils laid next to each other on a tabletop.

"Our tissue stays relatively thin and this makes it easy for the neurons to get enough oxygen and enough nutrients from the growth media," Yan says.

The results speak for themselves -- which is to say, the cells can speak to each other.

The printed cells reach through the medium to form connections inside each printed layer as well as across layers, forming networks comparable to human brains.

The neurons communicate, send signals, interact with each other through neurotransmitters, and even form proper networks with support cells that were added to the printed tissue.

"We printed the cerebral cortex and the striatum and what we found was quite striking," Zhang says.

"Even when we printed different cells belonging to different parts of the brain, they were still able to talk to each other in a very special and specific way."

The printing technique offers precision -- control over the types and arrangement of cells -- not found in brain organoids, miniature organs used to study brains.

The organoids grow with less organization and control.

"Our lab is very special in that we are able to produce pretty much any type of neurons at any time. Then we can piece them together at almost any time and in whatever way we like," Zhang says.

"Because we can print the tissue by design, we can have a defined system to look at how our human brain network operates. We can look very specifically at how the nerve cells talk to each other under certain conditions because we can print exactly what we want."

That specificity provides flexibility. The printed brain tissue could be used to study signaling between cells in Down syndrome, interactions between healthy tissue and neighboring tissue affected by Alzheimer's, testing new drug candidates, or even watching the brain grow.

"In the past, we have often looked at one thing at a time, which means we often miss some critical components. Our brain operates in networks. We want to print brain tissue this way because cells do not operate by themselves. They talk to each other. This is how our brain works and it has to be studied all together like this to truly understand it," Zhang says.

"Our brain tissue could be used to study almost every major aspect of what many people at the Waisman Center are working on. It can be used to look at the molecular mechanisms underlying brain development, human development, developmental disabilities, neurodegenerative disorders, and more."

The new printing technique should also be accessible to many labs.

It does not require special bio-printing equipment or culturing methods to keep the tissue healthy, and can be studied in depth with microscopes, standard imaging techniques and electrodes already common in the field.

The researchers would like to explore the potential of specialization, though, further improving their bio-ink and refining their equipment to allow for specific orientations of cells within their printed tissue..

"Right now, our printer is a benchtop commercialized one," Yan says.

Read more at Science Daily

Evolution is not as random as previously thought

A groundbreaking study has found that evolution is not as unpredictable as previously thought, which could allow scientists to explore which genes could be useful to tackle real-world issues such as antibiotic resistance, disease and climate change.

The study, which is published in the Proceedings of the National Academy of Sciences (PNAS), challenges the long-standing belief about the unpredictability of evolution, and has found that the evolutionary trajectory of a genome may be influenced by its evolutionary history, rather than determined by numerous factors and historical accidents.

The study was led by Professor James McInerney and Dr. Alan Beavan from the School of Life Sciences at the University of Nottingham, and Dr. Maria Rosa Domingo-Sananes from Nottingham Trent University.

"The implications of this research are nothing short of revolutionary," said Professor McInerney, the lead author of the study.

"By demonstrating that evolution is not as random as we once thought, we've opened the door to an array of possibilities in synthetic biology, medicine, and environmental science."

The team carried out an analysis of the pangenome -- the complete set of genes within a given species, to answer a critical question of whether evolution is predictable or whether the evolutionary paths of genomes are dependent on their history and so not predictable today.

Using a machine learning approach known as Random Forest, along with a dataset of 2,500 complete genomes from a single bacterial species, the team carried out several hundred thousand hours of computer processing to address the question.

After feeding the data into their high-performance computer, the team first made "gene families" from each of the gene of each genome.

"In this way, we could compare like-with-like across the genomes," said Dr. Domingo-Sananes.

Once the families had been identified, the team analysed the pattern of how these families were present in some genomes and absent in others.

"We found that some gene families never turned up in a genome when a particular other gene family was already there, and on other occasions, some genes were very much dependent on a different gene family being present."

In effect, the researchers discovered an invisible ecosystem where genes can cooperate or can be in conflict with one another.

"These interactions between genes make aspects of evolution somewhat predictable and furthermore, we now have a tool that allows us to make those predictions," adds Dr. Domingo-Sananes.

Dr Beavan said: "From this work, we can begin to explore which genes "support" an antibiotic resistance gene, for example. Therefore, if we are trying to eliminate antibiotic resistance, we can target not just the focal gene, but we can also target its supporting genes.

"We can use this approach to synthesise new kinds of genetic constructs that could be used to develop new drugs or vaccines. Knowing what we now know has opened the door to a whole host of other discoveries."

Read more at Science Daily

Scientists engineer plant microbiome to protect crops against disease

Breakthrough could dramatically cut the use of pesticides and unlock other opportunities to bolster plant health

Scientists have engineered the microbiome of plants for the first time, boosting the prevalence of 'good' bacteria that protect the plant from disease.

The findings published in Nature Communications by researchers from the University of Southampton, China and Austria, could substantially reduce the need for environmentally destructive pesticides.

There is growing public awareness about the significance of our microbiome -- the myriad of microorganisms that live in and around our bodies, most notably in our guts.

Our gut microbiomes influence our metabolism, our likelihood of getting ill, our immune system, and even our mood.

Plants too host a huge variety of bacteria, fungi, viruses, and other microorganisms that live in their roots, stems, and leaves.

For the past decade, scientists have been intensively researching plant microbiomes to understand how they affect a plant's health and its vulnerability to disease.

"For the first time, we've been able to change the makeup of a plant's microbiome in a targeted way, boosting the numbers of beneficial bacteria that can protect the plant from other, harmful bacteria," says Dr Tomislav Cernava, co-author of the paper and Associate Professor in Plant-Microbe Interactions at the University of Southampton.

"This breakthrough could reduce reliance on pesticides, which are harmful to the environment. We've achieved this in rice crops, but the framework we've created could be applied to other plants and unlock other opportunities to improve their microbiome. For example, microbes that increase nutrient provision to crops could reduce the need for synthetic fertilisers."

The international research team discovered that one specific gene found in the lignin biosynthesis cluster of the rice plant is involved in shaping its microbiome.

Lignin is a complex polymer found in the cell walls of plants -- the biomass of some plant species consists of more than 30 per cent lignin.

First, the researchers observed that when this gene was deactivated, there was a decrease in the population of certain beneficial bacteria, confirming its importance in the makeup of the microbiome community.

The researchers then did the opposite, over-expressing the gene so it produced more of one specific type of metabolite -- a small molecule produced by the host plant during its metabolic processes.

This increased the proportion of beneficial bacteria in the plant microbiome.

When these engineered plants were exposed to Xanthomonas oryzae -- a pathogen that causes bacterial blight in rice crops, they were substantially more resistant to it than wild-type rice.

Bacterial blight is common in Asia and can lead to substantial loss of rice yields.

It's usually controlled by deploying polluting pesticides, so producing a crop with a protective microbiome could help bolster food security and help the environment.

Read more at Science Daily

Serotonin loss may contribute to cognitive decline in the early stages of Alzheimer's disease

Comparing PET scans of more than 90 adults with and without mild cognitive impairment (MCI), Johns Hopkins Medicine researchers say relatively lower levels of the so-called "happiness" chemical, serotonin, in parts of the brain of those with MCI may play a role in memory problems including Alzheimer's disease.

The findings, first published online Sept. 13 in the Journal of Alzheimer's Disease, lend support to growing evidence that measurable changes in the brain happen in people with mild memory problems long before an Alzheimer's diagnosis, and may offer novel targets for treatments to slow or stop disease progression.

"The study shows that people with mild cognitive impairment already display loss of the serotonin transporter. This measure that reflects serotonin degeneration is associated with problems with memory, even when we take into account in our statistical model MRI measures of neurodegeneration and PET measures of the amyloid protein that are associated with Alzheimer's Disease," says Gwenn Smith, Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine.

MCI describes the diagnostic stage between normal brain function in aging and Alzheimer's Disease (AD). Symptoms of MCI include frequent forgetfulness of recent events, word finding difficulty, and loss of the sense of smell.

Those with MCI may stay in this stage indefinitely, or progress to more severe forms of cognitive deficits, giving urgency to the search for predictive markers, and possible early prevention interventions, investigators say.

The investigators cautioned that their study showed a correlation between lower serotonin transporter levels and memory problems in MCI, and was not designed to show causation or the role of serotonin in the progression from MCI to AD. To answer these questions, further research is needed to study over time healthy controls and individuals with MCI to demonstrate the role of serotonin in disease progression.

For the study, the Hopkins scientists recruited 49 volunteers with MCI, and 45 healthy adults ages 55 and older who underwent an MRI to measure changes in brain structure and two positron emission tomography (PET) scans of their brains at Johns Hopkins between 2009 and 2022.

The research team used PET scans to look specifically at the serotonin transporter -- a neurotransmitter, or brain chemical long associated with positive mood, appetite and sleep -- and to look at the amyloid-beta protein (Aβ) distribution in the brain.

Aβ is thought to play a central role in the pathology of AD. Studies in mice done at Johns Hopkins have shown that serotonin degeneration occurs before the development of widespread beta-amyloid deposits in the brain.

Loss of serotonin is often associated with depression, anxiety, and psychological disorders.

Researchers found that MCI patients had lower levels of the serotonin transporter, and higher levels of Aβ than healthy controls.

The MCI patients had up to 25% lower serotonin transporter levels in cortical and limbic regions than healthy controls.

In particular, they report, lower serotonin transporter levels were found in cortical, limbic, and subcortical regions of the brains in those with MCI, areas specifically responsible for executive function, emotion, and memory.

"The correlation we observed between lower serotonin transporters and memory problems in MCI is important because we may have identified a brain chemical that we can safely target that may improve cognitive deficits and, potentially, depressive symptoms," says Smith.

"If we can show that serotonin loss over time is directly involved in the transition from MCI to AD, recently developed antidepressant medications may be an effective way to improve memory deficits and depressive symptoms and thus, may be a powerful way forward to slow disease progression."

Researchers say future studies include longitudinal follow up of individuals with MCI to compare serotonin degeneration to the increase in and Aβ levels, as well as the increase in levels of the Tau protein that is also associated with AD compared to healthy adults.

They are also studying multi-modal antidepressant drugs to treat depression and memory deficits in hopes of mitigating and halting symptoms.

Read more at Science Daily

Nanoplastics promote conditions for Parkinson's across various lab models

Nanoplastics interact with a particular protein that is naturally found in the brain, creating changes linked to Parkinson's disease and some types of dementia.

In a Duke-led study appearing Nov. 17 in Science Advances, the researchers report that the findings create a foundation for a new area of investigation, fueled by the timely impact of environmental factors on human biology.

"Parkinson's disease has been called the fastest growing neurological disorder in the world," said principal investigator, Andrew West, Ph.D., professor in the Department of Pharmacology and Cancer Biology at Duke University School of Medicine. "Numerous lines of data suggest environmental factors might play a prominent role in Parkinson's disease, but such factors have for the most part not been identified."

Improperly disposed plastics have been shown to break into very small pieces and accumulate in water and food supplies, and were found in the blood of most adults in a recent study.

"Our study suggests that the emergence of micro and nanoplastics in the environment might represent a new toxin challenge with respect to Parkinson's disease risk and progression," West said. "This is especially concerning given the predicted increase in concentrations of these contaminants in our water and food supplies."

West and colleagues in Duke's Nicholas School of the Environment and the Department of Chemistry at Trinity College of Arts and Sciences found that nanoparticles of the plastic polystyrene -- typically found in single use items such as disposable drinking cups and cutlery -- attract the accumulation of the protein known as alpha-synuclein. West said the study's most surprising findings are the tight bonds formed between the plastic and the protein within the area of the neuron where these accumulations are congregating, the lysosome.

Researchers said the plastic-protein accumulations happened across three different models performed in the study -- in test tubes, cultured neurons, and mouse models of Parkinson's disease. West said questions remain about how such interactions might be happening within humans and whether the type of plastic might play a role.

"While microplastic and nanoplastic contaminants are being closely evaluated for their potential impact in cancer and autoimmune diseases, the striking nature of the interactions we could observe in our models suggest a need for evaluating increasing nanoplastic contaminants on Parkinson's disease and dementia risk and progression," West said.

"The technology needed to monitor nanoplastics is still at the earliest possible stages and not ready yet to answer all the questions we have," he said. "But hopefully efforts in this area will increase rapidly, as we see what these particles can do in our models. If we know what to look out for, we can take the necessary steps to protect ourselves, without compromising all the benefits we reap every day from plastics."

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Movement sensors can detect disease in wild boar

Behavioral sensors attached to wild boars have been used to detect when animals are sick with African Swine Fever, a fatal viral disease that affects both boar and domestic pigs. Accelerometer sensors, which measure tiny changes in movement, showed that wild boars reduced their daily activity by up to 20 percent when infected with the virus. The findings, published by scientists from the Max Planck Institute of Animal Behavior, show that lightweight sensors can detect sickness behavior in wild boar -- raising the possibility of a minimally invasive tool to assist in the control and prevention of African Swine Fever.

Although the virus cannot be transmitted to humans, African Swine Fever is a major threat to the global pig industry and has significant economic and social impact. The highly contagious virus spreads easily between wild boar and domestic pigs, and so knowing when a disease outbreak occurs in the wild and on farms is important for curbing the spread of African Swine Fever. But detecting disease in wild animals is not straight forward. Currently, testing for African Swine Fever in wild boar is done by sampling animals that are either hunted or found dead, which creates a long lag between when the disease emerges in a population to when it is actually detected.

Seeking to reduce this lag, scientists from Germany, Spain and Austria teamed up to investigate if technology that 'reads' an animal's behavior could be harnessed for early detection of disease in wild boar. Their findings point to the potential of accelerometer sensors as an accessible tool that can support the existing disease management approaches for African Swine Fever surveillance and control. "This is a game-changer for wildlife disease monitoring," says Kevin Morelle, first author of the study and a scientist with the Max Planck Institute of Animal Behavior. "We show that a lightweight behavioral sensor deployed on a wild animal can be a sentinel for potential health threats."

Accelometers measure animals' movements

The scientists attached accelerometer tags, weighting 30 grams, on twelve wild boars that were studied in controlled conditions. The boars were infected with African Swine Fever as part of a separate study aimed at developing a vaccine against the disease. The accelerometers, which are the equivalent of 'Fitbits' or pedometers, took ultra-high resolution measurements of the animals' movements. The measurements, called 'Overall Dynamic Body Acceleration', showed how much the boars were active. The scientists found that when boars became sick with African Swine Fever, they were ten to twenty percent less active daily than when they were healthy. To validate the findings, the study authors attached accelerometers to a group of healthy boars living in natural conditions. They then compared the activity patterns of infected and healthy wild boar.

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Engineers design more powerful RNA vaccines

RNA vaccines against Covid-19 have proven effective at reducing the severity of disease. However, a team of researchers at MIT is working on making them even better. By tweaking the design of the vaccines, the researchers showed that they could generate Covid-19 RNA vaccines that produce a stronger immune response, at a lower dose, in mice.

Adjuvants are molecules commonly used to increase the immune response to vaccines, but they haven't yet been used in RNA vaccines. In this study, the MIT researchers engineered both the nanoparticles used to deliver the Covid-19 antigen, and the antigen itself, to boost the immune response, without the need for a separate adjuvant.

If further developed for use in humans, this type of RNA vaccine could help to reduce costs, reduce the dosage needed, and potentially lead to longer-lasting immunity. The researchers' tests also showed that when delivered intranasally, the vaccine induced a strong immune response when compared to the response elicited by traditional, intramuscular vaccination.

"With intranasal vaccination, you might be able to kill Covid at the mucus membrane, before it gets into your body," says Daniel Anderson, a professor in MIT's Department of Chemical Engineering, a member of MIT's Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES), and the senior author of the study. "Intranasal vaccines may also be easier to administer to many people, since they don't require an injection."

The researchers believe that the effectiveness of other types of RNA vaccines that are now in development, including vaccines for cancer, could be improved by incorporating similar immune-stimulating properties.

Former MIT postdoc Bowen Li, who is now an assistant professor at the University of Toronto; graduate student Allen Jiang; and former MIT postdoc Idris Raji, who was a research fellow at Boston Children's Hospital, are the lead authors of the new study, which appears today in Nature Biomedical Engineering. The research team also includes Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute, and several other MIT researchers.

Boosting immunity

RNA vaccines consist of a strand of RNA that encodes a viral or bacterial protein, also called an antigen. In the case of Covid-19 vaccines, this RNA codes for a segment of the virus's spike protein. That RNA strand is packaged in a lipid nanoparticle carrier, which protects the RNA from being broken down in the body and helps it get into cells.

Once delivered into cells, the RNA is translated into proteins that the immune system can detect, generating antibodies and T cells that will recognize the protein if the person later becomes infected with the SARS-CoV-2 virus.

The original Covid-19 RNA vaccines developed by Moderna and Pfizer/BioNTech provoked strong immune responses, but the MIT team wanted to see if they could make them more effective by engineering them to have immune stimulatory properties.

In this study, the researchers employed two different strategies to boost the immune response. For the first, they focused on a protein called C3d, which is part of an arm of the immune response known as the complement system. This set of proteins helps the body fight off infection, and C3d's role is to bind to antigens and amplify the antibody response to those antigens. For many years, scientists have been evaluating the use of C3d as a molecular adjuvant for vaccines made from proteins, such as the DPT vaccine.

"With the promise of mRNA technologies being realized with the Covid vaccines, we thought that this would be a fantastic opportunity to see if C3d might also be able to play a role as an adjuvant in mRNA vaccine systems," Jiang says.

To that end, the researchers engineered the mRNA to encode the C3d protein fused to the antigen, so that both components are produced as one protein by cells that receive the vaccine.

In the second phase of their strategy, the researchers modified the lipid nanoparticles used to deliver the RNA vaccine, so that in addition to helping with RNA delivery, the lipids also intrinsically stimulate a stronger immune response.

To identify lipids that would work best, the researchers created a library of 480 lipid nanoparticles with different types of chemistries. All of these are "ionizable" lipids, which become positively charged when they enter acidic environments. The original Covid RNA vaccines also included some ionizable lipids because they help the nanoparticles to self-assemble with RNA and they help target cells to take up the vaccine.

"We understood that nanoparticles themselves could be immunostimulatory, but we weren't quite sure what the chemistry was that was needed to optimize that response. So instead of trying to make the perfect one, we made a library and evaluated them, and through that we identified some chemistries that seemed to improve their response," Anderson says.

Toward intranasal vaccines

The researchers tested their new vaccine, which included both RNA-encoded C3d and a top-performing ionizable lipid identified from their library screen, in mice. They found that mice injected with this vaccine produced 10 times more antibodies than mice given unadjuvanted Covid RNA vaccines. The new vaccine also provoked a stronger response among T cells, which play important roles in combating the SARS-CoV-2 virus.

"For the first time, we've demonstrated a synergistic boost in immune responses by engineering both the RNA and its delivery vehicles," Li says. "This prompted us to investigate the feasibility of administering this new RNA vaccine platform intranasally, considering the challenges presented by the mucociliary blanket barrier in the upper airways."

When the researchers delivered the vaccine intranasally, they observed a similarly strong immune response in the mice. If developed for use in people, an intranasal vaccine could potentially offer enhanced protection against infection because it would generate an immune response within the mucosal tissues that line the nasal passages and lungs.

Because self-adjuvanting vaccines elicit a stronger response at a lower dose, this approach could also help to reduce the cost of vaccine doses, which might allow them to reach more people, especially in developing nations, the researchers say.

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The physics of fat droplets reveal DNA danger

Fat is a normal and necessary part of the body. Fat cells store and release energy, as well as play significant roles in hormonal regulation and immunity.

In recent decades, a concerning rise in metabolic illnesses -- such as cardiovascular disease, high blood pressure and diabetes -- has focused scientific attention on the biology and chemistry of fat, resulting in a wealth of information about how fat cells work.

But fat cells and their metabolic activities are only part of the story.

Fat-filled lipid droplets, tiny spheres of fat many times smaller than fat cells, are a growing subject of scientific interest. Found inside many different cell types, these lipid particles have long been little understood. Studies have begun to illuminate these droplets' participation in metabolic functions and cellular protection, but we still know next to nothing about the physical nature of fat.

Now, researchers at the University of Pennsylvania School of Engineering and Applied Science have looked beyond biochemistry to publish groundbreaking work on the physics of these droplets, revealing them to be a potential threat to a cell's nucleus. In the August issue of the Journal of Cell Biology, they are the first to discover fat-filled lipid droplets' surprising capability to indent and puncture the nucleus, the organelle which contains and regulates a cell's DNA.

The stakes of their findings are high: a ruptured nucleus can lead to elevated DNA damage that is characteristic of many diseases, including cancer.

The study was led by Dennis E. Discher, Robert D. Bent Professor in the Department of Chemical and Biomolecular Engineering, Irena Ivanovska, Ph.D. Research Associate in Penn's Molecular and Cell Biophysics Lab, and Michael Tobin, Ph.D. Candidate in the Department of Bioengineering.

"Intuitively, people think of fat as soft," says Discher. "And on a cellular level it is. But at this small size of droplet -- measuring just a few microns rather than the hundreds of microns of a mature fat cell -- it stops being soft. Its shape has a much higher curvature, bending other objects very sharply. This changes its physics in the cell. It can deform. It can damage. It can rupture."

"Imagine," adds Ivanovska, "trying to pop a balloon with your fist. Impossible. You can deform the balloon, but you won't puncture it. Now imagine trying to pop it with a pen. That's the difference between a fat cell and a cell with small fat droplets in the body. It's a fundamental physical difference, not a metabolic one."

The team's research reframes scientific inquiry into fat, underlining that fat's role in the body is much more than just a number on the scales.

"This isn't fat canonically conceived," says Tobin. "This is about how fat works at scales smaller than a cell and poses physical risks to cellular components, even at the level of DNA."

The team's work builds on a decade of foundational research, including leading contributions by Ivanovska, into the behaviors of nuclear proteins that give the nucleus its protective structural qualities. These proteins are dynamic, shifting levels to respond to their mechanical environments and provide what the nucleus needs to maintain its integrity.

"There's a constant process of repair to DNA damage that goes on in cells," says Ivanovska. "For this to happen, the nucleus needs to have enough DNA repair proteins. If a nucleus is ruptured, these proteins scatter and cannot repair damage in a timely manner. This causes DNA damage accumulation and can potentially result in a cancer cell."

A cell lives in a dynamic physical and mechanical environment where things can and do go wrong. But it also has an army of molecular helpers always working to maintain and repair it.

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The more you walk, the lower your risk of early death, even if you walk fewer than 5,000 steps

The number of steps you should walk every day to start seeing benefits to your health is lower than previously thought, according to the largest analysis to investigate this.

The study, published in the European Journal of Preventive Cardiology [1] today (Wednesday), found that walking at least 3967 steps a day started to reduce the risk of dying from any cause, and 2337 steps a day reduced the risk of dying from diseases of the heart and blood vessels (cardiovascular disease).

However, the new analysis of 226,889 people from 17 different studies around the world has shown that the more you walk, the greater the health benefits. The risk of dying from any cause or from cardiovascular disease decreases significantly with every 500 to 1000 extra steps you walk. An increase of 1000 steps a day was associated with a 15% reduction in the risk of dying from any cause, and an increase of 500 steps a day was associated with a 7% reduction in dying from cardiovascular disease.

The researchers, led by Maciej Banach, Professor of Cardiology at the Medical University of Lodz, Poland, and Adjunct Professor at the Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, found that even if people walked as many as 20,000 steps a day, the health benefits continued to increase. They have not found an upper limit yet.

"Our study confirms that the more you walk, the better," says Prof. Banach. "We found that this applied to both men and women, irrespective of age, and irrespective of whether you live in a temperate, sub-tropical or sub-polar region of the world, or a region with a mixture of climates. In addition, our analysis indicates that as little as 4,000 steps a day are needed to significantly reduce deaths from any cause, and even fewer to reduce deaths from cardiovascular disease."

There is strong evidence that a sedentary lifestyle may contribute to an increase in cardiovascular disease and a shorter life. Studies have shown that insufficient physical activity affects more than a quarter of the world's population. More women than men (32% versus 23%), and people in higher income countries compared to low-income countries (37% versus 16%) do not undertake a sufficient amount of physical activity. According to World Health Organization data, insufficient physical activity is the fourth most frequent cause of death in the world, with 3.2 million deaths a year related to physical inactivity. The COVID-19 pandemic also resulted in a reduction in physical activity, and activity levels have not recovered two years on from it.

Dr Ibadete Bytyçi from the University Clinical Centre of Kosovo, Pristina, Kosovo, senior author of the paper, says: "Until now, it's not been clear what is the optimal number of steps, both in terms of the cut-off points over which we can start to see health benefits, and the upper limit, if any, and the role this plays in people's health. However, I should emphasise that there were limited data available on step counts up to 20,000 a day, and so these results need to be confirmed in larger groups of people."

This meta-analysis is the first not only to assess the effect of walking up to 20,000 steps a day, but also to look at whether there are any differences depending on age, sex or where in the world people live.

The studies analysed by the researchers followed up participants for a median (average) of seven years. The mean (average) age was 64, and 49% of participants were female.

In people aged 60 years or older, the size of the reduction in risk of death was smaller than that seen in people aged younger than 60 years. In the older adults, there was a 42% reduction in risk seen in those who walked between 6,000 and 10,000 steps a day, while there was a 49% reduction in risk in younger adults who walked between 7,000 and 13,000 steps a day.

Prof. Banach says: "In a world where we have more and more advanced drugs to target specific conditions such as cardiovascular disease, I believe we should always emphasise that lifestyle changes, including diet and exercise, which was a main hero of our analysis, might be at least as, or even more effective in reducing cardiovascular risk and prolonging lives. We still need good studies to investigate whether these benefits may exist for intensive types of exertion, such as marathon running and iron man challenges, and in different populations of different ages, and with different associated health problems. However, it seems that, as with pharmacological treatments, we should always think about personalising lifestyle changes."

Strengths of the meta-analysis include its size and that it was not restricted to looking at studies limited to a maximum of 16,000 steps a day. Limitations include that it was an observational study and so cannot prove that increased step counts cause the reduction in the risk of death, only that it is associated with it. The impact of step counts was not tested on people with different diseases; all the participants were generally healthy when they entered the studies analysed. The researchers were not able to account for differences in race and socioeconomic status, and the methods for counting steps were not identical in all the studies included in this meta-analysis.

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New study shows anti-inflammatory drugs as a promising target for Alzheimer's disease

A recent study from the lab of the University of Kentucky's Sanders-Brown Center on Aging Director Linda Van Eldik, Ph.D., has been published in PLOS ONE. The work centers around the idea that various anti-inflammatory drugs could be effective treatments for Alzheimer's disease (AD). This study focused on a protein known as p38. Many labs have been working with this protein as a potential target for drug development to treat Alzheimer's disease and other conditions with neuroinflammatory dysfunction.

Van Eldik and her team used genetic techniques to stop the production of p38 in the major immune cell type within the brain, the microglia. They tested the effects of this in an early-stage mouse model of AD to determine whether it would alter the trajectory of amyloid plaque formation, a major component of AD pathology. While the plaques themselves were not affected, the amount of microglia in proximity to these plaques was decreased, suggesting that suppression of microglial p38 may affect their interactions with aspects of AD pathology.

Some classes of anti-inflammatory drugs include p38 inhibitors, which are currently under clinical development and have shown encouraging results during recent human clinical trials. However, it is still not clear when during the disease process these p38 inhibitors should be administered and whether long-term suppression of p38 is harmful. The findings reported by the Van Eldik lab indicate that early inhibition of p38 may be able to alter interactions between brain immune cells and AD pathology, and they suggest that long-term suppression of p38 does not cause noticeable adverse effects.

From Science Daily

Detailed map of the heart provides new insights into cardiac health and disease

In a new study, published today (12 July) in Nature, researchers have produced the most detailed and comprehensive human Heart Cell Atlas to date, including the specialised tissue of the cardiac conduction system -- where the heartbeat originates.

The multi-centre team is led by the Wellcome Sanger Institute and the National Heart and Lung Institute at Imperial College London, and has also presented a new drug-repurposing computational tool called Drug2cell, which can provide insights into the effects of drugs on heart rate.

This study is part of the international Human Cell Atlas* (HCA) initiative, which is mapping every cell type in the human body, to transform our understanding of health and disease, and will form the foundation for a fully integrated HCA Human Heart Cell Atlas.

Charting eight regions of the human heart, the work describes 75 different cell states including the cells of the cardiac conduction system -- the group of cells responsible for the heartbeat -- not understood at such a detailed level in humans before. The human cardiac conduction system, the heart's 'wiring', sends electrical impulses from the top to the bottom of the heart and coordinates the heartbeat.

By using spatial transcriptomics, which gives a "map" of where cells sit within a tissue, researchers were also able to understand how these cells communicate with each other for the first time. This map acts as a molecular guidebook, showing what healthy cells look like, and providing a crucial reference to understand what goes wrong in disease. The findings will help understand diseases such as those affecting the heart rhythm.

The assembly of a Human Heart Cell Atlas is key given that cardiovascular diseases are the leading cause of death globally. Around 20,000 electronic pacemakers are implanted each year in the UK for these disorders. These can be ineffective and are prone to complications and side-effects. Understanding the biology of the cells of the conduction system and how they differ from muscle cells paves the way to therapies to boost cardiac health and develop targeted treatments for arrhythmias.

The team also presents a new computational tool called Drug2cell. The tool can predict drug targets as well as drug side effects. It leverages single-cell profiles and the 19 million drug-target interactions in the EMBL-EBI ChEMBL database.

Unexpectedly, this tool identified that pacemaker cells express the target of certain medications, such as GLP1 drugs, which are used for diabetes and weight loss and are known to increase the heart rate as a side-effect, the mechanism of which was unclear. This study suggests that the increase in heart rate might be partly due to a direct action of these drugs on pacemaker cells, a finding the team also showed in an experimental stem cell model of pacemaker cells.

Dr James Cranley, joint first author, a cardiologist specialising in heart rhythm disorders and PhD student at the Wellcome Sanger Institute, said: "The cardiac conduction system is critical for the regular and coordinated beating of our hearts, yet the cells which make it up are poorly understood. This study sheds new light by defining the profiles of these cells, as well as the multicellular niches they inhabit. This deeper understanding opens the door to better, targeted anti-arrhythmic therapies in the future."

Dr Kazumasa Kanemaru, joint first author and Postdoctoral Fellow in the Gene Expression Genomics team at the Wellcome Sanger Institute, said: "The mechanism of activating and suppressing pacemaker cell genes is not clear, especially in humans. This is important for improving cell therapy to facilitate the production of pacemaker cells or to prevent the excessive spontaneous firing of cells. By understanding these cells at an individual genetic level, we can potentially develop new ways to improve heart treatments."

The study unearthed an unexpected discovery: a close relationship between conduction system cells and glial cells. Glial cells are part of the nervous system and are traditionally found in the brain. They have been explored very little in the heart. This research suggests that glial cells are in physical contact with conduction system cells and may play an important supporting role: communicating with the pacemaker cells, guiding nerve endings to them, and supporting their release of glutamate, a neurotransmitter.

Another key finding of the study is an immune structure on the heart's outer surface. This contains plasma cells, which release antibodies into the space around the heart to prevent infection from the nearby lungs. The researchers also identified a cellular niche enriching for a hormone that could be interpreted as an early warning sign of heart failure.

Dr Michela Noseda, senior Lecturer in Cardiac Molecular Pathology at the National Heart and Lung Institute, Imperial College London, a Coordinator of the Human Cell Atlas Heart BioNetwork and a lead author, said: "We often don't fully know what impact a new treatment will have on the heart and its electrical impulses -- this can mean a drug is withdrawn or fails to make it to the market. Our team developed the Drug2cell platform to improve how we evaluate new treatments and how they can affect our hearts, and potentially other tissues too. This could provide us with an invaluable tool to identify new drugs which target specific cells, as well as help to predict any potential side-effects early on in drug development."

Professor Metin Avkiran, Associate Medical Director at the British Heart Foundation, which part-funded the research with the German Centre for Cardiovascular Research (DZHK), said: "Using cutting-edge technologies, this research provides further intricate detail about the cells that make up specialised regions of the human heart and how those cells communicate with each other. The new findings on the heart's electrical conduction system and its regulation are likely to open up new approaches to preventing and treating rhythm disturbances that can impair the heart's function and may even become life-threatening."

"International collaboration is key to scientific progress. This impactful study and other discoveries from the broader Human Cell Atlas initiative are excellent examples of what can be achieved when the international research community works together across borders. Our combined efforts can ultimately produce better outcomes for patients worldwide."

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Regular napping linked to larger brain volume

Daytime napping may help to preserve brain health by slowing the rate at which our brains shrink as we age, suggests a new study led by researchers at UCL and the University of the Republic in Uruguay.

The study, published in the journal Sleep Health, analysed data from people aged 40 to 69 and found a causal link between habitual napping and larger total brain volume -- a marker of good brain health linked to a lower risk of dementia and other diseases.

Senior author Dr Victoria Garfield (MRC Unit for Lifelong Health & Ageing at UCL) said: "Our findings suggest that, for some people, short daytime naps may be a part of the puzzle that could help preserve the health of the brain as we get older."

Previous research has shown that napping has cognitive benefits, with people who have had a short nap performing better in cognitive tests in the hours afterwards than counterparts who did not nap.

The new study aimed to establish if there was a causal relationship between daytime napping and brain health.

Using a technique called Mendelian randomisation, they looked at 97 snippets of DNA thought to determine people's likelihood of habitual napping. They compared measures of brain health and cognition of people who are more genetically "programmed" to nap with counterparts who did not have these genetic variants, using data from 378,932 people from the UK Biobank study, and found that, overall, people predetermined to nap had a larger total brain volume.

The research team estimated that the average difference in brain volume between people programmed to be habitual nappers and those who were not was equivalent to 2.6 to 6.5 years of ageing.

But the researchers did not find a difference in how well those programmed to be habitual nappers performed on three other measures of brain health and cognitive function -- hippocampal volume, reaction time and visual processing.

Lead author and PhD candidate Valentina Paz (University of the Republic (Uruguay) and MRC Unit for Lifelong Health & Ageing at UCL) said: "This is the first study to attempt to untangle the causal relationship between habitual daytime napping and cognitive and structural brain outcomes. By looking at genes set at birth, Mendelian randomisation avoids confounding factors occurring throughout life that may influence associations between napping and health outcomes. Our study points to a causal link between habitual napping and larger total brain volume."

Dr Garfield added: "I hope studies such as this one showing the health benefits of short naps can help to reduce any stigma that still exists around daytime napping."

The genetic variants influencing our likelihood to nap were identified in an earlier study looking at data from 452,633 UK Biobank participants. The study, led by Dr Hassan Dashti (Harvard University and Massachusetts General Hospital), also an author on the new study, identified the variants on the basis of self-reported napping, and this was supported by objective measurements of physical activity recorded by a wrist-worn accelerometer.

In the new study, researchers analysed health and cognition outcomes for people with these genetic variants as well as several different subsets of these variants, adjusted to avoid potential bias, for instance avoiding variants linked to excessive daytime sleepiness.

Genetic data and magnetic resonance imaging (MRI) scans of the brain were available for 35,080 individuals drawn from the larger UK Biobank sample.

In terms of study limitations, the authors noted that all of the participants were of white European ancestry, so the findings might not be immediately generalisable to other ethnicities.

While the researchers did not have information on nap duration, earlier studies suggest that naps of 30 minutes or less provide the best short-term cognitive benefits, and napping earlier in the day is less likely to disrupt night-time sleep.

Previous research looking at the UK and the Netherlands found that nearly a third of adults aged 65 or over had a regular nap.

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The Viking disease can be due to gene variants inherited from Neanderthals

Many men in northern Europe over the age of 60 suffer from the so-called Viking disease, which means that the fingers lock in a bent position. Now researchers at Karolinska Institutet, together with colleagues, have used data from over 7,000 affected individuals to look for genetic risk factors for the disease. The findings, which have been published in Molecular Biology and Evolution, show that three of the strongest risk factors are inherited from Neanderthals.

Up to 30 percent of men in northern Europe over 60 suffer from a condition called Dupuytren's contracture. The condition is sometimes called the Viking disease because it mainly affects individuals with northern European ancestry. The disease is significantly more common in men than women and usually begins as a lump in the palm of the hand that grows and causes one or more fingers to lock in a bent position. The condition is usually not painful, but the nodules may sometimes be tender to pressure.

The researchers in the study, led by Hugo Zeberg from Karolinska Institutet and Svante Pääbo from Max Planck Institute for Evolutionary Anthropology, set out to investigate whether genetic variants inherited from Neanderthals are involved in the disease.

Neanderthals lived in Europe and western Asia until about 40,000 years ago, when they were replaced by modern humans. However before Neanderthals disappeared, they mixed with modern humans. As a result, between one and two percent of the genomes of people with roots outside of Africa come from Neanderthals.

"Since Dupuytren's contracture is rarely seen in individuals of African descent, we wondered whether gene variants from Neanderthals can partly explain why people outside of Africa are affected," says Hugo Zeberg, assistant professor at the department of Physiology and Pharmacology, Karolinska Institutet.

The researchers used data from three large clinical cohorts in the US, UK, and Finland, which allowed them to compare the genomes of 7,871 sufferers and 645,880 healthy controls. They identified 61 genetic risk factors for Dupuytren's contracture. The researchers found that three of these were inherited from Neanderthals, and these included the second and third most important risk factors.

The study is further evidence that the intermingling between Neanderthals and our ancestors has important consequences for the prevalence of some diseases, particularly among certain groups.

"This is a case where the meeting with Neanderthals has affected who suffers from illness, although we should not exaggerate the connection between Neanderthals and Vikings," says Hugo Zeberg.

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Humanity's earliest recorded kiss occurred in Mesopotamia 4,500 years ago

Recent research has hypothesised that the earliest evidence of human lip kissing originated in a very specific geographical location in South Asia 3,500 years ago, from where it may have spread to other regions, simultaneously accelerating the spread of the herpes simplex virus 1.

But according to Dr Troels Pank Arbøll and Dr Sophie Lund Rasmussen, who in a new article in the journal Science draw on a range of written sources from the earliest Mesopotamian societies, kissing was already a well-established practice 4,500 years ago in the Middle East. And probably much earlier, moving the earliest documentation for kissing back 1,000 years compared to what was previously acknowledged in the scientific community.

"In ancient Mesopotamia, which is the name for the early human cultures that existed between the Euphrates and Tigris rivers in present-day Iraq and Syria, people wrote in cuneiform script on clay tablets. Many thousands of these clay tablets have survived to this day, and they contain clear examples that kissing was considered a part of romantic intimacy in ancient times, just as kissing could be part of friendships and family members' relations," says Dr Troels Pank Arbøll, an expert on the history of medicine in Mesopotamia.

He continues:

"Therefore, kissing should not be regarded as a custom that originated exclusively in any single region and spread from there but rather appears to have been practiced in multiple ancient cultures over several millennia."

Dr Sophie Lund Rasmussen adds:

"In fact, research into bonobos and chimpanzees, the closest living relatives to humans, has shown that both species engage in kissing, which may suggest that the practice of kissing is a fundamental behaviour in humans, explaining why it can be found across cultures."

Kissing as potential transmitter of disease

In addition to its importance for social and sexual behaviour, the practice of kissing may have played an unintentional role in the transmission of microorganisms, potentially causing viruses to spread among humans.

However, the suggestion that the kiss may be regarded as a sudden biological trigger behind the spread of particular pathogens is more doubtful. The spread of the herpes simplex virus 1, which researchers have suggested could have been accelerated by the introduction of the kiss, is a case in point:

"There is a substantial corpus of medical texts from Mesopotamia, some of which mention a disease with symptoms reminiscent of the herpes simplex virus 1," Dr Arbøll remarks.

He adds that the ancient medical texts were influenced by a variety of cultural and religious concepts, and it therefore must be emphasized that they cannot be read at face value.

"It is nevertheless interesting to note some similarities between the disease known as bu?shanu in ancient medical texts from Mesopotamia and the symptoms caused by herpes simplex infections. The bu'shanu disease was located primarily in or around the mouth and throat, and symptoms included vesicles in or around the mouth, which is one of the dominant signs of herpes infection."

"If the practice of kissing was widespread and well-established in a range of ancient societies, the effects of kissing in terms of pathogen transmission must likely have been more or less constant," says Dr Rasmussen.

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Detailed image of the human retina

What cell types are found in which human tissue, and where? Which genes are active in the individual cells, and which proteins are found there? Answers to these questions and more are to be provided by a specialised atlas -- in particular how the different tissues form during embryonic development and what causes diseases. In creating this atlas, researchers aim to map not only tissue directly isolated from humans, but also structures called organoids. These are three-dimensional clumps of tissue that are cultivated in the laboratory and develop in a way similar to human organs, but on a small scale.

"The advantage of organoids is that we can intervene in their development and test active substances on them, which allows us to learn more about healthy tissue as well as diseases," explains Barbara Treutlein, Professor of Quantitative Developmental Biology at the Department of Biosystems Science and Engineering at ETH Zurich in Basel.

To help produce such an atlas, Treutlein, together with researchers from the Universities of Zurich and Basel, has now developed an approach to gather and compile a great deal of information about organoids and their development. The research team applied this approach to the organoids of the human retina, which they derived from stem cells.

Many proteins visible simultaneously

At the heart of the methods the scientists used for their approach was the 4i technology: iterative indirect immunofluorescence imaging. This new imaging technique can visualise several dozen proteins in a thin tissue section at high resolution using fluorescence microscopy. The 4i technology was developed a few years ago by Lucas Pelkmans, a professor at the University of Zurich and coauthor of the study that has just been published in the scientific journal Nature Biotechnology. It is in this study that the researchers applied this method to organoids for the first time.

Typically, researchers use fluorescence microscopy to highlight three proteins in a tissue, each with a different fluorescent dye. For technical reasons, it is not possible to stain more than five proteins at a time. In 4i technology, three dyes are used, but these are washed from the tissue sample after measurements have been taken, and three new proteins are stained. This step was performed 18 times, by a robot, and the process took a total of 18 days. Lastly, a computer merges the individual images into a single microscopy image on which 53 different proteins are visible. They provide information on the function of the individual cell types that make up the retina; for example, rods, cones, and ganglion cells.

The researchers have supplemented this visual information of retinal proteins with information on which genes are read in the individual cells.

High spatial and temporal resolution

The scientists performed all these analyses on organoids that were of different ages and thus at different stages of development. In this way, they were able to create a time series of images and genetic information that describes the entire 39-week development of retinal organoids. "We can use this time series to show how the organoid tissue slowly builds up, where which cell types proliferate and when, and where the synapses are located. The processes are comparable to those of retinal formation during embryonic development," says Gray Camp, a professor at the University of Basel and a senior author of this study.

The researchers published their image information and more findings on retinal development on a publicly accessible website: EyeSee4is.

Further tissue types planned

So far, the scientists have been studying how a healthy retina develops, but in the future, they hope to deliberately disrupt development in retinal organoids with drugs or genetic modifications. "This will give us new insights into diseases such as retinitis pigmentosa, a hereditary condition that causes the retina's light-sensitive receptors to gradually degenerate and ultimately leads to blindness," Camp says. The researchers want to find out when this process begins and how it can be stopped.

Read more at Science Daily