The “glue” holding your cells together has a surprising second job

 A protein best known for helping cells and tissues stay connected has another unexpected role. Researchers have found that it also helps epithelial cells, which form continuous sealed layers throughout the body, engulf nearby dead cells.

The discovery could have implications for chronic inflammation. Debris from dying cells is a major contributor to inflammatory responses, so understanding how tissues remove that material may reveal new clues about what happens when the cleanup process fails.

The study, published in Nature Communications, focuses on the E-cadherin complex. This molecular system includes E-cadherin along with three additional proteins. Together, they connect epithelial cells lining areas such as the skin, gut and airways, giving tissues the structural strength they need to remain intact. In these tissues, each cell connects to E-cadherin molecules on neighboring cells.

Cellular Glue Takes on a Cleanup Role

A team led by Verena Ruprecht examined epithelial tissues in living zebrafish and mouse embryos. They found that the same molecular machinery also gathers at the exact location where a dying cell comes into contact with the tissue.

The researchers wanted to know whether E-cadherin and its partners were attaching to the dying cell in the same way they normally attach neighboring epithelial cells. To test that possibility, they carried out two experiments.

First, they presented the tissue with dying cells that had been stripped of E-cadherin. The epithelial tissue removed those cells just as effectively as it removed normal dying cells. Next, the team introduced fat droplets that contained no protein at all but carried a signal normally displayed on the surface of dying cells. The epithelial cells engulfed those droplets as well.

"We were intrigued to find out that epithelial cells repurpose their molecular adhesion machinery -- the 'glue' that normally holds them together -- to engulf dying cells," says ICREA Research Professor Verena Ruprecht, senior author of the study.

How Cells Eat Without Breaking the Barrier

Engulfing something roughly the size of another cell presents a difficult mechanical problem. Epithelial cells are tightly packed into barriers that often need to remain sealed, even while individual cells reshape themselves to remove debris.

Live imaging revealed how they accomplish this. The upper and lower surfaces of the same epithelial cell can behave differently from one another. The lower surface stretches and bends around the dead cell, while the opposite side remains relatively unchanged.

That upper surface, which may face the outside environment or an open space such as the inside of a lumen, continues maintaining the tissue barrier. Measurements taken before, during and after engulfment showed that the area of the upper surface changed very little. By contrast, the lower surface underwent substantial deformation during the 'eating' process.

Ruprecht compares the behavior to a row of dancers standing with their arms linked. Their upper bodies remain steady while their feet perform increasingly complicated movements when a dying cell appears. "It's the same dancer with a different choreography," she says.

A Molecular Rope and Brake

The researchers also examined the mechanics that allow the cells to perform this cleanup.

One protein in the E-cadherin complex acted much like a rope. It connected the molecular assembly to the cell's internal skeleton, allowing force to be transmitted across the surface of the material being engulfed. When cells lacked this tethering protein, or lacked the specific region that attaches it to the skeleton, they could no longer swallow dead cells.

Another component behaved more like a brake on the cell's contractile machinery. Surprisingly, removing this brake did not make the cleanup process more effective. Instead, the cell became too stiff and lost its ability to properly remove dying cells.

The Same Mechanism Appears in Mammals

The team next investigated whether the process extends beyond zebrafish.

In early mouse embryos, blocking E-cadherin caused dying cells to remain uncleared. This matched the results seen in zebrafish and suggests that the mechanism is shared among vertebrates.

The new work builds on earlier research from Ruprecht showing that embryos can use epithelial tissues to cooperatively remove dying cells. That behavior represents a form of early innate immune defense.

Embryos are particularly useful for studying these events because they are transparent. Researchers can observe living cells and tissues directly at a level of detail that cannot currently be achieved inside the human body.

Source: ScienceDaily

One immune switch may help drive aging across the body

 Aging happens at different speeds from one person to another, but it eventually affects everyone. New research from Stanford Medicine, conducted in mice and human cells, points to a particular failure in the immune system that may help explain why.

The researchers found that tissue-resident macrophages, a type of immune cell that lives permanently within organs, become less able with age to dispose of another class of immune cells. That decline appears to contribute to aging throughout the body.

When the scientists blocked a single receptor on these macrophages, multiple organs in mice retained more youthful characteristics. The effects were seen in the brain, heart, skeletal and heart muscle, liver, spleen, bone marrow, kidney, and colon. The receptor normally responds to a hormone involved in inflammation and pain in both mice and humans.

Disabling the receptor specifically in tissue-resident macrophages also protected mice from several problems associated with chronic inflammation and aging, including frailty, excess fat accumulation and heart trouble. Cognitive decline was substantially reduced as well, according to Katrin Andreasson, MD, the Edward F. and Irene Thiel Pimley Professor in Neurology and Neurological Sciences.

"We've been trying to figure out why we age," Andreasson said. "Now we know at least one big reason for it."

The findings are described in a paper published in Science. Andreasson is the senior author, and Jessy Tan, PhD, an instructor in neurology, is the lead author.

The results provide new insight into the important role that chronic, body-wide inflammation plays in aging and its associated health problems. They also point toward a potential drug strategy that could slow age-related deterioration in organs and possibly extend the number of years people remain healthy.

How the Immune System Clears Aging Cells

Neutrophils are the most abundant white blood cells in the immune system and serve as some of the body's most important first responders. They are produced in bone marrow and then enter the bloodstream, where they patrol for bacterial, viral, and fungal threats.

When neutrophils encounter pathogens, they can release toxic substances and even destroy themselves, spilling long strands of biological material that form web-like traps around invading microbes.

These cells do not live for long. A neutrophil may survive for as much as 24 hours, although 12 hours is more typical. Roughly 90% of circulating neutrophils eventually arrive in the liver, spleen, and bone marrow, where other immune cells remove them.

That disposal process is especially important as the body grows older. In aging animals, most neutrophils that never encounter a pathogen quickly enter senescence, a dysfunctional state in which they can release harmful chemicals that damage nearby cells and promote inflammation.

Neutrophil numbers increase with age, and a growing proportion of them become senescent.

"Senescent neutrophils are killing our tissues," Andreasson said. "Clearance of these cells is essential for preventing chronic inflammation."

The Body's Cellular Garbage Collectors

Macrophages are responsible for much of that cleanup. These versatile immune cells fight pathogens, coordinate responses from other cells and release growth factors that help damaged tissues repair themselves.

They also remove dead and dysfunctional cells.

"They're the body's garbage collection crew. A lot of that garbage is defunct cells." Andreasson said.

A large share of that cellular waste consists of neutrophils, with roughly 100 billion of them needing to be cleared every day.

There are several kinds of macrophages. Tissue resident macrophages are unusually long-lived cells that settle into organs during fetal development. Once established, they remain in those organs throughout life and adapt to perform specialized jobs in each location.

One of their most important responsibilities is swallowing senescent cells. The new findings show that neutrophils are particularly significant targets. About 100 billion neutrophils are produced each day, and they begin showing signs of senescence only 8 to 12 hours after entering the bloodstream. (Neutrophils that haven't arrived at senescence yet but have lived long enough and seen enough to put out "kill me now" flags of surrender on their cell surfaces are fair game.)

The problem is that tissue-resident macrophages themselves deteriorate with age. Andreasson and her colleagues reported in a 2021 Nature study that these long-lived immune cells become increasingly vulnerable to inflammation as animals grow older. They can then contribute to that inflammation themselves.

An Inflammatory Signal Grows Stronger With Age

One important part of this process involves prostaglandins, hormones produced by immune cells. One of the five types, called PGE2, can affect cells in different ways depending on which receptors are present on their surfaces.

One receptor for PGE2, known as EP2, strongly promotes inflammation. Tissue-resident macrophages contain large amounts of EP2.

PGE2 production rises in response to infection, injury and toxic substances, including compounds produced as the body ages. The researchers' earlier work showed that PGE2 levels increase substantially over time. At the same time, tissue resident macrophages develop higher concentrations of EP2.

Together, those changes create a harmful feedback process. Increasing PGE2 activity repeatedly stimulates EP2 receptors on tissue-resident macrophages. The new study found that this stimulation weakens the macrophages' ability to engulf neutrophils.

As a result, senescent neutrophils begin accumulating in the bloodstream and tissues.

Previous research from Andreasson's group also showed that the energy metabolism of tissue resident macrophages gradually deteriorates with age.

"Once that starts, there's a steady decline in a macrophage's performance," she said.

The new work suggests that EP2 is critical to that decline.

"We've shown that when tissue-resident macrophages don't have EP2 on their surfaces anymore or when that receptor is plugged up by a drug, this decline doesn't happen."

Blocking One Receptor Protects Multiple Organs

To investigate the receptor's role more closely, Andreasson's laboratory engineered mice whose EP2 gene could be deleted at a time chosen by the scientists, specifically in tissue-resident macrophages.

Removing EP2 restored the macrophages' ability to dispose of neutrophils, reversing the disruption caused by PGE2.

Source: ScienceDaily

Scientists say house cats could help unlock better cancer treatments for humans

 Scientists have taken a major step toward understanding cancer in cats, opening what researchers once described as a genetic "black box."

In a large international study published in Science, researchers genetically analyzed cat cancers on a scale that had not been attempted before. The work could improve cancer care for cats while also helping scientists better understand how some cancers develop in humans and other animals.

The researchers also created a freely available resource that other scientists can use to study the genetics of feline cancer.

Cancer is one of the leading causes of illness and death in cats, yet scientists have historically known far less about the genetic changes behind feline tumors than they do about cancers in humans or dogs.

Dr. Geoffrey Wood, a University of Guelph pathobiology professor and co-senior author of the study, said that gap has now begun to close.

"Despite domestic cats being common pets, there was very little known about the genetics of cancer in these animals," Wood says, "until now."

Cat and Human Cancers Share Key Genetic Changes

Researchers examined tumor samples from almost 500 domestic cats in five countries, searching for mutations and other genetic changes that help cancers form and grow.

Many cancers are driven by changes in certain genes that normally help control how cells grow, divide, repair damage, or die. When these genes are altered, cells can begin multiplying uncontrollably. Scientists often refer to genes that contribute directly to tumor growth as cancer driver genes.

The team found that many of the driver genes involved in cat cancers were also familiar from human and dog cancers.

One of the clearest examples appeared in aggressive mammary cancers, which arise in breast tissue.

The most common driver gene found in cat mammary tumors was FBXW7. More than 50 percent of the tumors examined carried a mutation in this gene.

FBXW7 normally helps regulate proteins involved in cell growth and division. When the gene is damaged, some of those growth promoting proteins can accumulate, potentially helping cancer cells survive and spread.

In humans, mutations in the FBXW7 gene in breast cancer are associated with worse prognosis - paralleling the change seen in cats.

Researchers also identified similarities between cat and human cancers affecting the blood, bones, lungs, skin, gastrointestinal system and central nervous system.

Shared Environments May Offer Cancer Clues

The similarities may be especially useful because domestic cats often live in the same environments as people.

Cats can encounter some of the same environmental factors as their owners, including household chemicals, air pollutants, smoke and other exposures that may influence cancer risk. Studying naturally occurring cancer in pets could therefore help researchers investigate how genetics and the surrounding environment interact.

"This study can help us understand more about why cancer develops in cats and humans, how the world around us influences cancer risk, and possibly find new ways to prevent and treat it," says Wood.

The genetic findings could also have implications for treatment.

Researchers found that certain chemotherapy drugs were more effective against cat mammary tumors carrying the mutated FBXW7 gene.

The result was observed only in tissue samples, so it does not yet show that the same approach will work in living cats or people. Still, the finding suggests that genetic information could eventually help doctors and veterinarians identify treatments that work better for particular tumors.

This type of approach is known as precision oncology. Instead of treating every cancer of the same general type in exactly the same way, precision oncology uses the molecular and genetic features of an individual tumor to help guide therapy.

"Having access to such a large set of donated tissues allowed us to assess drug responses across tumor types," says Dr. Sven Rottenberg, co-senior author at the University of Bern, "in a way that hasn't been possible at this scale before."

Bailey Francis, co-first author at the Wellcome Sanger Institute, said the findings could also have implications for dogs.

"When knowledge and data flows between different disciplines, we can all benefit."

Using Cat Cancer Research to Help Pets and People

The project brought together researchers from the Wellcome Sanger Institute, U of G's Ontario Veterinary College, the University of Bern and other institutions.

Rather than collecting all new samples, the team sequenced DNA from tissues that veterinarians had already obtained for diagnostic purposes.

That allowed scientists to study naturally occurring cancers from a large number of cats and compare the genetic patterns among different tumor types.

The findings also support a broader research strategy known as One Medicine.

The One Medicine approach emphasizes that human and veterinary medicine can inform one another. Cancer treatments developed for humans could potentially be evaluated in cats with naturally occurring tumors, while discoveries made during feline cancer studies and clinical trials could provide clues that help shape future human research.

That two way exchange is especially valuable because pets naturally develop many of the same diseases as people while sharing many aspects of the same environment.

Researchers hope the new genetic database will ultimately help bring more personalized cancer care to cats.

Dr. Louise Van Der Weyden, senior author at the Wellcome Sanger Institute, said the study provides a foundation for the next stage of feline cancer research.

"We can now begin to take the next steps forwards towards precision feline oncology, to catch up with the diagnostic and therapeutic options that are available for dogs with cancer, and ultimately one day, humans."

The research was funded in part by EveryCat Health Foundation, the CVS Group, Wellcome, the Natural Sciences and Engineering Research Council of Canada and the Swiss National Science Foundation.

Source: ScienceDaily

Stopping Ozempic may raise heart attack and stroke risk

 GLP-1 drugs such as semaglutide (Ozempic and Wegovy) and tirzepatide (Mounjaro and Zepbound) have surged in popularity for treating diabetes and helping people lose weight. About one in eight U.S. adults now use these medications, which are also known to provide cardiovascular benefits. But new research suggests that those heart benefits may fade quickly when treatment is stopped.

Researchers at Washington University School of Medicine in St. Louis tracked more than 333,000 U.S. veterans with type 2 diabetes for three years. They found that interrupting or stopping GLP-1 treatment for as little as six months was associated with a meaningful increase in the risk of major cardiovascular events compared with remaining on the medication.

The longer patients stayed off treatment, the greater the increase in risk. After two years without GLP-1 therapy, the risk of heart attack, stroke and death was up to 22% higher than among people who continued treatment, largely wiping out the cardiovascular protection gained while taking the drugs.

The findings, published in BMJ Medicine, suggest that stopping GLP-1 medications may have consequences that extend well beyond weight regain. They also point to the importance of uninterrupted treatment for maintaining heart protection.

"There is enormous exuberance about starting GLP-1 drugs, but not nearly enough attention to what happens when people stop," said senior author Ziyad Al-Aly, MD, a WashU Medicine clinical epidemiologist and chief of the Research and Development Service at the VA Saint Louis Health Care System. "Many quit after a few months because of cost, side effects or shortages. When they stop, it's not just weight that comes back; they experience a resurgence in inflammation, blood pressure, and cholesterol. Weight regain is visible; the metabolic reversal is not."

"Our data suggest this metabolic whiplash is detrimental to heart health," Al-Aly added. "Restarting the medication helped restore some protection, but only partially, showing that discontinuation leaves a lasting scar."

Heart protection depends on continued GLP-1 use

GLP-1 medications include the semaglutide drugs Ozempic and Wegovy and the tirzepatide drugs Mounjaro and Zepbound. After observing that about half of users stop taking GLP-1 drugs not long after beginning treatment, Al-Aly set out to examine what happens to cardiovascular health after therapy is discontinued.

The study focused on major adverse cardiovascular events, including heart attack, stroke and death. Researchers analyzed data from 333,687 veterans with type 2 diabetes. Of those, 132,551 had been prescribed GLP-1 drugs, while 201,136 had been prescribed sulfonylureas, another class of diabetes medications.

Sulfonylureas include glipizide (Glucotrol), glimepiride (Amaryl), and glyburide (Diabeta and others). Participants were followed for up to three years.

Researchers reassessed GLP-1 treatment status every six months. During the study, 26% of GLP-1 users stopped taking the medication altogether. Another roughly 23% experienced a treatment gap lasting at least six months before eventually restarting therapy.

Continuous treatment produced the greatest benefit

The clearest cardiovascular benefit appeared among people who remained on GLP-1 medications throughout the full three-year study period.

Compared with participants taking sulfonylureas, those who consistently stayed on GLP-1 therapy had an 18% lower risk of major cardiovascular events. That translated to about four fewer major cardiovascular events for every 100 people over three years.

Participants who stayed on GLP-1 treatment for two years or two-and-a-half years before stopping for the rest of the study also saw meaningful reductions in risk, at 7% and 15%, respectively.

By contrast, people who discontinued GLP-1 therapy before reaching 18 months showed no significant reduction in cardiovascular risk compared with those taking sulfonylureas by the end of the study.

Treatment gaps weakened heart protection

Interrupting treatment and then restarting it also appeared to reduce the cardiovascular benefit.

People who remained on GLP-1 drugs continuously for three years had an 18% reduction in risk, while those who stopped temporarily and later resumed treatment saw an average reduction of 12%.

Even a six-month interruption before restarting therapy was enough to weaken the benefit. Compared with continuous use, those treatment gaps were associated with a 4% to 8% increase in cardiovascular risk.

Longer periods off the drugs were linked to even greater losses of protection. People who stopped GLP-1 treatment for one year without restarting had a 14% higher risk of cardiovascular events compared with continuous users. After two years off treatment, that increase reached 22%.

The pattern suggests that cardiovascular benefits accumulated during GLP-1 treatment can be lost relatively quickly once the medication is discontinued.

Restarting may not fully restore lost benefits

The findings reinforce the importance of continuous treatment if patients and clinicians want to preserve the cardiovascular effects of GLP-1 therapy. They also suggest that reducing treatment interruptions could help maximize the drugs' protective effects on the heart.

"Clinicians should treat adherence to GLP-1 treatment as an important outcome in its own right -- not an afterthought," Al-Aly said. "Health systems need plans in place to help people continue their medication indefinitely, recognizing that GLP-1s treat chronic conditions. That includes proactive management of side effects, candid conversations about the long-term nature of treatment, infrastructure to identify and support patients at risk of stopping and addressing the cost barriers that make GLP-1 therapy unsustainable for many."

Al-Aly noted that this is especially important because cardiovascular protection from GLP-1 treatment appears to accumulate gradually but disappear much more quickly.

For study participants, spending only one year off the medication was enough to lose benefits that had taken years of continuous treatment to build. Restarting the drug restored some of that protection, but not all of it.

The research was funded by the United States Department of Veterans Affairs. The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication. The contents do not represent the views of the US Department of Veterans Affairs or the US Government.

Source: ScienceDaily

Hidden gut defect that may explain why IBD keeps coming back

 Researchers have identified early molecular warning signs of inflammatory bowel disease that may appear before symptoms and remain active even when patients seem to be doing well.

The study, led by WEHI in partnership with the Royal Melbourne Hospital, uncovered a hidden defect in intestinal cells that can make them vulnerable to damage. The problem was still detectable in some patients whose disease appeared to be well controlled.

Published in Science, the findings may help explain why people with inflammatory bowel disease can experience sudden flare-ups even after reaching remission.

Key findings

WEHI researchers identified a 'smoldering' molecular defect in gut cells from people with inflammatory bowel disease.

The defect involves abnormal cell death and could be detected even in patients whose disease was under good control.

The work, carried out through a broad collaboration with the Royal Melbourne Hospital, could eventually lead to earlier prediction of flare-ups, more precise monitoring and treatment tailored more closely to individual patients.

A hidden problem in intestinal cells

Inflammatory bowel disease (IBD), which includes conditions such as Crohn's disease and ulcerative colitis, is a chronic condition that affects around 180,000 Australians.

People with IBD can experience serious symptoms including rectal bleeding, abdominal pain, diarrhea, fatigue, and weight loss.

Modern therapies can help many patients achieve remission, but diagnosing and managing IBD remains challenging.

The disease often alternates between periods when symptoms are controlled and sudden flare-ups that can become severe enough to require hospital care.

Study co-author Dr. Andre Samson said the researchers discovered that intestinal cells could remain vulnerable even when patients felt well, and their disease appeared stable.

"Once you've got the diagnosis, IBD doesn't go away. Even if you become symptom-free on the current treatments, we know there's a likelihood you're going to have a flare or relapse," said Dr. Samson.

"What we found in patient samples was that intestinal cells are primed to die. Even in patients with essentially no symptoms, there's still this persistent problem sitting there."

Cell death may help drive IBD

The results challenge the assumption that cell death in IBD is simply damage caused by inflammation. Instead, the researchers say abnormal cell death may be involved in helping drive the disease itself.

The defect was already present during the earliest stages of disease activity, including in patients with clinically mild IBD. Detecting it required detailed molecular analysis.

Study co-author Professor James Murphy said the discovery revealed a 'smoldering' molecular problem and encouraged the researchers to focus more closely on what happens at the beginning of the disease process.

"Most people have been focusing on the major clinical problem, when someone comes to hospital with severe gut inflammation," Prof Murphy, a WEHI deputy director and lab head, said.

"We've gone to the other end of the spectrum and looked at gut tissue that doesn't have clear signs of active disease. What we're finding is this molecular defect happening very early in disease progression - one of the first dominoes to fall."

Human tissue reveals clues to future flare-ups

The research relied entirely on human tissue and patient-derived organoids.

Working with clinicians from the Royal Melbourne Hospital, the team collected around 900 biopsies from 80 people with and without IBD. Researchers used those samples to grow organoids, lab-grown tissues derived from patients, allowing them to investigate the disease directly in human cells.

Study co-author Professor Edwin Hawkins, head of the Colonial Foundation Diagnostics Center where samples were analyzed, said the size and nature of the patient group were important strengths of the research.

"While cell death has been implicated in IBD for a long time, how it arises in humans has remained unclear, probably because most studies rely on mouse models which often do not accurately mimic the human condition," Prof Hawkins, a WEHI lab head, said.

"Our study is based on human tissue and patient biopsies."

Researchers then tracked the patients for more than two years. They found that people showing stronger intestinal cell death signaling were also more likely to experience a relapse.

Toward earlier IBD detection

IBD can behave very differently from one person to another, making it difficult to know who will respond to a particular treatment or who is most likely to relapse.

Study co-author Dr. Jiyi Pang said the newly identified molecular signals could eventually help scientists develop more precise tools for monitoring patients and selecting treatments based on the biology of an individual's disease.

"The causes of IBD are largely unknown and quite variable," Dr. Pang said.

"Using mini-intestinal organoids grown in a dish and by working alongside a diverse team of researchers and clinicians, we uncovered the inflammatory signals responsible for this cell death response."

"We now have the hallmarks of what underlies disease at the molecular level. The question is which of those are therapeutically actionable and whether they might help us to better match treatments to patients, based on how their disease behaves at a molecular level."

More personalized treatment could follow

Study co-author Dr. Aysha Al-Ani cautioned that the findings are unlikely to produce a new diagnostic test or therapy immediately. However, they provide a foundation for future research into better forecasting tools and potential treatments.

"It opens new avenues for different prognostic tools, using more sophisticated and refined methods than are currently used clinically," Dr. Al-Ani said.

"The ethos behind IBD therapy is to reduce the frequency and severity of flares, halting disease progression and improving patients' lives. More sensitive molecular detection may help us keep patients in deep remission for longer and introduce new treatments."

Source: ScienceDaily

Scientists solve a 50-year mystery and discover a new human blood group

 More than half a century after scientists first encountered a mysterious marker on human red blood cells, researchers finally traced it to its genetic source. The breakthrough established MAL as a human blood group system and gave doctors a new way to identify the exceptionally rare people whose blood lacks the AnWj antigen.

The work was led by scientists at NHS Blood and Transplant in Bristol, including researchers from the International Blood Group Reference Laboratory (IBGRL), together with colleagues at the University of Bristol. Their findings solved a puzzle dating back to 1972 and could help prevent dangerous transfusion reactions in a small number of patients.

Although most people are familiar with the ABO and Rh blood groups, those are only part of a much larger biological system. Red blood cells carry hundreds of different molecules on their surfaces. Many of these molecules act as antigens, markers that the immune system can recognize.

For most transfusions, ABO and Rh compatibility receive the most attention. But in patients with unusual antibodies or rare blood types, matching some of these lesser-known antigens can become crucial.

A Blood Marker Found in More Than 99.9% of People

The AnWj antigen was discovered in 1972, but for decades scientists did not know which gene produced it or which protein carried it on red blood cells.[1]

More than 99.9% of people are AnWj positive. For the tiny minority who are AnWj negative, however, the distinction can matter enormously.

If an AnWj negative person develops antibodies against AnWj and then receives AnWj positive blood, those antibodies can attack the transfused red blood cells. In some circumstances, that can trigger a potentially serious transfusion reaction.

There are also two very different reasons someone can lack the antigen. In most cases, AnWj expression appears to be suppressed because of an underlying hematological disorder or certain cancers.[2] Much more rarely, a person is born without the antigen because of an inherited genetic change.

Only a handful of people with this inherited form had ever been identified, making the mystery especially difficult to investigate.

The Genetic Clue Was Hidden in MAL

To find the source, the researchers turned to whole exome sequencing. This technique examines the portions of DNA that contain instructions for making proteins, allowing scientists to search across thousands of genes for unusual variants shared by affected individuals.

The analysis pointed unexpectedly to the MAL gene.

The researchers found that people with the inherited AnWj negative phenotype carried homozygous deletions affecting MAL. Homozygous means that the relevant change was present in both copies of the gene, one inherited from each parent.

The MAL gene produces a small membrane protein called Mal. When the team examined red blood cells, people who were AnWj positive produced the full-length Mal protein on their cells, while it was missing from AnWj negative cells.

Five genetically AnWj negative individuals were included in the investigation, including members of an Arab Israeli family.[3] The samples also included blood donated in 2015 by the woman who had been the first AnWj negative person identified in the 1970s.

The researchers did not stop at finding a genetic association. They needed to demonstrate that Mal really was responsible for the antigen.

When scientists introduced the normal MAL gene into laboratory cells, the cells became reactive with AnWj antibodies. Introducing the altered form did not produce the same response. Additional experiments showed that Mal was both necessary and sufficient for expression of the AnWj antigen.

Source: ScienceDaily

Chronic stress may be quietly reshaping your heart

 Chronic stress linked to everyday life may leave a lasting physical mark on the heart, potentially damaging cardiovascular health and shortening lifespan.

That conclusion comes from a study of nearly half a million adults in the UK, led by researchers at the MRC Laboratory of Medical Sciences (LMS) and Imperial College London. The researchers believe it is the largest study of its kind.

Their findings suggest that chronic inflammation, which is associated with lifestyle and socioeconomic circumstances, may contribute to harmful changes in the heart's structure. It was also linked to a greater risk of heart attack and stroke.

Importantly, these changes may begin years before a person notices any cardiovascular symptoms, allowing the damage to build silently over time.

Hidden Inflammation May Change the Heart

Professor Declan O'Regan, British Heart Foundation Chair of Cardiovascular AI at Imperial College London and Head of the Computational Cardiac Imaging Group at the LMS, said: "Our study, which is the largest of its kind, suggests that millions of people could be living with hidden inflammation, which is slowly changing their heart and causing long-term damage - increasing the risk of heart attack and stroke. Chronic inflammation is complicated, but we know it's tied to our health and driven by a range of lifestyle and economic factors - meaning people may be at more risk just because of their surroundings, their economic status, their family's health and their lifestyle."

"But while tackling health inequalities remains an issue, there are things that we can do about inflammation, including reducing risk factors like smoking and obesity."

Chronic inflammation occurs when the immune system remains mildly activated for long periods rather than switching off after an immediate threat has passed. This persistent, low-level immune activity has been associated with several diseases, including cancer and diabetes, and researchers increasingly suspect that it may also play an important role in heart disease.

For the new study, the team examined UK Biobank data from nearly 480,000 adults in the UK. They assessed inflammation using a blood marker called glycoprotein acetyls (GlycA) and combined those measurements with heart imaging and genetic information.

A 43% Higher Risk of Heart Attack and Stroke

People with the highest inflammation levels (the top 20%) had a 43% higher risk of heart attack and stroke than participants with the lowest levels (the bottom 20%).

The researchers also found signs that inflammation was associated with physical remodeling of the heart. People with higher inflammation tended to have thicker heart walls, smaller heart chambers and poorer heart filling - all changes which may develop quietly for years before progressing to heart failure.

Inflammation was also strongly associated with socioeconomic disadvantage and psychological distress. More familiar cardiovascular risk factors, including smoking and excess body fat, were linked to higher inflammation as well.

People whose inflammation remained elevated over time had a 43% greater risk of heart attack and stroke, even when they had no previously existing heart disease.

The findings suggest that inflammation may provide one biological route through which pressures from everyday life, including poverty and mental health problems, can affect the body and increase cardiovascular risk.

Social Factors, Mental Health, and Genetics

Professor Declan O'Regan added, "The surprising thing was how much social factors and mental health are linked to inflammation and damage to the heart -- as well as more well-known risk factors like smoking and inactivity. There was also a strong genetic factor, with some people being naturally more resilient or susceptible to the inflammatory damage that comes from different lifestyles."

The researchers emphasize, however, that genetic susceptibility or difficult life circumstances do not make heart disease inevitable. There are still opportunities to reduce persistent inflammation and lower cardiovascular risk.

The analysis also highlighted inflammatory proteins in the interleukin-1 and TNF families as possible contributors to the observed heart damage.

Several of these proteins are already being targeted by drugs being tested in clinical trials. That raises the possibility that anti-inflammatory therapies could eventually help prevent cardiovascular disease before symptoms begin.

Blood Tests Could Help Identify People at Risk

The researchers also suggest that inflammation blood tests could potentially be combined with genetic risk scores to identify people who may benefit most from early intervention.

Source: ScienceDaily