Discovery of how blood clots harm brain and body in COVID-19 points to new therapy

In a study that reshapes what we know about COVID-19 and its most perplexing symptoms, scientists have discovered that the blood coagulation protein fibrin causes the unusual clotting and inflammation that have become hallmarks of the disease, while also suppressing the body's ability to clear the virus.

Importantly, the team also identified a new antibody therapy to combat all of these deleterious effects.

Published in Nature, the study by Gladstone Institutes and collaborators overturns the prevailing theory that blood clotting is merely a consequence of inflammation in COVID-19. Through experiments in the lab and with mice, the researchers show that blood clotting is instead a primary effect, driving other problems -- including toxic inflammation, impaired viral clearance, and neurological symptoms prevalent in those with COVID-19 and long COVID.

The trigger is fibrin, a protein in the blood that normally enables healthy blood coagulation, but has previously been shown to have toxic inflammatory effects. In the new study, scientists found that fibrin becomes even more toxic in COVID-19 as it binds to both the virus and immune cells, creating unusual clots that lead to inflammation, fibrosis, and loss of neurons.

"Knowing that fibrin is the instigator of inflammation and neurological symptoms, we can build a new path forward for treating the disease at the root," says Katerina Akassoglou, PhD, a senior investigator at Gladstone and the director of the Center for Neurovascular Brain Immunology at Gladstone and UC San Francisco. "In our experiments in mice, neutralizing blood toxicity with fibrin antibody therapy can protect the brain and body after COVID infection."

From the earliest months of the pandemic, irregular blood clotting and stroke emerged as puzzling effects of COVID-19, even among patients who were otherwise asymptomatic. Later, as long COVID became a major public health issue, the stakes grew even higher to understand the cause of this disease's other symptoms, including its neurological effects. More than 400 million people worldwide have had long COVID since the start of the pandemic, with an estimated economic cost of about $1 trillion each year.

Flipping the Conversation

Many scientists and medical professionals have hypothesized that inflammation from the immune system's rapid reaction to the COVID-causing virus is what leads to blood clotting and stroke. But even at the dawn of the pandemic in 2020, that explanation didn't sound right to Akassoglou and her scientific collaborators.

"We know of many other viruses that unleash a similar cytokine storm in response to infection, but without causing blood clotting activity like we see with COVID," says Warner Greene, MD, PhD, senior investigator and director emeritus at Gladstone, who co-led the study with Akassoglou.

"We began to wonder if blood clots played a principal role in COVID -- if this virus evolved in a way to hijack clotting for its own benefit," Akassoglou adds.

Indeed, through multiple experiments in mice, the researchers found that the virus spike protein directly binds to fibrin, causing structurally abnormal blood clots with enhanced inflammatory activity. The team leveraged genetic tools to create a specific mutation that blocks only the inflammatory properties of fibrin without affecting the protein's beneficial blood-clotting abilities.

When mice were genetically altered to carry the mutant fibrin or had no fibrin in their bloodstream, the scientists found that inflammation, oxidative stress, fibrosis, and clotting in the lungs didn't occur or were much reduced after COVID-19 infection.

In addition to discovering that fibrin sets off inflammation, the team made another important discovery: fibrin also suppresses the body's "natural killer," or NK, cells, which normally work to clear the virus from the body. Remarkably, when the scientists depleted fibrin in the mice, NK cells were able to clear the virus.

These findings support that fibrin is necessary for the virus to harm the body.

Mechanism Not Triggered by Vaccines

The fibrin mechanism described in the paper is not related to the extremely rare thrombotic complication with low platelets that has been linked to adenoviral DNA COVID-19 vaccines, which are no longer available in the U.S.

By contrast, in a study of 99 million COVID-vaccinated individuals led by The Global COVID Vaccine Safety Project, vaccines that leverage mRNA technology to produce spike proteins in the body exhibited no excessive clotting or blood-based disorders that met the threshold for safety concerns. Instead, mRNA vaccines protect from clotting complications otherwise induced by infection.

Protecting the Brain

Akassoglou's lab has long investigated how fibrin that leaks into the brain triggers neurologic diseases, such as Alzheimer's disease and multiple sclerosis, essentially by hijacking the brain's immune system and setting off a cascade of harmful, often irreversible, effects.

The team now showed that in COVID-infected mice, fibrin is responsible for the harmful activation of microglia, the brain's immune cells involved in neurodegeneration. After infection, the scientists found fibrin together with toxic microglia and when they inhibited fibrin, the activation of these toxic cells in the brains of mice was significantly reduced.

"Fibrin that leaks into the brain may be the culprit for COVID-19 and long COVID patients with neurologic symptoms, including brain fog and difficulty concentrating," Akassoglou says. "Inhibiting fibrin protects neurons from harmful inflammation after COVID-19 infection."

The team tested its approach on different strains of the virus that causes COVID-19, including those that can infect the brain and those that do not. Neutralizing fibrin was beneficial in both types of infection, pointing to the harmful role of fibrin in brain and body in COVID-19 and highlighting the broad implications of this study.

A New Potential Therapy

This study demonstrates that fibrin is damaging in at least two ways: by activating a chronic form of inflammation and by suppressing a beneficial NK cell response capable of clearing virally infected cells.

"We realized if we could neutralize both of these negative effects, we could potentially resolve the severe symptoms we're seeing in patients with COVID-19 and possibly long COVID," Greene says.

Akassoglou's lab previously developed a drug, a therapeutic monoclonal antibody, that acts only on fibrin's inflammatory properties without adverse effects on blood coagulation and protects mice from multiple sclerosis and Alzheimer's disease.

In the new study, the team showed that the antibody blocked the interaction of fibrin with immune cells and the virus. By administering the immunotherapy to infected mice, the team was able to prevent and treat severe inflammation, reduce fibrosis and viral proteins in the lungs, and improve survival rates. In the brain, the fibrin antibody therapy reduced harmful inflammation and increased survival of neurons in mice after infection.

A humanized version of Akassoglou's first-in-class fibrin-targeting immunotherapy is already in Phase 1 safety and tolerability clinical trials in healthy people by Therini Bio. The drug cannot be used on patients until it completes this Phase 1 safety evaluation, and then would need to be tested in more advanced trials for COVID-19 and long COVID.

Looking ahead to such trials, Akassoglou says patients could be selected based on levels of fibrin products in their blood -- a measure believed to be a predictive biomarker of cognitive impairment in long COVID.

"The fibrin immunotherapy can be tested as part of a multipronged approach, along with prevention and vaccination, to reduce adverse health outcomes from long COVID," Greene adds.

The Power of Team Science

The study's findings intersect the scientific areas of immunology, hematology, virology, neuroscience, and drug discovery -- and required many labs across institutions to work together to execute experiments required to solve the blood-clotting mystery. Akassoglou founded the Center for Neurovascular Brain Immunology at Gladstone and UCSF in 2021 specifically for the purpose of conducting multidisciplinary, collaborative studies that address complex problems.

"I don't think any single lab could have accomplished this on their own," says Melanie Ott, MD, PhD, director of the Gladstone Institute of Virology and co-author of the study, noting important contributions from teams at Stanford, UC San Francisco, UC San Diego, and UCLA. "This tour-de-force study highlights the importance of collaboration in tackling these big questions."

Not only did this study address a big question, but it did so in a way that paves a clear clinical path for helping patients who have few options today, says Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease.

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Scientists identify new brain circuit in mice that controls body's inflammatory reactions

The brain can direct the immune system to an unexpected degree, capable of detecting, ramping up and tamping down inflammation, shows a new study in mice from researchers at Columbia's Zuckerman Institute.

"The brain is the center of our thoughts, emotions, memories and feelings," said Hao Jin, PhD, a co-first author of the study published online today in Nature. "Thanks to great advances in circuit tracking and single-cell technology, we now know the brain does far more than that. It is monitoring the function of every system in the body."

Future research could identify drugs that can target this newfound brain circuit to help treat a vast range of disorders and diseases in which the immune system goes haywire.

"This new discovery could provide an exciting therapeutic venue to control inflammation and immunity," said Charles S. Zuker, PhD, the study's senior author, a principal investigator at Columbia's Zuckerman Institute and a Howard Hughes Medical Institute investigator.

Recent work from the Zuker lab and other groups is revealing the importance of the body-brain axis, a vital pathway that conveys data between the organs and the brain. For example, Dr. Zuker and his colleagues discovered that sugar and fat entering the gut use the body-brain axis to drive the craving and strong appetite for sugary and fatty foods.

"We found all these ways in which the body is informing the brain about the body's current state," said co-first author Mengtong Li, PhD, a postdoctoral researcher in the Zuker lab. "We wanted to understand how much farther the brain's knowledge and control of the body's biology went."

The scientists looked for connections the brain might have with inflammation and innate immunity, the defense system shared by all animals and the most ancient component of the immune system. Whereas the adaptive immune system remembers previous encounters with intruders to help it resist them if they invade again, the innate immune system attacks anything with common traits of germs. The relative simplicity of innate immunity lets it respond to new insults more quickly than adaptive immunity.

Prior studies in humans revealed that electrically stimulating the vagus nerve -- a bundle of thousands of nerve fibers linking the brain and the body's internal organs -- could reduce the response linked to a specific inflammatory molecule. However, much remained unknown about the nature of this body-brain system: for instance, the generality of the brain's modulation of immunity and the inflammatory response, the selective lines of communication between the body and the brain, the logic of the underlying neural circuit, and the identity of the vagal and brain components that monitor and regulate inflammation.

The Zuker lab turned to a bacterial compound that sets off innate immune responses. The scientists found that giving this molecule to mice activated the caudal nucleus of the solitary tract, or cNST, which is tucked inside the brainstem. The cNST plays a major role in the body-brain axis and is the primary target of the vagus nerve.

The scientists showed that chemically suppressing the cNST resulted in an out-of-control inflammatory response to the immune insult: levels of pro-inflammatory molecules released by the immune system were more than three times higher than usual, and levels of anti-inflammatory immune compounds were roughly three times lower than normal. In contrast, artificially activating the cNST reduced pro-inflammatory molecule levels by nearly 70 percent and increased anti-inflammatory chemical levels almost tenfold.

"Similar to a thermostat, this newfound brain circuit helps increase or decrease inflammatory responses to keep the body responding in a healthy manner," said Dr. Jin, who started this study as a postdoctoral researcher in Dr. Zuker's lab. Dr. Jin is now a tenure track investigator at the National Institute of Allergy and Infectious Diseases. "In retrospect, it makes sense to have a master arbiter controlling this vital response."

Previous vagus nerve stimulation research in humans suggests the findings go beyond mice. The new research may also be in line with thousands of years of thought on the potential importance of the mind on the body.

"A lot of psychosomatic effects could actually be linked to brain circuits telling your body something," Dr. Jin noted.

The scientists identified the specific groups of neurons in the vagus nerve and in the cNST that help detect and control pro- and anti-inflammatory activity. "This opens up a new window into how the brain monitors and modulates body physiology," said Dr. Zuker, a professor of biochemistry, molecular biophysics and neuroscience at Columbia's Vagelos College of Physicians and Surgeons.

Discovering ways to control this newfound brain circuit may lead to novel therapies for common auto-immune diseases such as rheumatoid arthritis, type I diabetes, multiple sclerosis, neurodegenerative diseases, lupus, inflammatory bowel disease and Crohn's disease, as well as conditions such as long COVID syndrome, immune rejection of transplanted organs, and the potentially deadly outbursts known as cytokine storms that COVID infections can trigger.

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Scientists work out the effects of exercise at the cellular level

The health benefits of exercise are well known but new research shows that the body's response to exercise is more complex and far-reaching than previously thought. In a study on rats, a team of scientists from across the United States has found that physical activity causes many cellular and molecular changes in all 19 of the organs they studied in the animals.

Exercise lowers the risk of many diseases, but scientists still don't fully understand how exercise changes the body on a molecular level. Most studies have focused on a single organ, sex, or time point, and only include one or two data types.

To take a more comprehensive look at the biology of exercise, scientists with the Molecular Transducers of Physical Activity Consortium (MoTrPAC) used an array of techniques in the lab to analyze molecular changes in rats as they were put through the paces of weeks of intense exercise. Their findings appear in Nature.

The team studied a range of tissues from the animals, such as the heart, brain, and lungs. They found that each of the organs they looked at changed with exercise, helping the body to regulate the immune system, respond to stress, and control pathways connected to inflammatory liver disease, heart disease, and tissue injury.

The data provide potential clues into many different human health conditions; for example, the researchers found a possible explanation for why the liver becomes less fatty during exercise, which could help in the development of new treatments for non-alcoholic fatty liver disease.

The team hopes that their findings could one day be used to tailor exercise to an individual's health status or to develop treatments that mimic the effects of physical activity for people who are unable to exercise. They have already started studies on people to track the molecular effects of exercise.

Launched in 2016, MoTrPAC draws together scientists from the Broad Institute of MIT and Harvard, Stanford University, the National Institutes of Health, and other institutions to shed light on the biological processes that underlie the health benefits of exercise. The Broad project was originally conceived of by Steve Carr, senior director of Broad's Proteomics Platform; Clary Clish, senior director of Broad's Metabolomics Platform; Robert Gerszten, a senior associate member at the Broad and chief of cardiovascular medicine at Beth Israel Deaconess Medical Center; and Christopher Newgard, a professor of nutrition at Duke University.

Co-first authors on the study include Pierre Jean-Beltran, a postdoctoral researcher in Carr's group at Broad when the study began, as well as David Amar and Nicole Gay of Stanford. Courtney Dennis and Julian Avila, both researchers in Clish's group, were also co-authors on the manuscript.

"It took a village of scientists with distinct scientific backgrounds to generate and integrate the massive amount of high quality data produced," said Carr, a co-senior author of the study. "This is the first whole-organism map looking at the effects of training in multiple different organs. The resource produced will be enormously valuable, and has already produced many potentially novel biological insights for further exploration."

The team has made all of the animal data available in an online public repository. Other scientists can use this site to download, for example, information about the proteins changing in abundance in the lungs of female rats after eight weeks of regular exercise on a treadmill, or the RNA response to exercise in all organs of male and female rats over time.

Whole-body analysis

Conducting such a large and detailed study required a lot of planning. "The amount of coordination that all of the labs involved in this study had to do was phenomenal," said Clish.

In partnership with Sue Bodine at the Carver College of Medicine at the University of Iowa, whose group collected tissue samples from animals after up to eight weeks of training, other members of the MoTrPAC team divided the samples up so that each lab -- Carr's team analyzing proteins, Clish's studying metabolites, and others -- would examine virtually identical samples.

"A lot of large-scale studies only focus on one or two data types," said Natalie Clark, a computational scientist in Carr's group. "But here we have a breadth of many different experiments on the same tissues, and that's given us a global overview of how all of these different molecular layers contribute to exercise response."

In all, the teams performed nearly 10,000 assays to make about 15 million measurements on blood and 18 solid tissues. They found that exercise impacted thousands of molecules, with the most extreme changes in the adrenal gland, which produces hormones that regulate many important processes such as immunity, metabolism, and blood pressure. The researchers uncovered sex differences in several organs, particularly related to the immune response over time. Most immune-signaling molecules unique to females showed changes in levels between one and two weeks of training, whereas those in males showed differences between four and eight weeks.

Some responses were consistent across sexes and organs. For example, the researchers found that heat-shock proteins, which are produced by cells in response to stress, were regulated in the same ways across different tissues. But other insights were tissue-specific. To their surprise, Carr's team found an increase in acetylation of mitochondrial proteins involved in energy production, and in a phosphorylation signal that regulates energy storage, both in the liver that changed during exercise. These changes could help the liver become less fatty and less prone to disease with exercise, and could give researchers a target for future treatments of non-alcoholic fatty liver disease.

"Even though the liver is not directly involved in exercise, it still undergoes changes that could improve health. No one speculated that we'd see these acetylation and phosphorylation changes in the liver after exercise training," said Jean-Beltran. "This highlights why we deploy all of these different molecular modalities -- exercise is a very complex process, and this is just the tip of the iceberg."

"Two or three generations of research associates matured on this consortium project and learned what it means to carefully design a study and process samples," added Hasmik Keshishian, a senior group leader in Carr's group and co-author of the study. "Now we are seeing the results of our work: biologically insightful findings that are yielding from the high quality data we and others have generated.That's really fulfilling."

Read more at Science Daily

Do astronauts experience 'space headaches'?

Space travel and zero gravity can take a toll on the body. A new study has found that astronauts with no prior history of headaches may experience migraine and tension-type headaches during long-haul space flight, which includes more than 10 days in space. The study was published in the March 13, 2024, online issue of Neurology®, the medical journal of the American Academy of Neurology.

"Changes in gravity caused by space flight affect the function of many parts of the body, including the brain," said study author W. P. J. van Oosterhout, MD, PhD, of Leiden University Medical Center in the Netherlands.

"The vestibular system, which affects balance and posture, has to adapt to the conflict between the signals it is expecting to receive and the actual signals it receives in the absence of normal gravity. This can lead to space motion sickness in the first week, of which headache is the most frequently reported symptom. Our study shows that headaches also occur later in space flight and could be related to an increase in pressure within the skull."

The study involved 24 astronauts from the European Space Agency, the U.S. National Aeronautics and Space Administration (NASA) and the Japan Aerospace Exploration Agency.

They were assigned to International Space Station expeditions for up to 26 weeks from November 2011 to June 2018.

Prior to the study, nine astronauts reported never having any headaches and three had a headache that interfered with daily activities in the last year.

None of them had a history of recurrent headaches or had ever been diagnosed with migraine.

Of the total participants, 22 astronauts experienced one or more episode of headache during a total of 3,596 days in space for all participants.

Astronauts completed health screenings and a questionnaire about their headache history before the flight.

During space flight, astronauts filled out a daily questionnaire for the first seven days and a weekly questionnaire each following week throughout their stay in the space station.

The astronauts reported 378 headaches in flight.

Researchers found that 92% of astronauts experienced headaches during flight compared to just 38% of them experiencing headaches prior to flight.

Of the total headaches, 170, or 90%, were tension-type headache and 19, or 10%, were migraine.

Researchers also found that headaches were of a higher intensity and more likely to be migraine-like during the first week of space flight.

During this time, 21 astronauts had one or more headaches for a total of 51 headaches.

Of the 51 headaches, 39 were considered tension-type headaches and 12 were migraine-like or probable migraine.

In the three months after return to Earth, none of the astronauts reported any headaches.

"Further research is needed to unravel the underlying causes of space headache and explore how such discoveries may provide insights into headaches occurring on Earth," said Van Oosterhout.

"Also, more effective therapies need to be developed to combat space headaches as for many astronauts this a major problem during space flights."

This research does not prove that going into space causes headaches; it only shows an association.

A limitation of the study was that astronauts reported their own symptoms, so they may not have remembered all the information accurately.

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Music causes similar emotions and bodily sensations across cultures

Music can be felt directly in the body. When we hear our favourite catchy song, we are overcome with the urge to move to the music. Music can activate our autonomic nervous system and even cause shivers down the spine. A new study from the Turku PET Centre in Finland shows how emotional music evokes similar bodily sensations across cultures.

"Music that evoked different emotions, such as happiness, sadness or fear, caused different bodily sensations in our study. For example, happy and danceable music was felt in the arms and legs, while tender and sad music was felt in the chest area," explains Academy Research Fellow Vesa Putkinen.

The emotions and bodily sensations evoked by music were similar across Western and Asian listeners.

The bodily sensations were also linked with the music-induced emotions.

"Certain acoustic features of music were associated with similar emotions in both Western and Asian listeners. Music with a clear beat was found happy and danceable while dissonance in music was associated with aggressiveness. Since these sensations are similar across different cultures, music-induced emotions are likely independent of culture and learning and based on inherited biological mechanisms," says Professor Lauri Nummenmaa.

"Music's influence on the body is universal. People move to music in all cultures and synchronized postures, movements and vocalizations are a universal sign for affiliation. Music may have emerged during the evolution of human species to promote social interaction and sense of community by synchronising the bodies and emotions of the listeners," continues Putkinen.

The study was conducted in collaboration with Aalto University from Finland and the University of Electronic Science and Technology of China (UESTC) as an online questionnaire survey.

Altogether 1,500 Western and Asian participants rated the emotions and bodily sensations evoked by Western and Asian songs.

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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.

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Microplastics infiltrate all systems of body, cause behavioral changes

Plastics -- in particular, microplastics -- are among the most pervasive pollutants on the planet, finding their way into the air, water systems and food chains around the world. While the prevalence of microplastics in the environment is well known -- as are their negative impacts on marine organisms -- few studies have examined the potential health impacts on mammals, prompting University of Rhode Island Professor Jaime Ross' new study.

Ross and her team focused on neurobehavioral effects and inflammatory response to exposure to microplastics, as well as the accumulation of microplastics in tissues, including the brain. They have found that the infiltration of microplastics was as widespread in the body as it is in the environment, leading to behavioral changes, especially in older test subjects.

"Current research suggests that these microplastics are transported throughout the environment and can accumulate in human tissues; however, research on the health effects of microplastics, especially in mammals, is still very limited," said Ross, an assistant professor of biomedical and pharmaceutical sciences at the Ryan Institute for Neuroscience and the College of Pharmacy. "This has led our group to explore the biological and cognitive consequences of exposure to microplastics."

Ross' team -- which includes Research Assistant Professor Giuseppe Coppotelli, biomedical and pharmaceutical sciences graduate student Lauren Gaspar, and Interdisciplinary Neuroscience Program graduate student Sydney Bartman -- exposed young and old mice to varying levels of microplastics in drinking water over the course of three weeks. They found that microplastic exposure induces both behavioral changes and alterations in immune markers in liver and brain tissues. The study mice began to move and behave peculiarly, exhibiting behaviors akin to dementia in humans. The results were even more profound in older animals.

"To us, this was striking. These were not high doses of microplastics, but in only a short period of time, we saw these changes," Ross said. "Nobody really understands the life cycle of these microplastics in the body, so part of what we want to address is the question of what happens as you get older. Are you more susceptible to systemic inflammation from these microplastics as you age? Can your body get rid of them as easily? Do your cells respond differently to these toxins?"

To understand the physiological systems that may be contributing to these changes in behavior, Ross' team investigated how widespread the microplastic exposure was in the body, dissecting several major tissues including the brain, liver, kidney, gastrointestinal tract, heart, spleen and lungs. The researchers found that the particles had begun to bioaccumulate in every organ, including the brain, as well as in bodily waste.

"Given that in this study the microplastics were delivered orally via drinking water, detection in tissues such as the gastrointestinal tract, which is a major part of the digestive system, or in the liver and kidneys was always probable," Ross said. "The detection of microplastics in tissues such as the heart and lungs, however, suggests that the microplastics are going beyond the digestive system and likely undergoing systemic circulation. The brain blood barrier is supposed to be very difficult to permeate. It is a protective mechanism against viruses and bacteria, yet these particles were able to get in there. It was actually deep in the brain tissue."

That brain infiltration also may cause a decrease in glial fibrillary acidic protein (called "GFAP"), a protein that supports many cell processes in the brain, results have shown. "A decrease in GFAP has been associated with early stages of some neurodegenerative diseases, including mouse models of Alzheimer's disease, as well as depression," Ross said. "We were very surprised to see that the microplastics could induce altered GFAP signaling."

She intends to investigate this finding further in future work. "We want to understand how plastics may change the ability for the brain to maintain its homeostasis or how exposure may lead to neurological disorders and diseases, such as Alzheimer's disease," she said.

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Biological network in cells helps body adapt to stresses on health

Every minute of every day, our body adapts to meet the needs of each moment. When we binge on carbs, exercise, or become sick, chemical reactions inside our cells switch on, slow down, or shift strategy so that we have the energy and strength we need.

All this happens without us knowing it, perhaps explaining why so little is understood about how the body senses and responds to these constant demands. Seeking answers to this question, scientists at University of Utah Health led research that opens up a whole new world within our cells. Their study, published in Science, uncovers a vast network of interactions that suggest how cells adjust in real time to withstand stresses on our health.

"We're discovering how nature has evolved to 'drug' its own proteins and pathways," says Jared Rutter, Ph.D., distinguished professor in the Department of Biochemistry at University of Utah and the study's corresponding author. "By following nature's lead, we're learning how to make better therapeutics."

These findings -- and the technology that made them possible -- has become the basis for the biotechnology company Atavistik Bio, co-founded by Rutter. The company is leveraging this new understanding to accelerate drug discovery for metabolic diseases and cancer.

At a more fundamental level, Rutter says, the advance deepens knowledge about how cells and our bodies work.

A New Frontier

The network described in the study represents an underappreciated layer of regulation in cells that comes from an unexpected source. For nearly 20 years, Rutter's lab has researched metabolism, the chemical reactions that produce energy and build essential components to keep cells running smoothly. Their new research finds that intermediate products of those chemical reactions are more than passive building blocks and sources of fuel for cells, as had long been thought.

Instead, these intermediate products, along with other metabolites, make up an expansive web of sentries that monitor the environment and prompt cells to adapt when needed. They do this by interacting with proteins and modifying how they work. Does a big meal pump too many carbs in the body? Or too much fat? Like a railroad switch that guides a train onto a new track, these protein-metabolite interactions shift metabolic operations to break down those nutrients and steady the course.

The study's first author Kevin Hicks, Ph.D., developed a new technology, termed MIDAS, that reveals the enormity of the regulatory network that acts as an interface between environmental cues and cell metabolism, called the protein-metabolite interactome. The highly sensitive technique identified interactions that had never been seen. An analysis of 33 human proteins involved in converting carbohydrates into fuel found 830 interactions with metabolites. Given that there are thousands of proteins in the cell, the full scale of the network is predicted to be much larger.

"It's surprising how little we know about the extent of these interactions," Hicks says. "We are pushing our understanding of the biological network in new directions."

Read more at Science Daily

Excess weight, obesity more deadly than previously believed

Excess weight or obesity boosts risk of death by anywhere from 22% to 91% -- significantly more than previously believed -- while the mortality risk of being slightly underweight has likely been overestimated, according to new CU Boulder research.

The findings, published Feb. 9 in the journal Population Studies, counter prevailing wisdom that excess weight boosts mortality risk only in extreme cases.

The statistical analysis of nearly 18,000 people also shines a light on the pitfalls of using body mass index (BMI) to study health outcomes, providing evidence that the go-to metric can potentially bias findings. After accounting for those biases, it estimates that about 1 in 6 U.S. deaths are related to excess weight or obesity.

"Existing studies have likely underestimated the mortality consequences of living in a country where cheap, unhealthy food has grown increasingly accessible, and sedentary lifestyles have become the norm," said author Ryan Masters, associate professor of sociology at CU Boulder.

"This study and others are beginning to expose the true toll of this public health crisis."

Challenging the obesity paradox

While numerous studies show that heart disease, high blood pressure and diabetes (which are often associated with being overweight) elevate mortality risk, very few have shown that groups with higher BMIs have higher mortality rates.

Instead, in what some call the "obesity paradox," most studies show a U-shaped curve: Those in the "overweight" category (BMI 25-30) surprisingly have the lowest mortality risk. Those in the "obese" category (30-35) have little or no increased risk over the so-called "healthy" category (18.5-25). And both the "underweight" (less than 18.5) and extremely obese (35 and higher) are at increased risk of death.

"The conventional wisdom is that elevated BMI generally does not raise mortality risk until you get to very high levels, and that there are actually some survival benefits to being overweight," said Masters, a social demographer who has spent his career studying mortality trends. "I have been suspicious of these claims."

He noted that BMI, which doctors and scientists often use as a health measure, is based on weight and height only and doesn't account for differences in body composition or how long a person has been overweight.

"It's a reflection of stature at a point in time. That's it," said Masters, noting that Tom Cruise (at 5 feet 7 inches and an extremely muscular 201 pounds at one point), had a BMI of 31.5, famously putting him in the category of "obese." "It isn't fully capturing all of the nuances and different sizes and shapes the body comes in."

To see what happened when those nuances were considered, Masters mined the National Health and Nutrition Examination Survey (NHANES) from 1988 to 2015, looking at data from 17,784 people, including 4,468 deaths.

He discovered that a full 20% of the sample characterized as "healthy" weight had been in the overweight or obese category in the decade prior. When set apart, this group had a substantially worse health profile than those in the category whose weight had been stable.

Masters pointed out that a lifetime carrying excess weight can lead to illnesses that, paradoxically, lead to rapid weight loss. If BMI data is captured during this time, it can skew study results.

"I would argue that we have been artificially inflating the mortality risk in the low-BMI category by including those who had been high BMI and had just lost weight recently," he said.

Meanwhile, 37% of those characterized as overweight and 60% of those with obese BMI had been at lower BMIs in the decade prior. Notably, those who had only recently gained weight had better health profiles.

"The health and mortality consequences of high BMI are not like a light switch," said Masters. "There's an expanding body of work suggesting that the consequences are duration-dependent."

By including people who had spent most of their life at low-BMI weight in the high-BMI categories, previous studies have inadvertently made high BMI look less risky than it is, he said.

When he looked at differences in fat distribution within BMI categories, he also found that variations made a huge difference in reported health outcomes.

Exposing a public health problem

Collectively, the findings confirm that studies have been "significantly affected" by BMI-related bias.

When re-crunching the numbers without these biases, he found not a U-shape but a straight upward line, with those with low BMI (18.5-22.5) having the lowest mortality risk.

Contrary to previous research, the study found no significant mortality risk increases for the "underweight" category.

While previous research estimated 2 to 3% of U.S. adult deaths were due to high BMI, his study pegs the toll at eight times that.

Masters said he hopes the research will alert scientists to be "extremely cautious" when making conclusions based on BMI. But he also hopes the work will draw attention to what he sees not as a problem for individuals alone to solve but rather a public health crisis fueled by an unhealthy or "obesogenic" environment in the U.S.

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Want to fire up the dance floor? Play low-frequency bass

To find out how different aspects of music influence the body, researchers turned a live electronic music concert into a lab study. By introducing levels of bass over speakers that were too low to hear and monitoring the crowd's movements, scientists found that people danced 11.8 percent more when the very low frequency bass was present. The study appears November 7 in the journal Current Biology.

"I'm trained as a drummer, and most of my research career has been focused on the rhythmic aspects of music and how they make us move," says first author Daniel Cameron, a neuroscientist from McMaster University. "Music is a biological curiosity -- it doesn't reproduce us, it doesn't feed us, and it doesn't shelter us, so why do humans like it and why do they like to move to it?"

Cameron conducts research at the McMaster LIVELab, which connects science with live performance in a unique research theater. It is equipped with 3D motion capture, a Meyer sound system that can replicate various concert environments, and enhanced speakers that can produce extremely low frequencies, so low they were undetectable to the human ear.

For the Current Biology study, Cameron and colleagues recruited participants attending a LIVELab concert for electronic musical duo Orphx. The concertgoers were equipped with motion-sensing headbands to monitor their dance moves. Additionally, they were asked to fill out survey forms before and after the event. These forms were used to ensure the sound was undetectable, measure concert enjoyment, and examine how the music felt physically.

Throughout the 45-minute concert, the researchers manipulated the very-low bass-playing speakers, turning them on and off every two minutes. They found the amount of movement was 12 percent greater when the speakers were on.

"The musicians were enthusiastic to participate because of their interest in this idea that bass can change how the music is experienced in a way that impacts movement," says Cameron. "The study had high ecological validity, as this was a real musical and dance experience for people at a real live show."

The feeling of vibration through touch and the interactions between the inner ear and the brain have close links to the motor system. The researchers speculate these physical processes are at work in the neurological connection between music and movement. This anatomy can pick up on low frequencies and can affect the perception of "groove," spontaneous movement, and rhythm perception.

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Brain discovery holds key to boosting body's ability to fight Alzheimer's, MS

UVA Health researchers have discovered a molecule in the brain responsible for orchestrating the immune system's responses to Alzheimer's disease and multiple sclerosis (MS), potentially allowing doctors to supercharge the body's ability to fight those and other devastating neurological diseases.

The molecule the researchers identified, called a kinase, is crucial to both removing plaque buildup associated with Alzheimer's and preventing the debris buildup that causes MS, the researchers found. It does this, the researchers showed, by directing the activity of brain cleaners called microglia. These immune cells were once largely ignored by scientists but have, in recent years, proved vital players in brain health.

UVA's important new findings could one day let doctors augment the activity of microglia to treat or protect patients from Alzheimer's, MS and other neurodegenerative diseases, the researchers report.

"Unfortunately, medical doctors do not currently possess effective treatments to target the root causes of most neurodegenerative diseases, such as Alzheimer's, Parkinson's or ALS [amyotrophic lateral sclerosis, commonly called Lou Gehrig's disease]. In our studies, we have discovered a master controller of the cell type and processes that are required to protect the brain from these disorders," said senior researcher John Lukens, PhD, of the University of Virginia School of Medicine and its Center for Brain Immunology and Glia (BIG), as well as the Carter Immunology Center and the UVA Brain Institute. "Our work further shows that targeting this novel pathway provides a potent strategy to eliminate the toxic culprits that cause memory loss and impaired motor control in neurodegenerative disease."

Toxic Brain Buildup

Many neurodegenerative diseases, including Alzheimer's and MS, are thought to be caused by the brain's inability to cleanse itself of toxic buildup. Recent advances in neuroscience research have shed light on the importance of microglia in removing harmful debris from the brain, but UVA's new discovery offers practical insights into how this cleaning process occurs -- and the dire consequences when it doesn't.

Using a mouse model of Alzheimer's disease, the UVA researchers found that a lack of the molecule they identified, spleen tyrosine kinase, triggered plaque buildup in the brain and caused the mice to suffer memory loss -- like the symptoms seen in humans with Alzheimer's. Further, the neuroscientists were able to reduce the plaque buildup by activating this molecule and microglia in the brain, suggesting a potential treatment approach for human patients, though that would require significantly more research and testing.

"Our work has described a critical element of microglial function during Alzheimer's disease and MS," said researcher Hannah Ennerfelt, the first author of a new scientific paper outlining the findings. "Understanding the underlying biology of these cells during neurodegeneration may allow for scientists and doctors to develop increasingly informed and effective therapeutic interventions."

A lack of the molecule in a mouse model of MS, meanwhile, led to the buildup of damaged myelin, a protective coating on nerve cells. When myelin is damaged, the cells cannot transmit messages properly, causing MS symptoms such as mobility problems and muscle spasms. The UVA researchers conclude in a new scientific paper that the molecule they identified, abbreviated as SYK, is "critically involved" in the crucial removal of myelin debris. "If boosting SYK activity in microglia can decrease the amount of myelin debris in MS lesions, developing new drugs to target SYK could stop the progression of MS and help to reverse the damage," said Elizabeth L. Frost, PhD, a critical researcher on the project. "This is an especially promising option given that most of the currently available drugs for MS treatment dampen adaptive immunity. These immunosuppressive drugs lead to susceptibility to infection and higher risk of potentially fatal side effects like progressive multifocal leukoencephalopathy. Additionally, some forms of MS do not have a strong involvement of the immune system, and therefore there are currently very limited treatment options for those patients."

"Targeting SYK in microglia," she noted, "would circumvent multiple limitations of present-day therapeutics for MS."

Based on their promising results, the researchers report that targeting the molecule to stimulate the brain's immune activity could offer a way to treat not just Alzheimer's and MS but a "spectrum" of neurodegenerative diseases.

"These findings are especially exciting because they point to a treatment avenue in which we could alter the behavior of these native brain cells, microglia, to behave in a more neuroprotective way," said researcher Coco Holliday, a UVA undergraduate working in the Lukens lab. "It could potentially be applied to a variety of different neurological diseases that all share the problem of a buildup of toxic waste in the brain. It's been a very exciting project to be a part of."

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Ancient viral elements embedded in human genome not from fossil retrovirus

Using a next generation sequencing analysis to examine human endogenous retrovirus (HERV) integration sites, researchers from Kumamoto University, the National Institute of Genetics (Japan), and the University of Michigan (USA) have discovered that these ancient retroviruses can undergo retrotransposition (DNA sequence insertion with RNA mediation) into iPS cells. The team believes that their discovery places a spotlight on a possible risk that HERVs pose when using iPS cells in regenerative medicine.

The study of ancient retroviruses embedded in our genome requires knowledge about our coexistence with viral threats throughout history. We know that HERVs occupy approximately 8% of the human genome and obtain mutations and deletions over long periods. HERVs are also expressed in early embryos and play several physiological roles in human development. For example, HERV-W and HERV-FRD Env proteins are important for placental formation, and HERV-K is thought to protect host cells from exogenous retrovirus infection. However, uncontrollable HERV-K expression is also thought to be associated with various diseases, including various cancers and neurological diseases, but the details of this association is not well known in humans.

Since no one has yet discovered replication competent HERVs in our genome, it is thought that they are from an extinct (fossil) virus. In their current work, the research team from Japan and the US discovered that HERV-K is expressed in SOX2-expressing cells, such as those in early embryos, cancer stem cells and iPS cells. They also found that some HERV-K are newly integrated into the host genome in the absence of Env, the viral envelope glycoprotein. This integration was dependent on reverse transcriptase, integrase and protease, thus the researchers hypothesized that the HERV-K embedded in our genome is actually not from a fossil virus, but moves on the genome through the synthesis of proviral DNA reverse transcription. Interestingly, when the researchers compared the HERV-K integration sites between iPS and fibroblast cells from the same donor, they found new HERV-K integration sites in iPS cells. However, the new integration sites were rarely preserved and disappeared during long-term culturing. HERV-K is likely to be randomly integrated into genome, thus the possibility remains that HERV-K retrotransposed-cells predominantly survive depending on their integration site.

The movement of HERV-K on the genome might cause cancer and neurological diseases by altering the gene expression profile. The researchers believe that the risk of HERV-K transposition is low in iPS cells but suggest that monitoring HERV-K integration sites should be seriously considered to improve the safety of regenerative medicine using iPS cells.

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Being in nature: Good for mind, body and nutrition

In late 2020, Canadian doctors made headlines for "prescribing nature," or recommended time outdoors based on research that suggests people who spent two or more hours in nature per week improved their health and wellbeing. Knowing this, transdisciplinary researchers from Drexel University investigated how nature relatedness -- simply feeling connected with the natural world -- benefits dietary diversity and fruit and vegetable intake, in a study recently published the American Journal of Health Promotion.

"Nature relatedness has been associated with better cognitive, psychological and physical health and greater levels of environmental stewardship. Our findings extend this list of benefits to include dietary intake," said Brandy-Joe Milliron, PhD, an associate professor in Drexel's College of Nursing and Health Professions and lead author of the publication. "We found people with higher nature relatedness were more likely to report healthful dietary intake, including greater dietary variety and higher fruit and vegetable consumption."

The research team surveyed over 300 adults in Philadelphia to measure their self-reported connection to nature, including their experience with and perspective of nature, and the foods and beverages they had consumed the previous day to assess their dietary diversity and estimate their daily fruit and vegetable consumption. Survey participants mirrored demographic characteristics (gender, income, education and race) of Philadelphia, as of the 2010 census. The data were collected between May and August 2017. The results of the survey showed that participants with a stronger connection to nature reported a more varied diet and ate more fruits and vegetables.

"This work can impact health promotion practices in two ways," said Milliron. "First, nature-based health promotion interventions may increase nature relatedness across the lifespan and potentially improve dietary intake. And second, augmenting dietary interventions with nature-based activities may lead to greater improvements in dietary quality."

The research team added that these findings highlight the potential for leveraging nature-based experiences or interventions such as incorporating green spaces or urban greening into city planning, integrating nature- and park-prescription programs into healthcare practices (similar to the Canadian model) and promoting nature-based experiences in the classroom settings, among many others.

But, the researchers noted, while improving dietary intake through nature-based interventions may be valuable, it is also complex.

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Octopus-like tentacles help cancer cells invade the body

With help from the best tweezers in the world a team of researchers from the University of Copenhagen has shed new light on a fundamental mechanism in all living cells that helps them explore their surroundings and even invade tissue. Their discovery could have implications for research into cancer, neurological disorders and much else.

Using octopus-like tentacles, a cell pushes toward its target, a bacterium, like a predator tracking down its prey. The scene could be playing out in a nature programme. Instead the pursuit is being observed at the nano-scale through a microscope at the University of Copenhagen's Niels Bohr Institute. The microscope recording shows a human immune cell pursuing and then devouring a bacterium.

With their new study, a team of Danish researchers has added to the world's understanding of how cells use octopus-like tentacles called filopodia to move around in our bodies. This discovery about how cells move had never been addressed. The study is being published today in the journal, Nature Communications.

"While the cell doesn't have eyes or a sense of smell, its surface is equipped with ultra-slim filopodia that resemble entangled octopus tentacles. These filopodia help a cell move towards a bacterium, and at the same time, act as sensory feelers that identify the bacterium as a prey," explains Associate Professor Poul Martin Bendix, head of the laboratory for experimental biophysics at the Niels Bohr Institute.

The discovery is not that filopodia act as sensory devices -- which was already well established -- but rather about how they can rotate and behave mechanically, which helps a cell move, as when a cancer cell invades new tissue.

"Obviously, our results are of interest to cancer researchers. Cancer cells are noted for their being highly invasive. And, it is reasonable to believe that they are especially dependent on the efficacy of their filopodia, in terms of examining their surroundings and facilitating their spread. So, it's conceivable that by finding ways of inhibiting the filopodia of cancer cells, cancer growth can be stalled," explains Associate Professor Poul Martin Bendix.

For this reason, researchers from the Danish Cancer Society Research Center are a part of the team behind the discovery. Among other things, the cancer researchers are interested in whether switching off the production of certain proteins can inhibit the transport mechanisms which are important for the filopodia of cancer cells.

The cell's engine and cutting torch

According to Poul Martin Bendix, the mechanical function of filopodia can be compared to a rubber band. Untwisted, a rubber band has no power. But if you twist it, it contracts. This combination of twisting and contraction helps a cell move directionally and makes the filopodia very flexible.

"They're able to bend -- twist, if you will -- in a way that allows them to explore the entire space around the cell, and they can even penetrate tissues in their environment," says lead author, Natascha Leijnse.

The mechanism discovered by the Danish researchers appears to be found in all living cells. Besides cancer cells, it is also relevant to study the importance of filopodia in other types of cells, such as embryonic stem cells and brain cells, which are highly dependent on filopodia for their development.

Studying cells with the best tweezers in the world

The project involved interdisciplinary collaboration at the Niels Bohr Institute, where Associate Professor Amin Doostmohammadi, who heads a research group that simulates biologically active materials, contributed with the modelling of filopodia behaviour.

"It is very interesting that Amin Doostmohammadi could simulate the mechanical movements we witnessed through the microscope, completely independent of chemical and biological details," explains Poul Martin Bendix.

The main reason that the team succeeded in being the first to describe the mechanical behaviour of filopodia is that NBI has unique equipment for this type of experiment, as well as skilled researchers with tremendous experience working with optical tweezers. When an object is extraordinarily small, holding onto it mechanically becomes impossible. However, it can be held and moved using a laser beam with a wavelength carefully calibrated to the object being studied. This is called an optical tweezers.

"At NBI, we have some of the world's best optical tweezers for biomechanical studies. The experiments require the use of several optical tweezers and the simultaneous deployment of ultra-fine microscopy," explains Poul Martin Bendix.

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Scientists discover body's natural alarm to battle blood loss

University of Virginia School of Medicine scientists have discovered a cluster of cells in the brainstem that controls the body's response to severe blood loss, a finding which could benefit efforts to develop new treatments for traumatic injuries.

The discovery pinpoints a collection of neurons that drives a response that maintains blood pressure during blood loss. However, severe blood loss eventually causes cardiovascular collapse -- a condition termed "decompensated hemorrhage" marked by an abrupt and dangerous loss of blood pressure -- and the new results shed light on why that happens.

"During blood loss, the brain coordinates a cardiovascular response that supports blood flow to critical organs, like the heart and brain,"said researcher George Souza, PhD, of UVA's Department of Pharmacology. "Our study shows that the cardiovascular response to blood loss depends on changes in the activity of a few hundred neurons in the brainstem."

Under Pressure

The new results, from UVA's Stephen Abbott, PhD, and collaborators, shed light on an important process the body uses to maintain its blood pressure. The neurons Abbott and his team describe -- properly known as "adrenergic C1 neurons" -- monitor blood pressure and swing into action during blood loss. When the neurons detect blood loss, they increase nerve activity that constricts blood vessels and maintains proper blood pressure.

The scientists were able to determine this using advanced imaging and a technique called optogenetics that allows for the remote control of neurons using light. Their research revealed that the C1 neurons are hyperactive during blood loss, and this maintains blood pressure. But these neurons become inactive with severe blood loss, resulting in cardiovascular collapse.

Decompensated hemorrhage is the prelude to hemorrhagic shock, in which the body begins to shut down. But the scientists found that re-activating the C1 neurons in lab rats restored both blood pressure and heart rate.

"Our study indicates that reactivating the brain pathways controlling blood pressure during decompensated hemorrhage effectively reverses cardiovascular collapse. We think this indicates that neuromodulation of the pathways described by our study could be a beneficial adjunct therapy for low blood pressure following blood loss," said Abbott, of UVA's Department of Pharmacology.

The scientists note that there may be several factors that contribute to the decline in the activity of the C1 neurons during the onset of decompensated hemorrhage. More research on that front is needed. But the team's findings identify important new directions for that future research.

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Why exercise gets harder the less you do

Doing less exercise could deactivate a vital protein in the body, causing further inactivity and making exercise more difficult, new research suggests.

University of Leeds scientists have discovered that deactivating the Piezo1 protein, a blood flow sensor, reduces the density of capillaries carrying blood to the muscles.

This restricted blood flow means activity becomes more difficult and can lead to a reduction in how much exercise is possible, the team found.

They say the results help to explain the biology of why exercise becomes harder the less you do.

The paper, Endothelial Piezo1 sustains muscle capillary density and contributes to physical activity, is published today in Journal of Clinical Investigation.

The experiments were carried out in mice, but the Piezo1 protein is found in humans, suggesting the same results could occur.

Lead author Fiona Bartoli, a Postdoctoral Researcher in the University of Leeds' School of Medicine, said: "Exercise protects against cardiovascular disease, diabetes, depression and cancer. Unfortunately, many people fail to exercise enough, for reasons such as injury and computer usage. This puts people at more risk of disease. The less people exercise, the less fit they become, often leading to a downward spiral.

"Although many responses to exercise are known, how the benefits of exercise are initially triggered at a molecular level is mysterious. Our study highlights the crucial link between physical activity and physical performance made at this level by Piezo1. Keeping our Piezo1s active by exercising may be crucial in our physical performance and health."

During the experiment, scientists compared two groups of mice -- a control group, and a group whose Piezo1 levels had been disrupted for 10 weeks. Walking, climbing and running wheel activity was observed, with the Piezo1 mice showing a striking reduction in activity levels. This suggests an important role for Piezo1 in sustaining normal physical activity.

The researchers considered whether the Piezo1 mice were less interested in exercise, but they found no differences in the amount or duration of activity between the two groups. Instead, there were fewer running wheel revolutions per exercise session, and slower running speed, suggesting a lowered ability to exercise, without a lesser desire.

Supervising author Professor David Beech, in the University of Leeds' School of Medicine, said: "Our work sheds new light on how Piezo1's role in blood vessels is connected to physical activity. A lot was already known about its role in blood vessel development, but far less was known about its contribution to vessel maintenance in adults.

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Make no bones about it: How our bodies shift between making bones and breaking them down

Osteoblasts act in a group to make bone over the course of several months. However, how osteoblasts cooperate with each other in vivo is still unknown. Now, researchers at Osaka University established an advanced high-resolution microscopy system to visualize extracellular vesicles secreted and captured by mature osteoblasts in vivo and identified a subset of osteoblast-derived vesicles limiting bone formation and stimulating bone-resorbing osteoclast differentiation through a microRNA (miRNA)-mediated mechanism. The osteoblast communication via extracellular vesicles controls the dynamic transition from bone-forming to bone-resorbing phases in vivo and could be a target for new treatments for bone diseases.

Bone remodeling occurs in different parts of the body throughout life to maintain bone architecture balance and systemic mineral homeostasis. During this "remodeling" process, osteoclasts remove mineralized bones, whereas osteoblasts form new bones. These resorption and formation phases are linked and balanced with intermittent coupling phases. "Functional coupling between these two cell types is critical for the maintenance of proper bone metabolism, and the mechanisms controlling the transition from bone-resorbing to bone-forming phases have been investigated. Nevertheless, the molecular and cellular mechanisms terminating osteoblastic bone formation and promoting osteoclastic bone resorption remain elusive," explains senior author Masaru Ishii.

Intravital optical imaging using multiphoton microscopy can help dissect in vivo cellular dynamics in various intact tissues and organs. To understand the spatiotemporal dynamics of bone remodeling in vivo, the researchers have established an intravital imaging technique to visualize the intact bone tissues of living mice. Using this method, they explored the interplay between bone-destroying osteoclasts and bone-forming osteoblasts. However, the spatial resolution of intravital bone imaging was insufficient to visualize structures smaller than cells.

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Small group of genetic variants found in extremely ill patients with COVID may help explain big differences in how sick people get

The search to better understand the tremendous range of responses to infection with the COVID-19 virus -- from symptom free to critically ill -- has uncovered in some of the sickest patients a handful of rare structural gene variants involved in body processes, like inflammation, which the virus needs to be successful.

"The virus has to attach to our cells, it has to get inside our cells and it has to multiply inside our cells. It also has to attract inflammation," says Dr. Ravindra Kolhe, director of the Georgia Esoteric and Molecular Laboratory at the Medical College of Georgia at Augusta University. "We have identified genes with structural changes in very sick individuals that are part of all four of these essential processes."

In apparently the first study of its kind, investigators used optical genome mapping, to get a thorough, three-dimensional assessment of the genome of 52 severally ill patients with COVID-19.

In nine of the sickest patients, they identified seven rare structural variants affecting a total of 31 genes involved in key pathways mediating the response between a person, or host, and a virus. These include innate immunity, our frontline immune defense against invaders like viruses; the inflammatory response, a key response to an infection that, gone awry, can also destroy the lungs of some of the sickest patients; and the ability of a virus to replicate and spread. As an example, one variant they identified can lead to overexpression of keratin genes. Keratins are proteins that are the structural components of things like our hair and nails, but that also have been identified as key to the transmission of both flu viruses and the COVID-19 virus between cells and are known to be upregulated in the respiratory tract during an infection.

"It's a hyperactivation of the normal systems," says Kolhe, corresponding author of the study, published by the international collaborative COVID-19 Host Genome Research consortium in the journal iScience.

"Millions of people get infected, and fortunately only a very small percentage become symptomatic, and a very small percentage of the symptomatic individuals require oxygen and a small percentage of those individuals are hospitalized and die," Kolhe says. "But even a small percentage amounts to millions of people and that is too many."

"Our data show that large (structural variants) identified using optical genome mapping might further explain the inter-individual clinical variability in response to COVID-19," the investigators write.

Large structural variants account for much of the genetic diversity among us, including changes that are just unique to the individual and those that can increase their risk of problems like cancer. Optical genome mapping is an emerging technology that can detect these larger variants with multiple changes, like deletion or insertion of genetic material and/or when a section of chromosome is reversed.

The investigators say that while more work needs to be done, their findings about the potential role of structural variants in the host-virus interaction point toward the need to look for genetic variations, ideally with a simple- to-use blood assay. Once identified, the goal would be to initiate proactive moves for these individuals like ensuring vaccination and boosting and potentially more aggressive treatment early on, like monoclonal antibody therapy, to help these individuals better combat COVID, Kolhe says.

Clinical studies have identified factors like older age, being male, hypertension, diabetes and other chronic conditions as risk factors associated with the degree of illness from COVID-19. The nine sickest patients in this study shared common comorbid conditions, 32 of the patients required mechanical ventilation to support their breathing and a total of 13 of the 52 patients died while in intensive care.

But in their studies, which also included individuals who were negative for the COVID-19 virus and those who were positive but asymptomatic, there were again outliers, including individuals with comorbid conditions who remained asymptomatic when infected with SARS-CoV-2 and those who were perfectly healthy but became extremely ill when infected, another indicator of a role for genetics in determining the degree of response, Kolhe says.

Kolhe notes that the large structural variants they found in the sickest patients were not caused by the virus rather used by the virus and may not increase susceptibility to other, even similar, conditions.

Overall, the individuals in this study had about 40 rare structural variants, which other studies have indicated is about average.

The COVID-19 Host Genome Research consortium currently has a membership of 34 institutions, including Duke and Columbia universities, the National Cancer Institute and the New York Genome Center, exploring different aspects of how structural variants impact the divergent individual responses to infection with the COVID-19 virus.

The group began to emerge after more commonplace gene sequencing studies, which essentially lay out the DNA in a straight line to look for problematic and smaller variations in the usual order of its four base pairs -- adenine, thymine, guanine and cytosine -- on thousands of patients have yielded little information to help explain -- and ideally predict -- the wide variations in how sick people will get. Better than 30% of the known disease-causing variants are larger than the single base pair changes sequencing can identify, according to the Human Gene Mutation Database.

Even the amount of virus in an individual does not directly correlate with how sick the individual gets, Kolhe says. "We had individuals with very high viral loads who did not even know they were positive," he says. "It is something in the host genome that is different."

Some studies have found that blood type might be a factor in predicting risk, specifically type A, and there have been some specific gene findings as well that predispose to immune deficiencies that may make people more susceptible.

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Haunted-house experience scares up interesting insights on the body’s reaction to threats

The so-called fight-or-flight response is evolution's way of preparing the body to defend itself or flee from a real or perceived threat, like a lion in the tall grass or -- in modern times -- an overdue performance review.

Scientists have struggled to study the effects of genuine threats on people's mental and physical state because of ethical and practical constraints of human lab experiments.

In new research published in the journal Psychological Science, researchers used a haunted-house experience to study participants' subjective and physiological responses to perceived threats in a safe yet immersive environment.

In this haunted-house setting, which included 17 rooms with various threats that formed an uninterrupted experience, the researchers examined how the body responds to threats differently depending on the social context (whether friends were around), features of the threats (whether they were expected), and emotions (whether individuals felt afraid).

"There are a lot of factors that influence how human bodies respond to threat," said Sarah M. Tashjian, of the Division of Humanities and Social Sciences at the California Institute of Technology and lead author of the study. "We found that friend-related emotional contagion, threat predictability, and subjective feelings of fear were all relevant for the body mounting a response."

All of these factors help increase a person's ability to survive when under threat, but in the study, each had slightly different influences, which demonstrate the dynamic nature of the sympathetic nervous system.

To study the effects of frightening experiences, previous studies used scary images, mild electric shocks, or loud noises. In the current study, 156 participants went through the haunted house in small groups. During the 30-minute experience, they encountered situations that mimicked the threat of suffocation, an oncoming speeding car, and a volley of shots (with pellets) from a firing squad.

Participants wore real-time physiological-monitoring wristbands to measure their electrodermal activity, or sweat-induced changes in the skin's electrical characteristics, including skin conductance level and skin conductance response.

Before visiting the haunted house, participants rated their expected fear on a scale from 1 to 10. Afterward, they rated their experienced fear level on the same scale. From these data, four factors were examined, including group composition, threat imminence, intrapersonal factors of fear, and a "baseline orienting response," or the participant's sensitivity to threats.

Results showed a positive association between the number of friends in a group and tonic arousal, which reflects the body's overall physical response to stress or emotion. On average, the more friends that participants had with them while touring the haunted house, the higher their physical response.

"We interpreted this to reflect fear contagion -- if your friends are around, your body picks up on their signals and has a higher level of arousal even in the absence of specific scares or startles," Tashjian said. "In the lab, it is difficult to study the effects of groups on physiology."

Studies usually involve testing one person at a time or, at most, pairs of friends. In this study, the researchers had the unique opportunity to study how being in groups with different mixes of friends and strangers affected people's perceptions of threat.

The researchers also noted positive associations between unexpected attacks, subjective fear, and phasic frequency. Phasic effects are rapid changes the body experiences as it responds to an event. Individuals who felt the most afraid during the haunted house had more peaks in these responses. "If your body is more cued-in to the threatening event, you also psychologically feel more fear," Tashjian said.

Other findings revealed that participants with an initially strong response to the first room of the haunted house showed increased responses as they visited other rooms. Participants with more frequent responses in the first room showed decreased responses over time.

"From a results perspective, this study is distinct because we measure multiple aspects of skin conductance, including slow responding, rapid responding, frequency of responses, and level of responses," Tashjian explained. "Most studies use just one of these measures, which limits our understanding of how dynamic the sympathetic nervous system is and how different factors exert different influences on biology."

She added that the research is a "major advance for cognitive and social psychology," because it furthers the understanding of how "naturalistic contexts," such as the immersive haunted house experience, influence the body's response to threats. Also significant is the finding that friends amplify the physical response.

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