There have always been generational conflicts, but the chasm between baby boomers (born between 1946 and 1964) and other generations after them seems particularly hard to bridge.
As challenging as it may feel sometimes, there’s a simple solution for those wanting to experience more closeness with their boomer relatives and to understand them better: ask more questions.
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Simple curiosity, by way of a thoughtful question, can make people feel heard and respected – and can also help change your perspective on why someone you love thinks the way they do, why they are the way they are. That dialogue may prove to be one of the most rewarding ones you undertake.
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Asking more questions is a great way to start the conversations you’re longing to have with your loved one.
“In my work with families, I’ve noticed that older relatives are rarely waiting to be corrected,” Anna Marchenko, a licensed mental health counsellor and principal practitioner at Miami Hypnosis and Therapy, tells HuffPost.
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“What they tend to want is to be understood in the context of the world they grew up in. These questions often slow conversations down in a way that makes real understanding possible.”
HuffPost asked family therapists to suggest some starter questions boomer relatives wish they’d get asked more – and they may appreciate having these conversations more than you could ever know.
‘What do you wish people asked you about more?’
If you’re new to opening this kind of dialogue with an older relative, the best start is often… to ask what they want to be asked. Yes, it’s a little like cheating, but this question in itself can lead the way to so much understanding on both sides.
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This question “gets at what a parent may want to share more in their relationship with you,” Sarah Epstein, a marriage and family therapist who specialises in family dysfunction, told HuffPost. “Maybe they wish you asked about their health, their hobbies, their careers or their travels.”
For Epstein, this question can open the door to a new dynamic between your parent or older relative and you. “Asking shows an interest in not only having parents support you, but you to invest in them,” she said. “You can then lean into that more by asking about their current excitement and stressors.”
Remember: the point of asking questions in the first place is to allow your relative to feel heard, so open-ended and even apparently vague conversation starters work like a charm.
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‘What was your family like when you were growing up?’
Imagine you were meeting a new friend for coffee. You are likely to ask questions about their upbringing. While you may already know the basics about your relative, like where they grew up and how many siblings they have, asking them about their family of origin is an amazing way to get to know them better – and even forge a new kind of relationship with them.
As well as the more general, “What was your family like?” Epstein also recommends asking more specific questions, such as, “What were your parents like?” or “Who in your extended family were you closest with and who were you not close with?”
“As their child, you only see their adult relationships, not the ones they experienced as children themselves,” Epstein said. “Asking these kinds of questions humanises parents to their children and other younger relatives, and gives parents a chance to tell their children more about themselves. It opens up possible vulnerable topics, like what felt good and what felt difficult in their upbringing and how they managed that.”
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‘What did the world expect from you when you were young?’
This is an amazing question to get people to reflect on what the world’s expectations of them might have cost them – as well as any gifts they might have brought.
When asked this question, “people usually talk about pressure rather than nostalgia,” Marchenko said. “They describe growing up fast, being needed early, and making tradeoffs that were not optional. It helps younger relatives see that many values were shaped by necessity rather than preference.”
This line of questioning may also naturally lead into other similar revelations from your older relative, such as how systems of power worked in the environment they grew up in and what beliefs their upbringing created that they may have challenged later in life, says Marchenko.
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You never got to know your parents or grandparents in certain ways — because you simply weren’t there for it. But it’s a perspective you won’t want to miss out on.
‘When you look at the world now, how does it feel to you?’
One of the greatest obstacles to creating mutually respectful relationships with our older relatives today is the stark difference in values and politics younger generations often have. But phrasing a question like this opens the door to curiosity rather than immediately creating defensiveness.
“This avoids debates about progress and invites reflection instead,” Marchenko said. “People speak about gains and losses at the same time, which allows disagreement without turning anyone into the problem.”
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‘Is there anything you still feel responsible for passing on?’
“This reframes older generations as caretakers rather than obstacles,” Marchenko said. “The answers are usually less about advice and more about values, restraint, and hard-earned perspective.”
This is a great question because they may have previously avoided sharing their thoughts on this subject for fear of how they might be received. For you, hearing about how your relative views their potential legacy may also be eye-opening and perspective-shifting.
‘What feels good in our relationship right now? What doesn’t?’
In the same way that you may find some aspects of your relationship with your older relative difficult, they might too. If you can ask this question and receive the answer without getting defensive, the two of you might be able to work together to deepen the relationship and smooth over areas of discontent.
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“When you ask straight out how the relationship feels, you can start to have open, honest discussions about how the relationship is going,” Epstein said. “It may turn out you each have things you love doing together, or discussing, that you can double down on. You may also identify things your relative has been feeling about the relationship that you can then work on together. The easiest route to clarity is gently, respectfully asking about the other person’s experience.”
If you’re a parent, “tummy time” is probably a familiar term, considered by many to be key to the physical development of babies. But now, tummy time is trending for adults, too.
Getting out of your desk chair and spending some time on your stomach might seem awkward at first, but if you think about how long you sit in the same position much of the day — at the office, on the couch and in the car — it makes sense. Experts say it’s offsetting the effects of tech neck and tight hips, too.
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According to the U.S. Bureau of Labor Statistics, the average worker spends 45% of the day sitting. In addition to sitting, they stare at electronics all day; 91% of Americans own a smartphone. Screen-based lives might be causing a variety of orthopedic problems.
“Lying on your stomach for 10 or more minutes a day while watching TV or reading can improve bad posture and relieve ‘tech neck’ — the strain in our necks and shoulders caused by looking down at phones and laptops for hours each day,” said Julie Landis, a physical therapist and ergonomist in Washington, D.C.
Here’s what to know as you consider getting out of your chair and down on your belly — a position that’s no longer just for babies.
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This baby perfectly demonstrates tummy time, an activity that helps build strength and mobility.
What is tummy time?
Tummy time is an activity in which new babies spend time while awake on their stomachs. There, they build multiple muscle groups and improve mobility as well as arm, trunk and neck strength.
In a TikTok post from 2023 that has recently gained popularity again, physical therapist “Sammy” on her profile “unifiedptandyoga” focuses on how adult tummy time can help one age gracefully by achieving more mobility. She shows viewers a progression of lying on your stomach with multiple pillows under you, and then reducing the number, assuming pain goes away each time.
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She recently made a new video, noting her old one probably gained traction due to tech neck, a term used to describe the chronic shoulder or neck pain experienced from using technology. She showed some updated techniques in the video and stated that it’s even hard for some patients in her clinic to get into that position on their stomachs — but it’s important to be able to do.
Tummy time can have an effect on tech neck.
“I’ve seen a noticeable increase in patients of all ages complaining about neck stiffness, tightness or pain, which can be linked to prolonged screen time,” said Dr. Ehsan Jazini, a spine surgeon at VSI in Reston, Virginia.
“The mechanics of looking down for long periods squishes our spinal discs, which I refer to as ‘shock absorbers’ of the spine,” Jazini said. “Over time, this pressure placed on the discs can accelerate disc degeneration, pinch nerves, reduce mobility and trigger symptoms that radiate into the shoulders, arms and hands.”
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He said not addressing poor posture affects your spine’s function in the long term. “That strain can lead to chronic neck pain, stiffness, instability and pain throughout the rest of the body. If left uncorrected, poor posture can lead to wear and tear on the spine that’s harder to reverse down the line.”
Tummy time can impact hip and back pain.
Adult tummy time also helps to open up the front of the hips and activate the core and back muscles, which are key players in everyday back pain.
“Many people spend far too much time sitting, whether at a desk, in a car, or on the couch. The human body was not designed for such inactivity,” said Dr. Gbolahan Okubadejo, a spinal and orthopedic surgeon at the Institute for Comprehensive Spine Care in New York and New Jersey. He fears if we don’t change these habits we will soon see “an increase in musculoskeletal issues across all age groups.” These include:
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Degenerative disc disease, where the discs between the vertebrae begin to wear down due to constant pressure and a lack of movement. “This can lead to stiffness, pain, and even nerve compression.”
Sciatica, occurring when the sciatic nerve is irritated or compressed, often by a herniated disc or tight muscles in the lower back. “People may experience sharp pain that radiates down the leg, along with numbness or weakness.”
Tight hip flexors, leading to pelvic misalignment and lower back pain. “Over time, this can impact your gait and make everyday movements more difficult.”
Flipping onto your stomach can counteract extended sitting just as it does for infants, he said. “When you lie on your stomach, you naturally extend the spine, which helps reverse the flexed posture that sitting creates. This gentle spinal extension relieves pressure on the discs, especially in the lower back, and allows the back muscles to stretch and activate differently.”
In addition, you are able to open the hip flexors, which are often tightened and shortened from sitting too much. “By relaxing into a prone position, the hips and pelvis can realign more naturally, which supports better posture when you return to standing or sitting,” Okubadejo said. So, your tummy time actually makes you better at sitting too.
Here’s what tummy time looks like for adults.
“The adult tummy time position isn’t natural for most of us, so I recommend starting slow, and breaking adult tummy time into increments,” Jazini said. “Take three to five minutes at a time, a few times a day, lying on your stomach while propped on your elbows. You should feel a stretch in the front of the neck, as well as in your back and in your hips.”
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Katie Breaker, a sales director in Denver, said she’d tried various seat cushions and stretches without much improvement in back pain. Then, her physical therapist suggested tummy time — simply lying face down for 10 minutes per day. “No devices or setup. Just a flat surface, arms by the side, and a quiet room. After about a week of doing this twice a day, I added a thin towel under my chest and held it for fifteen minutes,” she said. Two weeks later, she could feel her back decompressing and had less hip tension and more flexibility.
“I could walk longer during event setups without fatigue,” she said. So, she kept upping her time and now does two 20-minute sessions per day, especially during long workdays on a computer.
Jazini recommended pairing this practice with a screen break, too. “Take five minutes to do something away from your screen whether it’s going for a short walk, stretching, or grabbing some water.” You can work up to hourly breaks of around five to 10 minutes, setting a reminder or timer to stay on schedule.
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Breaker said: “I still sit most of the day, but I do not carry the same tightness I used to. It has been the simplest thing I have added, and it has worked better than anything else I tried.”
The original version of this story was published on HuffPost at an earlier date.
It’s fair to say that the censors had plenty to keep them busy during this year’s Brit Awards.
Saturday night’s Brits broadcast saw the sound being pulled on numerous occasions due to a variety of comments that were made over the course of the event.
One such moment came during musician Max Bassin’s acceptance speech, after he accepted the International Group Of The Year prize on behalf of his band Geese.
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Choosing to keep things short, he began his speech by stating simply: “What’s up, ‘the Brits’? I just want to say, free Palestine…”
However, after Max said the word “free”, the audio was pulled, resulting in the rest of what he had to say being cut from broadcast.
It later emerged that Max concluded his speech: “Fuck ICE, go Geese.”
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Many Brits viewers were quick to voice their upset at what appeared to be ITV censoring Max’s politically-charged speech right as the drummer was about to speak out in solidarity with Palestine.
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However, in response to this backlash, the broadcaster has indicated to HuffPost UK that Max’s speech was censored due to his language after his pro-Palestine message – in other words, his use of the word “fuck” – rather than because of his political statements.
This year’s Brit Awards featured some of the biggest names in music taking to the stage, including Harry Styles, Raye and the night’s top winner Olivia Dean.
While all of these performances were fabulous in their own ways, the one that blew us away the most was by Rosalía.
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If you were already familiar with Rosalía’s work, you’ll know she’s always had a flair for the dramatic, but this reached new heights last year with the release of her theatrical album Lux, merging classical and operatic influences with the hip-hop and more traditional Spanish-infused sounds she was already known for.
And on Saturday night, she brought this all to life with a flawless performance of Lux’s lead single Berghain, complete with elaborate sets, a live orchestra and, at the centre of it all, Rosalía’s incomparable vocals.
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The Spanish star even managed to get the always-enigmatic Björk to perform her Berghain verse live, in an unbilled appearance from the Iceland pop icon.
In fact, this marked Björk’s first time performing on the Brits stage in more than 30 years.
via Associated Press
To put it simply, we think this is a Brits performance we’re still going to be thinking about for years to come.
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Having already stolen the show with her jaw-dropping performance, Rosalía’s night just kept getting better when she was awarded the International Artist Of The Year prize, beating some seriously stiff competition from the likes of Sabrina Carpenter, Taylor Swift, Chappell Roan, Bad Bunny, Bruno Mars and Lady Gaga.
“I was so grateful just to be here tonight, just to perform, so this is insane,” she beamed during her acceptance speech.
Rosalía added: “Let’s keep celebrating the ‘other’-ness. Let’s keep celebrating different music, different cultures and different languages.”
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Even Jack Whitehall – who pulled no punches elsewhere on the night – was clearly in awe of Rosalía, heaping praise on her performance during a fun segment between the two of them later in the show.
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The biggest night in British music was an especially big one this year.
On Saturday night, the 2026 Brit Awards took place in Manchester for the first time, in a night that delivered glittering performance, a few surprise wins and plenty of moments that kept ITV’s censors busy.
If you missed this year’s broadcast and want to catch up (or, indeed, if you were only half-watching, and you’re wondering if there were any bits that completely passed you by), then you’re in luck, because we’ve rounded up X of the top must-see moments from the 2026 Brit Awards…
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Before the ceremony was even underway, Harry Styles made us smile on the red carpet with this business suit/ballet pumps combo
Anthony Harvey/Shutterstock
Rosalía got her night off to a suitably dramatic start with this complete serve
Anthony Harvey/Shutterstock
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And it was a strong showing all-round from some of our fave celeb couples, including Jade and Jordan Stephens…
via Associated Press
Anthony Harvey/Shutterstock
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…and darts icon Luke Littler and his long-term girlfriend Faith Millar
via Associated Press
Comedian Jack Whitehall kicked off his sixth time hosting the Brits with a skit paying homage to his love of Harry Styles
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The man himself then opened the show properly with a performance of Aperture, complete with a lot of hand-ography and bum-wiggling
Jack Whitehall pulled absolutely no punches with his introductory Brits monologue, coming for everyone from Alex Warren (‘what you get if you order Ed Sheeran on Temu’), Lily Allen (‘her album was launched into the charts like a torpedo – only this torpedo didn’t sink a ship, it destroyed a Harbour’), Robbie Williams (‘he’s had more comebacks than his hairline’) and Noel Gallagher (‘Songwriter Of The Year… 1996’)
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Jack Whitehall dings the BAFTAS at the #BRITAwards: “There may be some swearing but don’t worry, we’ve got the best in the business on the bleep button. It’s the guy who did the BAFTAS. Nothing gets past him” pic.twitter.com/qeNewZyYQm
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I need non raye stans to know how crazy the nightingale lane brits performance is, she’s been sick for WEEKSSSSS like she really gave this one her all omfg pic.twitter.com/SswFYVgV7O
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I need non raye stans to know how crazy the nightingale lane brits performance is, she’s been sick for WEEKSSSSS like she really gave this one her all omfg pic.twitter.com/SswFYVgV7O
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Mark Ronson’s Outstanding Contribution performance featured some lovely tributes to Amy Winehouse…
…as well as a surprise(-ish) appearance from Dua Lipa
via Associated Press
Rosalía’s special night just kept getting better as she was crowned International Artist Of The Year, beating some seriously stiff competition including Taylor Swift, Chappell Roan, Bad Bunny, Bruno Mars, Sabrina Carpenter and Lady Gaga
via Associated Press
And CMAT had some fun with the cameras at losing out in this category for the second time
The night’s top winner Olivia Dean was visibly elated to pick up the Brits’ top honour, Album Of The Year
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Broadcasting from Co-op Live and hosted by Jack Whitehall, the show featured standout performances from Harry Styles, Olivia Dean, RAYE, Wolf Alice, SOMBR, HUNTR/X, ROSALÍA, Alex Warren, Mark Ronson and more.\n\nSubscribe to the BRITs channel – http://bit.ly/1aob2oV\nJoin The BRITs WhatsApp channel – https://brits.co.uk/whatsapp\nOfficial BRITs website – http://www.BRITs.co.uk\nInstagram – http://instagram.com/BRITs\nTikTok – https://vm.tiktok.com/9pM4XN/\nFacebook – http://www.facebook.com/BRITs\nTwitter – http://www.twitter.com/BRITs\nThreads – https://www.threads.net/@brits","options":{"_cc_load_policy":{"label":"Closed captions","value":false},"_end":{"label":"End on","placeholder":"ex.: 11, 1m10s","value":""},"_start":{"label":"Start from","placeholder":"ex.: 11, 1m10s","value":""}},"provider_name":"YouTube","thumbnail_height":720,"thumbnail_url":"https://i.ytimg.com/vi/PIH_57sGTb4/maxresdefault.jpg","thumbnail_width":1280,"title":"Olivia Dean’s Reaction to Winning Mastercard 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And finally, following a speech by Sharon Osbourne and her daughter Kelly, Robbie Williams was absolutely spot-on with his musical tribute to Ozzy Osbourne, which closed the show
Growing older brings a higher risk of serious illnesses such as cancer, heart disease, and dementia. For years, researchers have tackled these conditions individually. Now, many scientists are stepping back to ask a broader question. Instead of treating diseases one by one, could slowing the aging process reduce the risk of several at once? To answer that, they first need to understand what sparks the biological changes that come with age.
A new study published in Science offers an unprecedented look at that process. Researchers at The Rockefeller University built the most detailed atlas so far of how aging affects thousands of cell subtypes across 21 mammalian tissues. By examining nearly 7 million individual cells from mice at three different ages, the team identified which cells are most vulnerable over time and what factors may be driving their decline.
“Our goal was to understand not just what changes with aging, but why,” says Junyue Cao, who heads the Laboratory of Single Cell Genomics and Population Dynamics. “By mapping both cellular and molecular changes, we can identify what drives aging. That opens the door to interventions that target the aging process itself.”
One of the most striking findings was that many age-related shifts happen in sync across multiple organs. The researchers also found that nearly half of these changes differ between males and females.
A Massive Cellular Census Across 21 Organs
To map aging at this scale, Cao’s team, led by graduate student Ziyu Lu, refined a method known as single-cell ATAC-seq. This approach looks at how DNA is packaged inside each cell, revealing which regions of the genome are accessible and active, a key indicator of a cell’s state and function.
The researchers applied this technique to millions of individual cells taken from 21 organs in 32 mice at three ages: one month (young adult), five months (middle-aged), and 21 months (elderly).
“What’s remarkable is that this entire atlas was generated by a single graduate student,” Cao says. “Most large atlases like this require large consortia with dozens of laboratories but our method is far more efficient than other approaches.”
In total, the lab identified more than 1,800 distinct cell subtypes, including many rare groups that had never been fully described. The team then tracked how the numbers of these cells changed as the mice moved from young adulthood to middle age and then to old age.
Early and Coordinated Cellular Shifts
For decades, scientists believed aging mainly altered how cells function, not how many of each type exist. This new analysis challenges that view. About one quarter of all cell types showed significant changes in abundance over time. Certain muscle and kidney cell populations declined sharply, while immune cells expanded considerably.
“The system is far more dynamic than we realized,” says Cao. “And some of these changes begin surprisingly early. By five months of age, some cell populations had already begun to decline. This tells us that aging isn’t just something that happens late in life; it’s a continuation of ongoing developmental processes.”
Equally surprising was how synchronized these changes were. Similar cellular states rose and fell together across different organs. This pattern suggests that shared signals, possibly factors circulating in the bloodstream, help coordinate aging throughout the body.
The study also revealed pronounced differences between males and females. Roughly 40 percent of aging-associated changes varied significantly by sex. For example, females showed much broader immune activation as they aged.
“It’s possible this could explain the higher prevalence of autoimmune diseases in women,” Cao speculates.
Genetic Hotspots and Future Anti-Aging Therapies
Beyond counting how cell populations shifted, the researchers examined how accessible regions of DNA changed within those cells over time. Out of 1.3 million genomic regions analyzed, about 300,000 displayed significant aging-related alterations. Around 1,000 of those changes appeared across many different cell types, reinforcing the idea that common biological programs drive aging across the body. Many of these shared regions were linked to immune function, inflammation, or stem cell maintenance.
“This challenges the idea that aging is just random genomic decay,” Cao says. “Instead, we see specific regulatory hotspots that are particularly vulnerable, and these are precisely the regions we should be studying if we want to understand what drives the aging process.”
When the team compared their findings with earlier research, they discovered that immune signaling molecules called cytokines can trigger many of the same cellular changes observed during aging. Cao suggests that drugs designed to adjust these cytokines could potentially slow coordinated aging processes across multiple organs.
“This is really a starting point,” Cao says. “We’ve identified the vulnerable cell types and molecular hotspots. Now the question is whether we can develop interventions that target these specific aging processes. Our lab is already working on that next step.”
The full aging atlas is available to the public at epiage.net.
For years, researchers studying the Southern Ocean have pointed to one possible upside in an otherwise troubling climate outlook. A widely discussed idea known as iron fertilization proposed that as Antarctica warms and glaciers melt, iron trapped in the ice would be released into nearby waters. That iron would fuel blooms of microscopic algae, which absorb heat trapping carbon dioxide as they grow.
But new evidence suggests that expectation may not be accurate.
In what the team calls the most precise measurement so far of iron flowing from an Antarctic glacier, scientists from Rutgers University-New Brunswick found that meltwater from an ice shelf contributes far less iron to surrounding ocean waters than previously believed.
The study, published in Communications Earth and Environment, raises new questions about where iron in the Southern Ocean actually originates. According to the researchers, the results could influence how climate change forecasts and models are developed.
“It has been widely assumed that glacial melting underneath ice shelves contributes considerable bioavailable iron to these shelf waters, in a process of natural glacier-driven iron fertilization,” said Rob Sherrell, a professor in the Department of Marine and Coastal Sciences at the Rutgers School of Environmental and Biological Sciences and the study’s principal investigator.
Sherrell said the findings revise those assumptions. The amount of iron carried by meltwater is several times lower than earlier estimates. In addition, much of that iron appears to come from a different form of meltwater than the kind produced directly by melting ice shelves.
Why Iron in the Southern Ocean Matters
Even though Antarctic waters are dark for months at a time, the Southern Ocean supports abundant phytoplankton growth. These microscopic plants form the foundation of the food web, feeding krill that sustain penguins, seals, and whales. As phytoplankton grow, they remove large quantities of carbon dioxide from the atmosphere through photosynthesis, making this region the world’s largest oceanic sink for the climate warming gas.
Until now, much of what scientists understood about iron sources in these waters came from simulations and computer models. Sherrell and colleagues from Rutgers and partner institutions in the United States and the United Kingdom chose to gather direct field measurements instead.
In 2022, the researchers traveled aboard the now-decommissioned U.S. icebreaker, the Nathaniel B. Palmer, to the Dotson Ice Shelf in the Amundsen Sea of West Antarctica. The Amundsen Sea accounts for most of the sea level rise driven by Antarctic melting. Their goal was to collect glacial meltwater at its source.
Sampling Beneath the Ice Shelf
In the Amundsen Sea, meltwater forms under floating ice shelves, which extend from glaciers on land into the ocean. The melting is driven mainly by relatively warm water from the deep ocean that flows into cavities beneath the ice.
At the Dotson Ice Shelf, the team located where seawater flows into one of these cavities and where it exits after mixing with meltwater. Water samples were taken at both entry and exit points.
Back in New Jersey, Venkatesh Chinni, a postdoctoral scholar and lead author of the study, measured iron concentrations in the samples, analyzing both dissolved iron and iron attached to suspended particles. Collaborators Jessica Fitzsimmons and Janelle Steffen at Texas A&M University examined isotopic ratios to “fingerprint” the iron and trace its origin. Steffen performed the initial isotopic analyses in the laboratory of Tim Conway at the University of South Florida.
Using these measurements, Chinni and the team calculated how much additional iron was present in water leaving the cavity compared with water entering it. The isotopic signatures also helped identify which melting processes were responsible.
Deep Water and Sediments Supply Most Iron
The results were unexpected, Sherrell said. Meltwater accounted for only about 10% of the dissolved iron flowing out of the cavity. Most of the iron came from deep ocean water (62%), while another 28% originated from sediments on the continental shelf.
“Roughly 90% of the dissolved iron coming out of the ice shelf cavity comes from deep waters and sediments outside the cavity, not from meltwater,” Chinni said.
The isotope data also point to processes occurring beneath the glacier itself. The samples suggest the presence of a liquid meltwater layer that lacks dissolved oxygen. Under such conditions, solid iron oxides in bedrock can dissolve more readily, releasing iron into the water. According to Chinni, this mechanism may contribute more iron than melting ice shelves do.
Rethinking Antarctic Iron and Climate Models
Together, these findings challenge long standing assumptions about iron sources in the Southern Ocean as the planet warms. The researchers emphasize that more work is needed to fully understand how subglacial processes influence iron release.
“Our claim in this paper is that the meltwater itself carries very little iron, and that most of the iron that it does carry comes from the grinding up and dissolving of bedrock into the liquid layer between the bedrock and the ice sheet, not from the ice that is driving sea level rise,” Sherrell said.
He added that many scientists may find this conclusion surprising.
Scientists have revealed how viruses that infect bacteria shut down MurJ, a protein essential for building the bacterial cell wall. Remarkably, different viruses evolved separate proteins that all block MurJ in the same way, highlighting it as a promising new antibiotic target.
The findings appear in the February 26 issue of Nature. The research was led by Yancheng Evelyn Li, a graduate student in the lab of Bil Clemons at Caltech. Clemons, the Arthur and Marian Hanisch Memorial Professor of Biochemistry, is the corresponding author.
The Urgent Need for New Antibiotics
Bacteria evolve quickly, and that adaptability is fueling a growing public health crisis. As Clemons explains, “Evolution is powerful, and in bacteria, resistance to antibiotics develops quickly. This means that we now deal with bacteria that are resistant to all the medicines that we have.” He adds, “In the USA alone, tens of thousands of people die every year from antibiotic-resistant bacterial infections, and that number is rising rapidly. We need new antibiotics to combat this.”
With existing drugs losing effectiveness, researchers are searching for entirely new bacterial weak points.
Targeting the Bacterial Cell Wall
One long standing focus has been the pathway bacteria use to construct peptidoglycan, the rigid material that forms their cell wall. This process, called the peptidoglycan biosynthesis pathway, is especially attractive because peptidoglycan is found in bacteria but not in human cells. As Clemons notes, “Peptidoglycan is a unique feature of bacteria, and that makes it an attractive antibiotic target.”
Several antibiotics already disrupt this pathway. Penicillin, discovered by Alexander Fleming in the mid 20th century, blocks a late stage of peptidoglycan production. Related drugs such as amoxicillin work in a similar way.
Key Proteins MraY, MurG, and MurJ
Three essential proteins drive the movement of peptidoglycan building blocks across the bacterial inner membrane: MraY, MurG, and MurJ. These proteins help transport the components needed to assemble the cell wall outside the inner membrane barrier. If any one of them fails, peptidoglycan cannot be produced and the bacterium dies, making them promising drug targets.
Although researchers understand much about how these proteins function, Clemons points out that important mechanistic details remain unclear.
At present, no approved drugs directly inhibit these three proteins. Still, Clemons says there is potential. “We do know that we can find small molecules, either derived from nature or synthesized in chemical libraries, that will inhibit these proteins. Excitingly, recent discoveries have shown that bacteriophages have figured out how to target this pathway.”
How Bacteriophages Break Through Bacterial Defenses
Bacteriophages, or phages, are viruses that infect bacteria. To survive, they must enter a bacterial cell, replicate, and then escape to infect others. Breaking out requires getting through the peptidoglycan layer. Clemons explains, “Getting back out means that they have to get past the peptidoglycan layer. Because it acts like chainmail, the phages get stuck if they can’t break through it.”
The Clemons lab studies small phages that contain single stranded DNA or RNA. These viruses have compact genomes and rely on simple strategies to kill bacteria. In 2023, the team reported in Science on φX174, a phage with a long research history at Caltech.
Viral Proteins That Disable MurJ
Small phages rely on specialized protein antibiotics called single-gene lysis proteins, or Sgls (pronounced like “sigils”), to kill bacteria. Li and Clemons have focused on Sgls that target MurJ, one of the key cell wall proteins.
MurJ acts as a flippase. It transports peptidoglycan precursors from the inside of the cell across the membrane so they can be incorporated into the growing cell wall. Earlier work from collaborators showed that two unrelated Sgls, SglM and SglPP7, both kill bacteria by blocking MurJ.
To understand how this happens, Li used cryo electron microscopy at Caltech’s Beckman Institute Biological and Cryogenic Transmission Electron Microscopy (Cryo-EM) Resource Center. Flippases such as MurJ move molecules by alternately exposing them to each side of the membrane without forming a permanent opening. When MurJ binds its cargo inside the cell, it changes shape to release the molecule on the outside.
Li found that both SglM and SglPP7 attach to a groove in MurJ, preventing the structural shift required for transport.
“It is clear that both of these Sgls bind to MurJ in an outward-facing conformation, locking it into this position,” Li says. Researchers are encouraged by this because the outward-facing form of MurJ is exposed to the surrounding environment, which could make it more accessible to future drugs than a conformation that faces inward.
Convergent Evolution Highlights a Promising Drug Target
Clemons says the result was surprising for another reason. “These peptides, which have no evolutionary links to each other, have both figured out how to target MurJ in a very similar way. These are two examples of convergent evolution, in which different evolutionary paths arrive at the same solution. We were surprised!”
Because viruses evolve rapidly, the team believes many more phages likely carry similar Sgls. Phages are relatively easy to isolate, and studying their genomes could reveal additional biological insights and new antibiotic targets.
In the Nature study, the researchers analyzed another phage genome with the help of a collaborator. They identified a new Sgl called SglCJ3 (from a genome sequence that is predicted to be a phage and is called Changjiang3) and examined it using cryo electron microscopy. Li determined the structure of SglCJ3 bound to MurJ and found that it also locks the protein in the same outward-facing conformation.
“This is a third genome that evolved a distinct peptide to inhibit the same target in a similar way,” Clemons says. “It is the first strong evidence that evolution identifies MurJ as a great target for killing bacteria, which means we should follow evolution’s lead and develop therapeutics that target MurJ. This demonstrates the power of basic biology to help us solve problems in medicine. Our path is set on leveraging Sgl discovery, and we hope to continue to be supported to turn these concepts into realities.”
Authors and Funding
The paper is titled “Convergent MurJ flippase inhibition by phage lysis proteins.” In addition to Clemons and Li, the authors include Caltech graduate student Grace F. Baron and Francesca S. Antillon, Karthik Chamakura, and Ry Young of Texas A&M University. The research was supported by the Chan Zuckerberg Initiative, the National Institutes of Health, the G. Harold and Leila Y. Mathers Foundation, and the Center for Phage Technology at Texas A&M, jointly sponsored by Texas A&M AgriLife.