Novel C. diff structures are required for infection, offer new therapeutic targets

 Iron storage "spheres" inside the bacterium C. diff -- the leading cause of hospital-acquired infections -- could offer new targets for antibacterial drugs to combat the pathogen.

A team of Vanderbilt researchers discovered that C. diff (Clostridioides difficile) produces the spheres, called ferrosomes, and that these structures are important for infection in an animal model. The findings, reported Nov. 15 in the journal Nature, are also a rare demonstration of a membrane-bound structure inside a pathogenic bacterium.

Bacteria have long been thought not to contain organelles (such as a nucleus, mitochondria and other specialized structures) like eukaryotic cells, but that biological dogma appears to be incorrect.

"The emerging idea that bacteria do compartmentalize biochemical processes in a way similar to eukaryotic cells really flips the field of microbiology on its head," said Eric Skaar, PhD, MPH, the Ernest W. Goodpasture Professor of Pathology and director of the Vanderbilt Institute for Infection, Immunology, and Inflammation.

Skaar, co-corresponding author Qiangjun Zhou, PhD, assistant professor of Cell and Developmental Biology, and their colleagues were intrigued by findings reported several years ago that some environmental bacteria produce iron-containing ferrosomes.

They knew that the genes in these bacteria were conserved in C. diff and other anaerobic bacteria (bacteria that die in the presence of oxygen), and they set out to determine if C. diff produces ferrosomes to manage its need for iron. Like all living organisms, C. diff requires iron to survive and grow. Skaar and his team have focused on how pathogens like C. diff acquire iron and other metals, with a goal of finding new pathways that could be exploited to "starve" pathogens of essential nutrients.

C. diff causes about 500,000 infections and more than 29,000 deaths in the United States each year, according to the Centers for Disease Control and Prevention, and treatment options are limited. People taking antibiotics that disrupt the healthy microbes in the gut are at increased risk for C. diff infection, which causes diarrhea and colitis. New strategies for treating this urgent public health threat are needed, Skaar said.

To look for iron inside C. diff, the researchers first drew on expertise and resources in the Vanderbilt Institute of Nanoscale Science and Engineering (VINSE).

"The best way to look for the accumulation of elements in a small space like a cell is with a method called STEM-EDS, which has not commonly been used for biological samples," Skaar said. "We were fortunate to have access to a STEM-EDS instrument and collaborators at VINSE, and we quickly proved that there was an accumulation of iron 'dots' within the bacterium."

Co-first authors Hualiang Pi, PhD, and Rong Sun, PhD, led studies to show that those iron dots represented organelles that were important to C. diff infection.

Pi and Skaar's team found that two genes (fezA and fezB), which are similar to those in environmental bacteria, were required for ferrosome formation. Using C. diff bacteria missing these genes, they showed that ferrosomes are required for C. diff to fully colonize and cause disease in an animal model. They found that ferrosomes were even more important for C. diff infection in a model of inflammatory bowel disease, demonstrating that these iron-containing structures help the bacterium combat "nutritional immunity" -- the host response of producing proteins to bind iron and attempt to starve the pathogen.

Sun and Zhou's team used cryogenic electron microscopy (cryo-EM) and cryo-tomography to show that the ferrosome structures were encased in a membrane, classifying them as organelles.

Skaar noted that "Vanderbilt's unique geography" -- the proximity of experts in engineering, cell biology and the Medical Center -- and specialized tools for STEM-EDS and cryo-EM made the research possible.

The results "establish ferrosome formation and all the factors involved in ferrosome formation as potential targets for new antibacterial drugs against an important infectious disease," Skaar said. "Anytime we find new factors involved in host-pathogen interactions and show that they're important for infection, that opens entirely new opportunities to make classes of antibacterial drugs that have not existed before. That is especially important in the face of rising antimicrobial resistance that we're seeing globally."

In future studies, the researchers plan to explore how ferrosomes are formed, whether other gut pathogens produce ferrosomes, and whether these structures might be shared in the gut as a source of iron. Skaar is also particularly interested in pursuing the emerging area of bacterial organelles.

"We think our study is a rare demonstration of an organelle in a pathogenic bacterium," he said. "Now we want to know if there are other subcellular compartments in bacteria that we're interested in that could teach us about how these cells perform various physiologic processes."

Scientists 3D-print hair follicles in lab-grown skin

 A team led by scientists at Rensselaer Polytechnic Institute has 3D-printed hair follicles in human skin tissue cultured in the lab. This marks the first time researchers have used the technology to generate hair follicles, which play an important role in skin healing and function.

The finding, published in the journal Science Advances, has potential applications in regenerative medicine and drug testing, though engineering skin grafts that grow hair are still several years away.

"Our work is a proof-of-concept that hair follicle structures can be created in a highly precise, reproducible way using 3D-bioprinting. This kind of automated process is needed to make future biomanufacturing of skin possible," said Pankaj Karande, Ph.D., an associate professor of chemical and biological engineering and a member of Rensselaer's Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies, who led the study.

"The reconstruction of hair follicles using human-derived cells has historically been a challenge. Some studies have shown that if these cells are cultured in a three-dimensional environment, they can potentially originate new hair follicles or hair shafts, and our study builds on this work," Karande said.

When it comes to engineering human skin, hair may at first seem superfluous. However, hair follicles are quite important: They produce sweat, helping regulate body temperature, and they contain stem cells that help skin heal.

Hair follicles are also an entry point for topical drugs and cosmetics, making them an important part of dermatological testing. But today, initial safety testing is done on engineered skin tissues that lack hair follicles.

"Right now, contemporary skin models -- the engineered structures that mimic human skin -- are quite simple. Increasing their complexity by adding hair follicles would give us even more information about how skin interacts with topical products," said Carolina Catarino, Ph.D., first author of the study, who earned her doctorate at Rensselaer and is now a researcher developing new skin testing methods at Grupo Boticário, a cosmetics company in her home country of Brazil.

"Dr. Karande's lab is at the forefront of skin tissue engineering. This team has already successfully printed skin with working blood vessels, and this latest research is an exciting next step in developing and testing better treatments for burns and other skin conditions," said Deepak Vashishth, Ph.D., director of the Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies.

"Dr. Karande's work is a great example of advances being made by RPI researchers at the interface of engineering and life sciences with impact on human health," said Shekhar Garde, Ph.D., dean of Rensselaer's School of Engineering. "Bringing multichannel 3-D printing to biological realm is opening exciting opportunities that would have been hard to imagine in the past."

The researchers created their follicle-bearing skin with 3D-printing techniques adapted for printing at the cellular level.

The scientists begin by allowing samples of skin and follicle cells to divide and multiply in the lab until there are enough printable cells. Next, the researchers mix each type of cell with proteins and other materials to create the "bio-ink" used by the printer. Using an extremely thin needle to deposit the bio-ink, the printer builds the skin layer by layer, while also creating channels for depositing the hair cells. Over time, the skin cells migrate to these channels surrounding the hair cells, mirroring the follicle structures present in real skin.

Right now, these tissues have a lifespan of two to three weeks, which is not enough time for hair shafts to develop. The research team's future work aims to extend that period, allowing the hair follicle to mature further and paving the way for their use in drug testing and skin grafts.

Realistic talking faces created from only an audio clip and a person's photo

 A team of researchers from Nanyang Technological University, Singapore (NTU Singapore) has developed a computer program that creates realistic videos that reflect the facial expressions and head movements of the person speaking, only requiring an audio clip and a face photo.

DIverse yet Realistic Facial Animations, or DIRFA, is an artificial intelligence-based program that takes audio and a photo and produces a 3D video showing the person demonstrating realistic and consistent facial animations synchronised with the spoken audio (see videos).

The NTU-developed program improves on existing approaches, which struggle with pose variations and emotional control.

To accomplish this, the team trained DIRFA on over one million audiovisual clips from over 6,000 people derived from an open-source database called The VoxCeleb2 Dataset to predict cues from speech and associate them with facial expressions and head movements.

The researchers said DIRFA could lead to new applications across various industries and domains, including healthcare, as it could enable more sophisticated and realistic virtual assistants and chatbots, improving user experiences. It could also serve as a powerful tool for individuals with speech or facial disabilities, helping them to convey their thoughts and emotions through expressive avatars or digital representations, enhancing their ability to communicate.

Corresponding author Associate Professor Lu Shijian, from the School of Computer Science and Engineering (SCSE) at NTU Singapore, who led the study, said: "The impact of our study could be profound and far-reaching, as it revolutionises the realm of multimedia communication by enabling the creation of highly realistic videos of individuals speaking, combining techniques such as AI and machine learning. Our program also builds on previous studies and represents an advancement in the technology, as videos created with our program are complete with accurate lip movements, vivid facial expressions and natural head poses, using only their audio recordings and static images."

First author Dr Wu Rongliang, a PhD graduate from NTU's SCSE, said: "Speech exhibits a multitude of variations. Individuals pronounce the same words differently in diverse contexts, encompassing variations in duration, amplitude, tone, and more. Furthermore, beyond its linguistic content, speech conveys rich information about the speaker's emotional state and identity factors such as gender, age, ethnicity, and even personality traits. Our approach represents a pioneering effort in enhancing performance from the perspective of audio representation learning in AI and machine learning." Dr Wu is a Research Scientist at the Institute for Infocomm Research, Agency for Science, Technology and Research (A*STAR), Singapore.

The findings were published in the scientific journal Pattern Recognition in August.

Speaking volumes: Turning audio into action with animated accuracy

The researchers say that creating lifelike facial expressions driven by audio poses a complex challenge. For a given audio signal, there can be numerous possible facial expressions that would make sense, and these possibilities can multiply when dealing with a sequence of audio signals over time.

Since audio typically has strong associations with lip movements but weaker connections with facial expressions and head positions, the team aimed to create talking faces that exhibit precise lip synchronisation, rich facial expressions, and natural head movements corresponding to the provided audio.

To address this, the team first designed their AI model, DIRFA, to capture the intricate relationships between audio signals and facial animations. The team trained their model on more than one million audio and video clips of over 6,000 people, derived from a publicly available database.

Assoc Prof Lu added: "Specifically, DIRFA modelled the likelihood of a facial animation, such as a raised eyebrow or wrinkled nose, based on the input audio. This modelling enabled the program to transform the audio input into diverse yet highly lifelike sequences of facial animations to guide the generation of talking faces."

Dr Wu added: "Extensive experiments show that DIRFA can generate talking faces with accurate lip movements, vivid facial expressions and natural head poses. However, we are working to improve the program's interface, allowing certain outputs to be controlled. For example, DIRFA does not allow users to adjust a certain expression, such as changing a frown to a smile."

Besides adding more options and improvements to DIRFA's interface, the NTU researchers will be finetuning its facial expressions with a wider range of datasets that include more varied facial expressions and voice audio clips.

New compound outperforms pain drug by indirectly targeting calcium channels

 A compound -- one of 27 million screened in a library of potential new drugs -- reversed four types of chronic pain in animal studies, according to new research led by NYU College of Dentistry's Pain Research Center and published in the Proceedings of the National Academy of Sciences (PNAS).

The small molecule, which binds to an inner region of a calcium channel to indirectly regulate it, outperformed gabapentin without troublesome side effects, providing a promising candidate for treating pain.

Calcium channels play a central role in pain signaling, in part through the release of neurotransmitters such as glutamate and GABA -- "the currency of the pain signal," according to Rajesh Khanna, director of the NYU Pain Research Center and professor of molecular pathobiology at NYU Dentistry. The Cav2.2 (or N-type) calcium channel is the target for three clinically available drugs, including gabapentin (sold under brand names including Neurontin) and pregabalin (Lyrica), which are widely used to treat nerve pain and epilepsy.

Gabapentin mitigates pain by binding to the outside of the Cav2.2 calcium channel, affecting the channel's activity. However, like many pain medications, gabapentin use often comes with side effects.

"Developing effective pain management with minimal side effects is crucial, but creating new therapies has been challenging," said Khanna, the senior author of the PNAS study. "Rather than directly going after known targets for pain relief, our lab is focused on indirectly targeting proteins that are involved in pain."

Inside the channel

Khanna has long been interested in a protein called CRMP2, a key regulator of the Cav2.2 calcium channel that binds to the channel from the inside. He and his colleagues previously discovered a peptide (a small region of amino acids) derived from CRMP2 that could uncouple CRMP2 from the calcium channel. When this peptide -- dubbed the calcium channel-binding domain 3, or CBD3 -- was delivered to cells, it acted as a decoy, blocking CRMP2 from binding to the inside of the calcium channel. This resulted in less calcium entering the calcium channel and less neurotransmitter release, which translated to less pain in animal studies.

Peptides are difficult to synthesize as drugs because they are short-acting and easily degrade in the stomach, so the researchers sought to create a small molecule drug based on CBD3. Starting with the 15 amino acids that make up the CBD3 peptide, they honed in on two amino acids that studies showed were responsible for inhibiting calcium influx and mitigating pain.

"At that point, we realized that these two amino acids could be the building blocks for designing a small molecule," said Khanna.

From 27 million to one

In collaboration with colleagues at the University of Pittsburgh, the researchers ran a computer simulation that screened a library of 27 million compounds to look for a small molecule that would "match" the CBD3 amino acids.

The simulation narrowed the library down to 77 compounds, which the researchers experimentally tested to see if they lessened the amount of calcium influx. This further pared the pool down to nine compounds, which were assessed using electrophysiology to measure decreases in electrical currents through the calcium channels.

One compound, which the researchers named CBD3063, emerged as the most promising candidate for treating pain. Biochemical tests revealed that CBD3063 disrupted the interaction between the CaV2.2 calcium channel and CRMP2 protein, reduced calcium entering the channel, and lessened the release of neurotransmitters.

"Many scientists have screened the same library of compounds, but have been trying to block the calcium channel from the outside. Our target, these two amino acids from CRMP2, is on the inside of the cell, and this indirect approach may be the key to our success," said Khanna.

Four labs, four types of pain

Khanna's lab then tested CBD3063 with mouse models for pain related to injury. The compound was effective in alleviating pain in both male and female mice -- and notably, in a head-to-head test with the drug gabapentin, the researchers needed to use far less CBD3063 (1 to 10 mg) than gabapentin (30 mg) to reduce pain.

To explore whether CBD3063 helped with different types of chronic pain, Khanna partnered with researchers at Virginia Commonwealth University, Michigan State University, and Rutgers University. Collaborators ran similar studies administering CBD3063 to treat animal models of chemotherapy-induced neuropathy, inflammatory pain, and trigeminal nerve pain -- all successfully reversing pain, similar to gabapentin.

But unlike gabapentin, the use of CBD3063 did not come with side effects, including sedation, changes to cognition such as memory and learning, or changes to heart rate and breathing.

What's next

The researchers are continuing to study CBD3063, refining its chemical composition and running additional tests to study the compound's safety and assess if tolerance develops.

Long-term, they hope to bring a CBD3063-derived drug to clinical trials in an effort to offer new options for safe and effective pain relief.

"Identifying this first-in-class small molecule has been the culmination of more than 15 years of research. Though our research journey continues, we aspire to present a superior successor to gabapentin for the effective management of chronic pain," said Khanna.

Additional authors include Kimberly Gomez, Tyler Nelson, Heather Allen, Aida Calderon-Rivera, Sara Hestehave, Erick Rodríguez Palma, Paz Duran, Santiago Loya-Lopez, Samantha Perez-Miller, and May Khanna of NYU Dentistry's Pain Research Center; Elaine Zhu and Jing Wang of NYU Grossman School of Medicine; Handoko and Paramjit Arora of NYU's Department of Chemistry; Ulises Santiago and Carlos Camacho of the University of Pittsburgh; Yuan Zhou, Angie Dorame, and Aude Chefdeville of the University of Arizona; Upasana Kumar, Rory Shields, Wanhong Zuo, Huijuan Hu, and Olga Korczeniewska of Rutgers University; Eda Koseli, Bryan McKiver, and M. Imad Damaj of Virginia Commonwealth University; Denise Giuvelis and Tamara King of the University of New England; Kufreobong Inyang and Geoffroy Laumet of Michigan State University; Dongzhi Ran, Yi Lu, and Xia Liu of Chongqing Medical University; Marcel Patek of Bright Rock Path LLC; and Aubin Moutal of St. Louis University.

Scientists tame biological trigger of deadly Huntington's disease

 Huntington's disease causes involuntary movements and dementia, has no cure, and is fatal. For the first time, UC Riverside scientists have shown they can slow its progression in flies and worms, opening the door to human treatments.

Key to understanding these advancements is the way that genetic information in cells is converted from DNA into RNA, and then into proteins. DNA is composed of chemicals called nucleotides: adenine (A), thymine (T), guanine (G), and cytosine (C). The order of these nucleotides determines what biological instructions are contained in a strand of DNA.

On occasion, some DNA nucleotides repeat themselves, expanding the DNA strand. In Huntington's disease, this expansion occurs with three nucleotides, cytosine-adenine-guanine, or CAG.

Expansion into an extraordinary number of repeated CAG sequences of DNA is associated with earlier onset and increased severity of Huntington's disease symptoms. Similar observations were made for a number of other neurodegenerative diseases.

When these DNA repeats are translated into RNA, there is an insidious side effect. The cell chemically modifies the extra RNA buildup. Wang and his collaborators learned that the modified RNA plays a crucial role in neurodegeneration.

"We are first to discover that a type of chemical modification, called methylation, occurs more frequently with extra repeats in RNA. Then we see abnormal distribution and buildup of a particular protein in cells," said Yinsheng Wang, distinguished UCR professor of chemistry. "In other words, methylation converts an important cellular protein into waste."

These findings parallel observations made for the same protein in brain tissues of Huntington's disease, ALS and frontotemporal dementia patients. Longer RNA repeats mean a higher modification rate, which generates more protein waste and exacerbates disease.

"Even healthy people have up to 34 CAG repeats on a particular gene, the HTT gene," Wang said. "However, due to environmental or genetic causes, there might be as many as 100 CAG repeats in the cells of people with Huntington's disease."

Long, repetitive RNA sequences can turn into an excess of protein in cells, creating "cellular trash," which has toxic effects.

A new Nature journal article details how RNA methylation on CAG repeats is implicated in the complex mechanism underlying Huntington's disease. The article also explains how the researchers greatly reduced the progression of disease in worms and fruit flies and extended the lifespan of flies by introducing a protein into cells that removes methylation.

At present there is no way to cure or even slow the progression of Huntington disease. Health care providers typically offer medications to help with some symptoms. While this breakthrough is not a cure, it represents the possibility of an effective therapy where none currently exists.

The research team, which includes professors Weifeng Gu at UCR, X. William Yang at UCLA and Nancy M. Bonini at the University of Pennsylvania, is now searching for small molecules that can inhibit methylation and form the basis of a Huntington's therapy.

Because RNA repeats are present in similar diseases, like ALS and certain types of spinocerebellar ataxia, the door is open to treatments for these other fatal, degenerative diseases.

"We don't think the mechanisms we studied are the only ones that contribute to Huntington's," Wang said. "However, we have shown that by targeting them we can reduce the disease in model organisms, which could lead to longer, better lives for those who suffer from this and potentially other diseases as well."

187 new genetic variants linked to prostate cancer found in largest, most diverse study of its kind

 A globe-spanning scientific team has compiled the most comprehensive list of genetic variants associated with prostate cancer risk -- 451 in all -- through a whole-genome analysis that ranks as the largest and most diverse investigation into prostate cancer genetics yet. The research, led by the USC Center for Genetic Epidemiology, the Keck School of Medicine of USC and USC Norris Comprehensive Cancer Center, and in the United Kingdom by The Institute of Cancer Research, London, included major increases in representation among men from racial and ethnic groups that have often been left out of such research, revising what is known about genetic risk for the disease.

With these findings, the researchers improved a system they developed for measuring genetic risk so that it was more effective in predicting who would or wouldn't develop prostate cancer -- even distinguishing between the likelihood of aggressive and less-serious cases among men of African descent. The finding that higher risk scores based on the 451 variants correlated with more-aggressive disease in men of African ancestry is a meaningful step toward improving early detection and making better informed decisions about screening.

The study, published in Nature Genetics, builds on 2021 research documented in the same journal that found 269 genetic variants correlating with prostate cancer risk, based on a sample of nearly 235,000 men. The new results were derived from genomic information from close to 950,000 men.

"We're not going to learn everything there is to know about the genetics of prostate cancer by studying only white men," said co-senior author Christopher Haiman, ScD, holder of the AFLAC Chair in Cancer Research and professor of population and public health sciences at the Keck School of Medicine. "Larger and larger studies, engaging a broader spectrum of populations, are important if we're going to identify genetic markers of risk and develop risk prediction tools that are equally effective across populations."

A substantial revision of what's known about genetic risk for prostate cancer

The researchers compared genomic data from 156,319 prostate cancer patients with that of a control group totaling 788,443. From the previous study, there was an 87% increase in the number of prostate cancer cases included from men of African ancestry, 45% from Latino ethnicity, 43% from European ancestry and 26% from Asian ancestry.

Haiman and his colleagues found 187 new genetic variants associated with prostate cancer risk. They also found 150 genetic variants from earlier research that were replaced by variants in nearby spots on the DNA double helix that better correlated with prostate cancer risk through the lens of the larger, more diverse sample.

"It's an important refinement to find markers that are better at capturing risk across populations," said Haiman, who is also director of the USC Center for Genetic Epidemiology and co-leader of the Cancer Epidemiology Program at USC Norris cancer center. "The idea of precision medicine and global medicine for all rely on including and integrating information across populations, because the best marker determined in whites might not be the best marker overall."

Progress in assessing risk thanks to an international effort

In addition to fueling further research, the results have the potential to benefit human health by providing men with personalized risk information that they can use when having discussions with their doctors about screening and treatment. Ultimately the research could lay the ground work for genetic testing to identify those at greater risk for aggressive prostate cancer and enable early detection by screening them earlier and more often.

Because many prostate cancer cases diagnosed today might never reach the point where they are life-threatening -- leading to unnecessary treatment that can degrade quality of life -- differentiating between risk for aggressive disease is key. Up until now, the scientists' system for calculating risk scores has correlated with likelihood of developing prostate cancer, but lacked predictive value about how serious a given case may be.

"We'll continue to improve this risk score, and look for markers that help to distinguish aggressive from less aggressive disease," Haiman said. "Clinical trials will be required to evaluate the effectiveness of the risk score in helping doctors and patients make decisions about screening."

This research combined the data from virtually every study to date examining DNA for genetic variants associated with prostate cancer risk. The U.S. Veterans Health Administration's Million Veteran Program and Argonne National Laboratory proved to be essential partners [for including diverse populations in the study]. Bringing it all together required a team effort encompassing more than 300 researchers from well over 100 institutions, in 26 nations -- from Barbados to Bulgaria, Nigeria to the Netherlands and Japan to Ghana.

"This shows what happens when the world research community comes together to make improvements for all," Haiman said. "The fact that everyone was so willing to collaborate was enormously critical."

Allergic responses to common foods could significantly increase risk of heart disease, cardiovascular death

 Sensitivity to common food allergens such as dairy and peanuts could be an important and previously unappreciated cause of heart disease, new research suggests -- and the increased risk for cardiovascular death includes people without obvious food allergies.

That increased risk could be comparable to -- or exceed -- the risks posed by smoking, as well as diabetes and rheumatoid arthritis, the researchers report.

UVA Health scientists and their collaborators looked at thousands of adults over time and found that people who produced antibodies in response to dairy and other foods were at elevated risk of cardiovascular-related death. This was true even when traditional risk factors for heart disease, such as smoking, high blood pressure and diabetes, were taken into account. The strongest link was for cow's milk, but other allergens such as peanut and shrimp were also significant.

The troubling finding represents the first time that "IgE" antibodies to common foods have been linked to increased risk of cardiovascular mortality, the researchers report. The findings do not conclusively prove that food antibodies are causing the increased risk, but the work builds on prior studies connecting allergic inflammation and heart disease.

Approximately 15% of adults produce IgE antibodies in response to cow's milk, peanuts and other foods. While these antibodies cause some people to have severe food allergies, many adults who make these antibodies have no obvious food allergy. The new research found that the strongest link with cardiovascular death was in people who had the antibodies but continued to consume the food regularly -- suggesting they didn't have a severe food allergy.

"What we looked at here was the presence of IgE antibodies to food that were detected in blood samples," said researcher Jeffrey Wilson, M.D., Ph.D., an allergy and immunology expert at the University of Virginia School of Medicine. "We don't think most of these subjects actually had overt food allergy, thus our story is more about an otherwise silent immune response to food. While these responses may not be strong enough to cause acute allergic reactions to food, they might nonetheless cause inflammation and over time lead to problems like heart disease."

Unexpected Food Allergy Findings

The researchers were inspired to investigate the possibility that common food allergies could be harming the heart after members of the UVA team previously linked an unusual form of food allergy spread by ticks to heart disease. That allergy, first identified by UVA's Thomas Platts-Mills, M.D., Ph.D., is transmitted by the bite of the lone star tick, found throughout much of the country.

The allergy -- commonly if inaccurately called the "red meat allergy" -- sensitizes people to a particular sugar, alpha-gal, found in mammalian meat. The symptomatic form of the allergy, known as "alpha-gal syndrome," can cause hives, upset stomach and breathing difficulties -- even potentially deadly anaphylaxis -- three to eight hours after affected people eat beef or pork. (Poultry and fish don't contain the sugar, so they don't trigger a reaction.)

To see if other food allergies could be affecting the heart, a team including Wilson, Platts-Mills and collaborators from UVA, as well as Corinne Keet, M.D., Ph.D., of the University of North Carolina, reviewed data collected from 5,374 participants in the National Health and Examination Survey (NHANES) and the Wake Forest site of the Multi-Ethnic Study of Atherosclerosis (MESA). Of those people, 285 had died from cardiovascular causes.

Among the NHANES participants, IgE antibodies to at least one food was associated with a significantly higher risk of cardiovascular death, the researchers found. This was particularly true for people sensitive to milk, a finding that held true among the MESA participants as well. Additional analysis also identified peanut and shrimp sensitization as significant risk factors for cardiovascular death in those individuals who routinely ate them.

"We previously noted a link between allergic antibodies to the alpha-gal red meat allergen and heart disease," Wilson explained. "That finding has been supported by a larger study in Australia, but the current paper suggests that a link between allergic antibodies to food allergens and heart disease is not limited to alpha-gal. In some ways, this is a surprising finding. On the other hand, we are not aware that anyone has looked before."

Allergies and the Heart

While this is the first time that allergic antibodies to common foods have been linked to cardiovascular mortality, other allergic conditions -- such as asthma and the itchy rash known as eczema or atopic dermatitis -- previously have been identified as risk factors for cardiovascular disease.

The researchers speculate that allergic antibodies to food may be affecting the heart by leading to the activation of specialized cells, called mast cells. Mast cells in the skin and gut are known to contribute to classic allergic reactions, but they are also found in the cardiac blood vessels and heart tissue. Persistent activation of mast cells could drive inflammation, contributing to harmful plaque buildup that can cause heart attacks or other heart damage, the researchers believe.

The scientists underscore, however, that this is not yet certain. It's possible that other genetic or environmental factors could be at play. It's even possible that cardiovascular disease could increase the risk for food sensitization -- meaning that heart disease could up your risk for food allergies, rather than the other way round -- though the new results suggest this is unlikely.

The researchers are calling for further studies to better understand the implications of their finding before recommending any changes in how doctors treat or manage food allergies.

"This work raises the possibility that in the future a blood test could help provide personalized information about a heart-healthy diet," Wilson said. "Though before that could be recommended, we still have a lot of work to do understand these findings."

Left-handers aren't better spatially, gaming research shows

 Leonardo Da Vinci was one, so too Albert Einstein and Joan of Arc, while the footballer Diego Maradona was famous for using his against England, we are of course talking about left-handers.

It's been debated for decades, but now researchers at the University of York and University College London have suggested that left-handedness is not linked to better spatial skills.

By asking participants to download and play a video game that captured user information and tracked navigational challenges, researchers were able to measure demographic data -- including hand preference -- and activity from more than 420,000 international participants, across 41 different countries. They found that left handers were neither better nor worse than right handers at the tasks, clarifying a long-running debate about the links between handedness and spatial skills.

The brain has two hemispheres, controlling the opposite sides of the body; so in right handers, the left hemisphere controls the dominant right hand, whereas the situation is reversed in left-handers. Many cognitive abilities are also dominated by one of the two brain hemispheres, while right and left handers also show different patterns of lateralisation -- the specialisation of a particular area. As a result, many debates about cognitive differences related to handedness are also debates about the effects of brain lateralisation on cognitive abilities.

Spatial cognition, the ability of humans to perceive and navigate our physical environment, is a fundamental set of brain-based skills. It is also not clearly dominated by either hemisphere, leaving scientists unclear as to whether it has any link to handedness.

Some, inconclusive, research has suggested that left-handers might be better at navigating virtual and real games and left-handed athletes are known to be over-represented in the in professional sports requiring rapid and accurate responses.

However, it's been a tricky issue to research, partly because handedness prevalence changes from culture to culture, and partly because testing for handedness effects requires a large number of participants. Using the video game Sea Hero Quest, the researchers were able to overcome both challenges.

Dr Pablo Fernandez-Velasco, a researcher at the Department of Philosophy at the University of York, who co-led the study, said: "Recruiting participants in our study through a video game is a new approach, which allowed us to standardise a test across a very large sample. We found no reliable evidence for any difference in spatial ability between left and right handers, across all countries. Moreover, that large data sample allowed us to confirm that factors like age, gender and education don't play a part in the relationship between hand preference and spatial ability."

The users in the study downloaded and played Sea Hero Quest, a free app that measures spatial navigational ability and was originally designed to contribute to research on dementia. It asks participants to view a map featuring both their current position and their goal locations, and they are then asked to navigate a boat as quickly as possible towards goal locations in a specified order. Only participants reaching level 11 of the game were included.

Informed in-app consent was obtained from all participants. Left handers in the sample made up an average of 9.94% of the participants, with more males using their left hand compared with women, similar to what had previously been found in the general population.

Dr Fernandez-Velasco adds: "We're still finding out so much about cognition, and although we've shown that large-scale spatial skills aren't affected by left and right handedness, perhaps further research will find some differences based on handedness when it comes to navigation styles, or to preferences for different types of environments"

Super melanin' heals skin injuries from sunburn, chemical burns

 Imagine a skin cream that heals damage occurring throughout the day when your skin is exposed to sunlight or environmental toxins. That's the potential of a synthetic, biomimetic melanin developed by scientists at Northwestern University.

In a new study, the scientists show that their synthetic melanin, mimicking the natural melanin in human skin, can be applied topically to injured skin, where it accelerates wound healing. These effects occur both in the skin itself and systemically in the body.

When applied in a cream, the synthetic melanin can protect skin from sun exposure and heals skin injured by sun damage or chemical burns, the scientists said. The technology works by scavenging free radicals, which are produced by injured skin such as a sunburn. Left unchecked, free radical activity damages cells and ultimately may result in skin aging and skin cancer.

The study will be published Nov. 2 in Nature npj Regenerative Medicine.

Melanin in humans and animals provides pigmentation to the skin, eyes and hair. The substance protects your cells from sun damage with increased pigmentation in response to sunlight -- a process commonly referred to as tanning. That same pigment in your skin also naturally scavenges free radicals in response to damaging environmental pollution from industrial sources and automobile exhaust fumes.

"People don't think of their everyday life as an injury to their skin," said co-corresponding author Dr. Kurt Lu, the Eugene and Gloria Bauer Professor of Dermatology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine dermatologist. "If you walk barefaced every day in the sun, you suffer a low-grade, constant bombardment of ultraviolet light. This is worsened during peak mid-day hours and the summer season. We know sun-exposed skin ages versus skin protected by clothing, which doesn't show age nearly as much."

The skin also ages due to chronological aging and external environmental factors, including environmental pollution.

"All those insults to the skin lead to free radicals which cause inflammation and break down the collagen," Lu said. "That's one of the reasons older skin looks very different from younger skin."

When the scientists created the synthetic melanin engineered nanoparticles, they modified the melanin structure to have higher free radical scavenging capacity.

"The synthetic melanin is capable of scavenging more radicals per gram compared to human melanin," said co-corresponding author Nathan Gianneschi, the Jacob and Rosaline Cohn Professor of Chemistry, Materials Science & Engineering, Biomedical Engineering and Pharmacology at Northwestern. "It's like super melanin. It's biocompatible, degradable,nontoxic and clear when rubbed onto the skin. In our studies, it acts as an efficient sponge, removing damaging factors and protecting the skin."

Once applied to the skin, the melanin sits on the surface and is not absorbed into the layers below.

"The synthetic melanin stabilizes and sets the skin on a healing pathway, which we see in both the top layers and throughout the body," Gianneschi said.

Pivoting to a new theory

The scientists, who have been studying melanin for nearly 10 years, first tested their synthetic melanin as a sunscreen.

"It protected the skin and skin cells from damage," Gianneschi said. "Next, we wondered if the synthetic melanin, which functions primarily to soak up radicals, could be applied topically after a skin injury and have a healing effect on the skin? It turns out to work exactly that way."

Lu envisions the synthetic melanin cream being used as a sunscreen booster for added protection and as an enhancer in moisturizer to promote skin repair.

"You could put it on before you go out in the sun and after you have been in the sun," Lu said. "In both cases, we showed reduction in skin damage and inflammation. You are protecting the skin and repairing it simultaneously. It's continuous repair."

The cream could also potentially be used for blisters and open sores, Lu said.

Topical cream quiets immune system

Gianneschi and Lu discovered that the synthetic melanin cream, by soaking up the free radicals after an injury, quieted the immune system. The stratum corneum, the outer layer of mature skin cells, communicates with the epidermis below. It is the surface layer, receiving signals from the body and from the outside world. By calming the destructive inflammation at that surface, the body can begin healing instead of becoming even more inflamed.

"The epidermis and the upper layers are in communication with the entire body," Lu said. "This means that stabilizing those upper layers can lead to a process of active healing."

How the experiment worked

The scientists used a chemical to create a blistering reaction to a human skin tissue sample in a dish. The blistering appeared as a separation of the upper layers of the skin from each other.

"It was very inflamed, like a poison ivy reaction," Lu said.

They waited a few hours, then applied their topical melanin cream to the injured skin. Within the first few days, the cream facilitated an immune response by initially helping the skin's own radical scavenging enzymes to recover, then by halting the production of inflammatory proteins. This initiated a cascade of responses in which they observed greatly increased rates of healing. This included the preservation of healthy skin layers underneath. In samples that did not have the melanin cream treatment, the blistering persisted.

"The treatment has the effect of setting the skin on a cycle of healing and repair, orchestrated by the immune system," Lu said.

Melanin could protect people from toxins including nerve gas

Gianneschi and Lu are studying melanin as part of research programs funded by the U.S. Department of Defense (DOD) and the National Institutes of Health (NIH). This has included looking at melanin as a dye for clothing that would also act as an absorbent for toxins in the environment, particularly nerve gas. They showed they could dye a military uniform black with the melanin, and that it would absorb the nerve gas.

Melanin also absorbs heavy metals and toxins. "Although it can act this way naturally, we have engineered it to optimize absorption of these toxic molecules with our synthetic version," Gianneschi said.

The scientists are pursuing clinical translation and trials testing for efficacy of the synthetic melanin cream. In an initial step, the scientists recently completed a trial showing that the synthetic melanins are non-irritating to human skin.

Given their observation that melanin protects biologic tissue from high energy radiation, they surmise that this could be an effective treatment for skin burns from radiation exposure.

The promising work may well provide treatment options for cancer patients in the future, undergoing radiation therapy.

Other Northwestern authors include: Dauren Biyashev, Zofia Siwicka, Ummiye Onay, Michael Demczuk, Madison Ernst, Spencer Evans, Cuong Nguyen, Florencia Son, Navjit Paul, Naneki McCallum, Omar Farha, Stephen Miller and Dan Xu.

A step closer to injection-free diabetes care: Innovation in insulin-producing cells

 A University of Alberta team has developed a new step to improve the process for creating insulin-producing pancreatic cells from a patient's own stem cells, bringing the prospect of injection-free treatment closer for people with diabetes.

The researchers take stem cells from a single patient's blood and chemically wind them back in time, then forward again in a process called "directed differentiation," to eventually become insulin-producing cells.

In research published this month, the team treated pancreatic progenitor cells with an anti-tumour drug known as AKT/P70 inhibitor AT7867. They report the method produced the desired cells at a rate of 90 per cent, compared with previous methods that produced just 60 per cent target cells. The new cells were less likely to produce unwanted cysts and led to insulin injection-free glucose control in half the time when transplanted into mice. The team believes its efforts will soon be able to eliminate the final five to 10 per cent of cells that do not result in pancreatic cells.

"We need a stem cell solution that provides a potentially limitless source of cells," says James Shapiro, Canada Research Chair in Transplant Surgery and Regenerative Medicine and head of the Edmonton Protocol, which has allowed 750 transplantations of donated islet cells since it was first developed 21 years ago. "We need a way to make those cells so that they can't be seen and recognized as foreign by the body's immune system."

The researchers suggest this safer and more reliable way to grow insulin-producing cells from a patient's own blood could eventually allow transplants without the need for anti-rejection drugs. Recipients of donated cells must take anti-rejection drugs for life, and the therapy is limited by the small number of donated organs available.

Shapiro says further safety and efficacy studies will need to be carried out before transplantation of stem-cell-derived islet cells is ready for human trials, but he is excited by the progress.

"What we're trying to do here is peer over the horizon and try to imagine what diabetes care is going to look like 15, 20, 30 years from now," he says. "I don't think people will be injecting insulin anymore. I don't think they'll be wearing pumps and sensors."

Epigenetic changes are paramount in cancer progression

 The path a cell takes from healthy to metastatic cancer is mostly driven by epigenetic changes, according to a new computational study. Dr. Eduard Porta, group leader of the Cancer Immunogenomics group at the Josep Carreras Leukaemia Research Institute, participated in the new analysis that has been recently published in the journal Nature.

Every cell makes its own proteins by accessing the genetic information on its genes. Changes in this information, called mutations, may ruin the function of the affected proteins. In oncology, this is regarded as the genetics of cancer. The last decades, however, have seen the rise of a new field: the epigenetics of cancer.

Epigenetic modifications do not change the information but transiently modifies the cell's ability to read some of its own genes and produce the associated proteins instead. There is a vast epigenetic programme controlling in such way the general working of the cell and, when altered, it may put it at the starting line of malignant transformation. Is there a way to track these changes and understand the epigenetics of cancer transition?

An international team of researchers has started to unlocked this long-awaited milestone. In a tour de force, they analysed 1.7 million cells from 225 samples from primary and metastatic origin, from 205 patients of 11 different cancer types. For each cell, the team obtained the full transcriptome, exome and epigenome. This covers virtually all gene mutations, gene accessibility and its consequences. Using vast computational power, they could deduce the whole functional status of each analysed cell and link it to its particular cancer type.

The results of the work, published in the scientific journal Nature, demonstrate that many regions in the DNA are differentially activated or inactivated in a cancer-specific manner, creating a signature for each tumour. These differences are relevant for cancer progression and many correspond to already identified hallmarks of cancer, the steps a cell must undergo to become malignant. Dr. Eduard Porta, group leader at the Josep Carreras Leukaemia Research Institute (IJC-CERCA), is part of the team and contributed with his experience in the analysis of large amounts of biological data.

Epigenetic changes at the DNA level stand out as an underlying cause of cancer, according to the new publication. Particularly, the accessibility of enhancer regions, a kind of master regulator acting upon many genes at once. Taken together, the results converges into a short list of genes that can be used as markers for good or poor prognosis, valuable information for the clinical management of patients.

The analysis has also identified the cellular pathways of these important genes, making it possible to track their distant interactions. Sometimes, the affected genes are so fundamental that is impossible to drug them directly without side effects but, knowing the full pathway, researchers may develop strategies to target the weakest link in the chain, maximising the therapeutic benefits while minimising undesirable effects.

New antifungal molecule kills fungi without toxicity in human cells, mice

 A new antifungal molecule, devised by tweaking the structure of prominent antifungal drug Amphotericin B, has the potential to harness the drug's power against fungal infections while doing away with its toxicity, researchers at the University of Illinois Urbana-Champaign and collaborators at the University of Wisconsin-Madison report in the journal Nature.

Amphotericin B, a naturally occurring small molecule produced by bacteria, is a drug used as a last resort to treat fungal infections. While AmB excels at killing fungi, it is reserved as a last line of defense because it also is toxic to the human patient -- particularly the kidneys.

"Fungal infections are a public health crisis that is only getting worse. And they have the potential, unfortunately, of breaking out and having an exponential impact, kind of like COVID-19 did. So let's take one of the powerful tools that nature developed to combat fungi and turn it into a powerful ally," said research leader Dr. Martin D. Burke, an Illinois professor of chemistry, a professor in the Carle Illinois College of Medicine and also a medical doctor.

"This work is a demonstration that, by going deep into the fundamental science, you can take a billion-year head start from nature and turn it into something that hopefully is going to have a big impact on human health," Burke said.

Burke's group has spent years exploring AmB in hopes of making a derivative that can kill fungi without harm to humans. In previous studies, they developed and leveraged a building block-based approach to molecular synthesis and teamed up with a group specializing in molecular imaging tools called solid-state nuclear magnetic resonance, led by professor Chad Rienstra at the University of Wisconsin-Madison. Together, the teams uncovered the mechanism of the drug: AmB kills fungi by acting like a sponge to extract ergosterol from fungal cells.

In the new work, Burke's group worked again with Rienstra's group to find that AmB similarly kills human kidney cells by extracting cholesterol, the most common sterol in people. The researchers also resolved the atomic-level structure of AmB sponges when bound to both ergosterol and to cholesterol.

"The atomic resolution models were really the key to zoom in and identify these very subtle differences in binding interactions between AmB and each of these sterols," said Illinois graduate student Corinne Soutar, a co-first author of the paper.

"Using this structural information along with functional and computational studies, we achieved a significant breakthrough in understanding how AmB functions as a potent fungicidal drug," Rienstra said. "This provided the insights to modify AmB and tune its binding properties, reducing its interaction with cholesterol and thereby reducing the toxicity."

Armed with the information from the NMR studies, the Illinois team began synthesizing and testing derivatives with slight changes to the region that binds to ergosterol and cholesterol, while also boosting the kinetics of the ergosterol-removing process to maintain efficacy.

Enabled by collaborators and facilities at the Carl R. Woese Institute of Genomic Biology and U. of I. veterinary clinical medicine professor Dr. Timothy Fan, the researchers tested the most promising derivatives -- first with in vitro assays, quickly assessing the efficacy in killing fungi; then moving to cell cultures and eventually live mice, assessing toxicity.

One molecule, dubbed AM-2-19, stood out from the rest.

"This molecule is kidney-sparing, it is resistance evasive and it has broad spectrum efficacy," said postdoctoral researcher Arun Maji, a co-first author of the paper. "We tested this molecule against over 500 different clinically relevant pathogen species in four different locations. And this molecule completely surprised us by either mimicking or surpassing the efficacy of current clinically available antifungal drugs."

The researchers tested AM-2-19 in human blood and kidney cells to screen for toxicity. They also tested AM-2-19 in mouse models of three common, stubborn fungal infections and saw high efficacy.

"During my medical rotations, we called AmB 'ampho-terrible,' because of how hard it was on patients," Burke said. "Decoupling the efficacy from the toxicity turns 'ampho-terrible' into 'ampho-terrific.' We are very excited about the potential we are seeing, although clinical study is needed to see if this potential translates to people."

As a first step toward clinical application, AM-2-19 has been licensed to Sfunga Therapeutics and recently entered Phase 1 clinical trials. Sfunga Therapeutics also supported the work in part, and Burke received consulting income and equity in the company

New research links high salt consumption to risk of Type 2 diabetes

 Those at risk for Type 2 diabetes may already know to avoid sugar, but new research suggests they may want to skip the salt as well.

A new study from Tulane University published in Mayo Clinic Proceedings found that frequently adding salt to foods was associated with an increased risk of developing Type 2 diabetes.

The study surveyed more than 400,000 adults registered in the UK Biobank about their salt intake. Over a median of 11.8 years of follow-up, more than 13,000 cases of Type 2 diabetes developed among participants. Compared to those who "never" or "rarely" used salt, participants who "sometimes," "usually," or "always" added salt had a respective 13%, 20%, and 39% higher risk of developing Type 2 diabetes.

"We already know that limiting salt can reduce the risk of cardiovascular diseases and hypertension, but this study shows for the first time that taking the saltshaker off the table can help prevent Type 2 diabetes as well," said lead author Dr. Lu Qi, HCA Regents Distinguished Chair and professor at the Tulane University School of Public Health and Tropical Medicine.

Further research is needed to determine why high salt intake could be linked to a higher risk of Type 2 diabetes. However, Qi believes salt encourages people to eat larger portions, increasing the chances of developing risk factors such as obesity and inflammation. The study found an association between frequent consumption of salt and higher BMI and waist-to-hip ratio.

Qi said the next step is to conduct a clinical trial controlling the amount of salt participants consume and observing the effects.

Still, Qi said it's never too early to start searching for low-sodium ways to season your favorite foods.

"It's not a difficult change to make, but it could have a tremendous impact on your health," Qi said.

Protein interaction causing rare but deadly vaccine-related clotting found

 A mechanism that led some patients to experience cases of deadly clotting following some types of Covid-19 vaccination has been identified in new research.

In a paper published in Blood, scientists from the University of Birmingham funded by the National Institute for Health and Care Research and the British Heart Foundation have been able to identify how deadly blood clots, in the disease known as Vaccine-Induced Immune Thrombocytopenia and Thrombosis (VITT), occur.

Previous studies have shown that patients with VITT produce antibodies that stick to a protein called Platelet factor 4 (PF4) to create a large cluster of molecules called an immune complex. Following the development of a complex, platelets and cells of the immune system causing clotting and inflammation are activated, but the precise nature of what PF4 does in this event was unknown.

In this latest study, the team used blood taken from healthy donors, as well as serum and plasma from patients with VITT, and have been able to learn for the first time how PF4 was directly involved in the activation of platelets and resulted in thrombotic events. By sticking to a receptor called c-Mpl on the surface of platelets, PF4 triggered the production of the small cells known to cause clotting.

Dr Pip Nicolson, Associate Clinical Professor in Cardiovascular Medicine at the University of Birmingham and senior author of the study said: "The major advances seen in vaccine development during the global Covid-19 pandemic were thrown into sharp relief following the tragic, rare cases of vaccine-induced immune thrombosis. While there were alternative vaccines available to continue to provide protection against the coronavirus in some countries around the world, understanding the mechanisms behind these cases is critical to ensuring that the technology for delivering vaccines can be used with confidence in the future."

Dr Richard Buka, Research Fellow in the Institute of Cardiovascular Sciences and co-lead author "As well as identifying a new way in which platelets are being activated in a potentially deadly manner in VITT, our research has also been able to find how this mechanism may lead to new drugs to protect against blood clots in VITT and blood clots in general."

Variations on a drug used to treat bone marrow cancers could be developed to protect VITT patients from deadly clotting, the research also found.

The team used ruxolitinib, a drug used to treat some types of blood cancer, to block the receptor being triggered by PF4 following the vaccine-induced event. Although they note that the current form of the drug is unsuitable for use in VITT patients, the team nevertheless identified that blocking the pathway through ruxolitinib slowed down platelet aggregation and demonstrates a potential future way to protect patients from blood clots.

Dr Samantha Montague, Research Fellow in the Institute of Cardiovascular Sciences at the University of Birmingham and co-lead author of the paper said: "It is gratifying that we have been able to identify a new, important biological mechanism through trying to thoroughly understand a new disease. This work helps us to understand more fundamental things about how blood clots form and may also be relevant in other related diseases that are more common.

"Our ongoing research funded by the British Heart Foundation is looking at how we can identify patients who may develop VITT, with a view that future vaccine programmes around the world can be delivered while understanding and 

Contraceptive pill users less likely to report depression

 A new study has shown that women who are taking the oral contraceptive pill are less likely to report depression.

The research, which analysed data from 6,239 women in the United States aged 18-55 years old, found that the prevalence of major depression amongst users of the oral contraceptive pill (OCP) was significantly lower, at 4.6%, compared to former OCP users (11.4%).

The study was led by researchers at Anglia Ruskin University (ARU), alongside experts from the Dana-Farber Cancer Institute in Boston and University of California, Davis.

The researchers suggest two possible explanations for their findings, which are contrary to a commonly held belief that OCP can cause depression.

One is that taking the pill can remove concerns about unwanted pregnancy, therefore helping to improve the mental health of OCP users. It is also possible the results could be influenced by "survivor bias," where women who experience signs of depression while using OCP stop taking it, moving them into the category of former users.

The cross-sectional study, which used data collected by the Center for Disease Control and Prevention in the United States, controlled for demographic characteristics, chronic conditions, and the use of antidepressants.

In both users and former users, widowed, divorced or separated women, obese women or those with a history of cancer were more likely to report depression. In addition, in former users, depression was more commonly reported in women who were Black or Hispanic, were smokers, had lower levels of education, or were experiencing poverty.

Lead author Dr Julia Gawronska, a Postdoctoral Research Fellow at Anglia Ruskin University (ARU), said: "Contraception is a crucial component of preventive health care. Most women tolerate taking the oral contraceptive pill without experiencing depressive symptoms but there is a subset of women that may experience adverse mood side effects and even develop depression, and the reasons are not entirely clear.

"Unlike some previous studies, we found that women currently taking the oral contraceptive pill were much less likely to report clinically relevant depression compared to women who previously took the pill.

"Taking the pill could provide positive mental health benefits for some women, simply by removing their concerns about becoming pregnant. The 'survivor effect' could also play a part, with women who experience symptoms of depression more likely to discontinue taking it, placing them into the group of former users.

"However, stopping taking the pill without a suitable alternative increases the risk of unintended pregnancy. It is important that women are fully supported, provided with full information

Breakthrough discovery sheds light on heart and muscle health

 The human heart, often described as the body's engine, is a remarkable organ that tirelessly beats to keep us alive. At the core of this vital organ, intricate processes occur when it contracts, where thick and thin protein-filaments interact within the sarcomere, the fundamental building block of both skeletal and heart muscle cells. Any alterations in thick filament proteins can have severe consequences for our health, leading to conditions such as hypertrophic cardiomyopathy and various other heart and muscle diseases.

In a remarkable scientific achievement, an international team, led by Stefan Raunser, Director at the Max Planck Institute of Molecular Physiology in Dortmund, in collaboration with Mathias Gautel at King's College London, has achieved a groundbreaking milestone. They have successfully obtained the world's first high-resolution 3D image of the thick filament in its natural cellular environment, utilizing a cutting-edge technique known as electron cryo-tomography. This unprecedented accomplishment offers a glimpse into the molecular organization and arrangement of the components within the thick filament. This newfound insight is nothing short of a crucial framework for comprehending how muscles operate in both health and disease. By understanding the intricate mechanics at play, scientists are now better equipped to develop innovative pharmacological approaches and treatments that can target heart and muscle disorders, potentially revolutionizing medical intervention in these areas.

Atrial fibrillation, heart failure and stroke -- hypertrophic cardiomyopathy can lead to many serious health conditions and is a major cause of sudden cardiac death in people younger than 35. "The heart muscle is a central engine of the human body. Of course, it is easier to fix a broken engine, if you know how it is built and how it functions," says Stefan Raunser. "At the beginning of our muscle research we have successfully visualized the structure of the essential muscle building blocks and how they interact using electron cryo-microscopy. However, these were static images of proteins taken out of the living cell. They only tell us little about how the highly variable, dynamic interplay of muscle components moves the muscle in its native environment," says Raunser.

Through thick and thin

Skeletal and heart muscles contract upon the interaction of two types of parallel protein filaments in the sarcomere: thin and thick. The sarcomere is subdivided in several regions, called zones and bands, in which these filaments are arranged in different ways. The thin filament consists of F-actin, troponin, tropomyosin, and nebulin. The thick filament is formed of myosin, titin and myosin binding protein C (MyBP-C). The latter can form links between the filaments, whereas myosin, the so-called motor protein interacts with the thin filament to generate force and muscle contraction. Alterations in the thick filament proteins are associated with muscle diseases. A detailed picture of the thick filament would be of immense importance for developing therapeutical strategies to cure these diseases, but has been missing so far.

Milestones in muscle research

"If you want to fully understand how the muscle works on the molecular level, you need to picture its components in their natural environment -- one of the biggest challenges in biological research nowadays that cannot be tackled by traditional experimental approaches," says Raunser. To overcome this obstacle his team developed an electron cryo-tomography workflow specifically tailored to the investigation of muscle samples: The scientists flash-freeze mammalian heart muscle samples, produced by the Gautel group in London, at a very low temperature (- 175 °C). This preserves their hydration and fine structure and thus their native state. A focused ion beam (FIB milling) is then applied to thin out the samples to an ideal thickness of around 100 nanometers for the transmission electron microscope, which acquires multiple images as the sample is tilted along an axis. Finally, computational methods reconstruct a three-dimensional picture at high resolution. In recent years, Raunser's group successfully applied the customized workflow, resulting in two recent groundbreaking publications: They produced the first high-resolution images of the sarcomere and of a so far nebulous muscle protein called nebulin. Both studies provide unprecedented insights into the 3D organization of muscle proteins in the sarcomere, e. g. how myosin binds to actin to control muscle contraction and how nebulin binds to actin to stabilize it and to determine its length.

Completing the painting

In their current study the scientists produced the first high-resolution image of the cardiac thick filament spanning across several regions in the sarcomere. "With 500 nm length this makes for the longest and biggest structure ever resolved by cryo-ET," says Davide Tamborrini from the MPI Dortmund, first-author of the study. Even more impressive are the newly gained insights into the thick filament's molecular organization and thus into its function. The arrangement of the myosin molecules depends on their position in the filament. The scientists suspect, that this allows the thick filament to sense and process numerous muscle-regulating signals and thus to regulate the strength of muscle contraction depending on the sarcomere region. They also revealed how titin chains run along the filament. Titin chains intertwine with myosin, acting as a scaffold for its assembly and probably orchestrating a length-depending activation of the sarcomere.

"Our aim is to paint a complete picture of the sarcomere one day. The image of the thick filament in this study is 'only' a snapshot in the relaxed state of the muscle. To fully understand how the sarcomere functions and how it is regulated, we want to analyze it in different states e. g. during contraction," says Raunser. Comparison with samples from patients with muscle disease will ultimately contribute to a better understanding of diseases like hypertrophic cardiomyopathy and to the development of innovative therapies.