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Axolotl Discovery Brings Us Closer Than Ever to Regrowing Human Limbs

Axolotl Discovery Brings Us Closer Than Ever to Regrowing Human Limbs

Yahoo22-06-2025
Axolotls (Ambystoma mexicanum) have the incredible ability to regenerate limbs, and even entire organs. And of course, people want to know how we might get our own human bodies to do it, too.
A team of biologists from Northeastern University and the University of Kentucky has found one of the key molecules involved in axolotl regeneration. It's a crucial component in ensuring the body grows back the right parts in the right spot: for instance, growing a hand, from the wrist.
"The cells can interpret this cue to say, 'I'm at the elbow, and then I'm going to grow back the hand' or 'I'm at the shoulder… so I'm going to then enable those cells to grow back the entire limb'," biologist James Monaghan explains.
That molecule, retinoic acid, is arranged through the axolotl body in a gradient, signaling to regenerative cells how far down the limb has been severed.
Closer to the shoulder, axolotls have higher levels of retinoic acid, and lower levels of the enzyme that breaks it down. This ratio changes the further the limb extends from the body.
The team found this balance between retinoic acid and the enzyme that breaks it down plays a crucial role in 'programming' the cluster of regenerative cells that form at an injury site.
When they added surplus retinoic acid to the hand of an axolotl in the process of regenerating, it grew an entire arm instead.
In theory, the human body has the right molecules and cells to do this too, but our cells respond to the signals very differently, instead forming collagen-based scars at injury sites. Next, Monaghan is keen to find out what's going on inside cells – the axolotl's, and our own – when those retinoic acid signals are received.
"If we can find ways of making our fibroblasts listen to these regenerative cues, then they'll do the rest. They know how to make a limb already because, just like the salamander, they made it during development," Monaghan says.
"It could help with scar-free wound healing but also something even more ambitious, like growing back an entire finger," he adds. "It's not out of the realm [of possibility] to think that something larger could grow back like a hand."
The research is published in Nature Communications.
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Repairing the Aging Blood-Brain Barrier: Real Possibilities
Repairing the Aging Blood-Brain Barrier: Real Possibilities

Medscape

time18 minutes ago

  • Medscape

Repairing the Aging Blood-Brain Barrier: Real Possibilities

A study recently published in Nature has identified a key factor in the age-related breakdown of the blood-brain barrier (BBB) and has demonstrated that this damage may be reversible, potentially paving the way for new therapeutic strategies for neurodegenerative and cerebrovascular diseases, such as Alzheimer's disease, Parkinson's disease, and stroke. The study, led by Sophia M. Shi, PhD, now a principal investigator at the Rowland Institute at Harvard but a PhD student at Stanford University during the study, focuses on the endothelial glycocalyx of the brain's vasculature, also known as the brain's 'sugar shield.' This catchy moniker is given by the fact that the glycocalyx is a sugar-rich layer lining the luminal surface of endothelial cells in the brain vasculature. Sophia M. Shi, PhD Composed of proteoglycans, glycoproteins, and glycolipids, the glycocalyx — literally meaning 'sugar coat' — is the first point of contact between the blood and the vasculature of the entire body, assisting in cell adhesion, providing protection, and helping control the movement of fluids and molecules between the bloodstream and surrounding tissues. It also plays a critical role in maintaining the integrity of BBB. 'This blood-brain barrier or vascular dysfunction is a really common hallmark in aging but also a lot of age-related diseases like Alzheimer's disease, Parkinson's disease, stroke,' Shi said. 'We have these early changes in the vasculature that we can see.' The research team demonstrated how a class of proteins of the glycocalyx known as mucin-domain glycoproteins are crucial for the barrier's function, and their age- and disease-related decline is linked to a 'leaky' BBB. The study showed how this decline can lead to brain hemorrhaging in mice. Lianchun Wang, MD 'There's a lot of proteins from the brain, like IgG [immunoglobulin G] and fibronectins, that will be toxic for the neurons if they leak. For years, people have found that during aging, one of the major problems people have been vascular damage from leaking. So people think that's one of the reasons to look at [this leaking and vascular damage] in neuroendocrine disease,' said Lianchun Wang, MD, professor of molecular pharmacology and physiology at the Morsani School of Medicine at the University of South Florida, Tampa, Florida. Wang was not part of the study. The Stanford study was able to restore the integrity of the glycocalyx, improving the barrier's function, reducing leaking, and reducing neuroinflammation and cognitive deficits in the mice. 'We really wanted to see if we could ameliorate aspects of pathology and cognitive function in disease models to make it more disease relevant and potentially translational,' Shi added. Bridging Glycobiology and the Aging Brain: A Tale of Two Labs The study's inception came during Shi's PhD studies at Stanford University while she was jointly advised in the labs of Carolyn Bertozzi, PhD, a Nobel laureate and professor of chemical and systems biology at Stanford, and Tony Wyss-Coray, PhD, professor of neurology at Stanford. Tony Wyss-Coray, PhD 'I was really interested in trying to understand small chemical modification to proteins like glycans, and I found an interest in studying brain aging. We came up with fusing these two fields: glycobiology from Carolyn Bertozzi's lab and neurology from Tony Wyss-Coray's lab,' said Shi. Both Bertozzi and Wyss-Coray served as principal investigators of the study and are authors of the paper. Shi and the research team investigated a handful of older papers that had begun to investigate the endothelial glycocalyx in the brain. They noticed the researchers who authored those papers didn't follow up on their results — they'd stained glycocalyx sugars but didn't examine what these sugars really did. Realizing the field was understudied, Shi saw an opportunity to characterize the structural changes in the glycocalyx in age-related diseases. The team used a specialized staining tool — a product of Bertozzi's expertise in mucins — derived from a bacterial enzyme (StcE) to visualize mucin-domain glycoproteins lining the brain's blood vessels. '[Carolyn] had made this tool that allowed us to measure mucins…a very ingenious tool,' explained Wyss-Coray. 'It's an enzyme that bacteria make to cleave off mucins in the gut so they can infect. Carolyn used this [StcE] enzyme and introduced a mutation so it's no longer active but still binds to the mucins. That tool allowed us to visualize the mucins. We had a new tool that nobody could even imagine one could use.' This tool revealed a strong, continuous layer of these proteins in young mice that was significantly reduced and patchier in aged mice, a change that appeared specific to the brain. They then injected an active, 'cutting' version of the enzyme into young mice, which caused a significant breakdown of this entire protective glycocalyx layer. Clearly seeing this degradation on electron micrograph images served as the study's 'eureka' moment. 'I distinctly remember getting our first electron microscopy images back, those big pictures of the blood vessels showing degradation with age, and that was really striking,' said Shi. 'But we also did many orthogonal approaches to make sure it's really robust as a finding. Flow cytometry…transcriptional analysis…all of them pointed towards the same direction.' Restoring the Sugar Shield BBB's integrity relies on specialized endothelial cells with tight junctions and controlled transport systems. But the levels of two key sugar-building enzymes, C1GALT1 and B3GNT3, were significantly lower in the brain's blood vessels of old mice than in those of young mice. This decrease in the 'builder' enzymes directly correlated with the reduced amount of the final mucin 'sugar coat' that was present. Remarkably, the team successfully fixed this degeneration using adeno-associated viruses (AAVs) to overexpress these enzymes, which restored core 1 mucin-type O-glycans of the glycocalyx to the brain endothelium. This intervention not only improved the barrier's function but also led to a reduction in neuroinflammation and cognitive deficits in the animals. 'We're overexpressing these sugar molecules in the vasculature, which reduces leakiness, and then we showed that it reduces neuroinflammation, and then has these wonderful improvements in cognitive function,' explained Shi. The successful reversal of BBB leakiness and its cognitive consequences in this study's preclinical model suggests that strategies aimed at restoring the integrity of the brain's 'sugar shield' could be a potent strategy to combat the age-related breakdown of the BBB and mitigate diseases, though human trials would need to utilize other methods than viral vectors. Where This Takes Us While viral vector gene therapy proved effective in restoring the integrity of the glycocalyx, the exact mechanisms underlying its success require further explication. Restoring the glycocalyx can protect the brain by limiting the influx of neurotoxic circulatory factors like albumin and fibrinogen. However, the enzymes used in the therapy influence a wide range of proteins and glycan structures. A deeper understanding of all the molecular pathways affected may be warranted to fully grasp the processes of brain aging and rejuvenation. 'We do want to work on better understanding this pathway, to see where in the pathway we should really be targeting and see if there are small molecules that would be more therapeutically practical,' said Shi. Added Wyss-Coray, 'I think there's much more research that could be done. Do [mucins] have something to do with preventing pathogens from getting into the brain, more so than into another organ, once they make it into circulation? Do we have microorganisms that can enter the brain more easily? Another direction is to go find out where these sugars stick to.' The hope is this underappreciated class of mucin proteins can one day soon serve as a powerful new therapeutic target, opening a new frontier in the quest to combat age-related cognitive decline by focusing on rebuilding the brain's own protective shield. 'I think this is fantastic in the field,' said Wang. 'It really is a very fundamental study that shows how this mucin-type O-glycosylation in the vasculature is functionally very important....I think the [AVV therapy] is really important. It's possible [translational therapy on humans] can move quickly because AAV for the gene therapies are relatively common.'

Mosquitoes bite! 5 tips for making yourself less attractive to them
Mosquitoes bite! 5 tips for making yourself less attractive to them

CNN

time20 minutes ago

  • CNN

Mosquitoes bite! 5 tips for making yourself less attractive to them

EDITOR'S NOTE: The podcast Chasing Life With Dr. Sanjay Gupta explores the medical science behind some of life's mysteries big and small. You can listen to episodes here. (CNN) — For summertime beachgoers, the threat of sharks may loom large, but nature's deadliest predator is actually much smaller. The tiny mosquito is not only a warm-weather nuisance but also wears the crown for 'No. 1 killer of humanity across our existence,' according to historian Dr. Timothy C. Winegard. The predatory insect takes more than 1 million lives each year by transmitting lethal diseases. Sharks, meanwhile, are estimated to have a kill streak orders of magnitude smaller, at fewer than 10 people per year. Where humans go, mosquitoes have followed. Their itchy bites and the disease-causing pathogens they carry are infamous, and the insects are also responsible for driving many of humanity's most essential turning points throughout history, said Winegard, author of 'The Mosquito: A Human History of Our Deadliest Predator.' 'Malaria and yellow fever (have shaped) our historical journey from our hominid ancestral evolution … right to present day,' Winegard told CNN Chief Medical Correspondent Dr. Sanjay Gupta recently on his podcast, Chasing Life. Winegard, an associate professor of history at Colorado Mesa University, got the initial idea for his best-selling book from his dad's interest in malaria. The wee pest didn't intrigue Winegard too much at first. 'I kind of disparaged him and said, 'Sure, dad, I'll write a book on mosquitoes,'' he recalled. But once Winegard began going down the rabbit hole of mosquito-borne pathogens' impact on humanity — including, but not limited to malaria, Zika virus, dengue fever, yellow fever, chikungunya and West Nile virus — he couldn't stop. The mosquito's impact on history is still deeply felt in the present. More than half a million people die of malaria alone each year, and disease-heavy regions have suffered financially as a result. 'Northern Hemisphere countries don't have endemic malaria, (so) they're able to develop more affluent economies because they're not continuously suffering from malaria,' Winegard said. You can listen to the full episode here. Humans have been battling mosquitoes for millennia, and amid the season's summer peak in the Northern Hemisphere, Winegard offered some insight into how you can keep them away this summer. 'Eighty-five percent of what makes you alluring or less alluring to mosquitoes is prewired in your genetic circuit board,' according to Winegard. However, there are a few ways you can manage mosquitoes. He has these five tips. Booze makes it easier for mosquitoes to see you, Winegard said. Mosquitoes hunt by sight, but they don't see the world like people do. The predatory insects employ thermal, or infrared, vision. 'They see heat signatures,' Winegard noted. 'Consuming alcohol raises your body temperature,' he explained over email, 'which make(s) you an identifiable heat signature for your soon-to-be tormentor.' So, maybe reach for a refreshing glass of water or lemonade instead of that beer. In addition to using heat-based vision, mosquitoes hunt down humans primarily through smell. Winegard said mosquitoes 'can smell carbon dioxide from over 200 feet (60 meters) away.' 'So if you're exercising or breathing heavily, they'll smell that and be attracted to it,' Winegard told Gupta. And just like alcohol, high CO2 emissions make detecting heat signatures easier for mosquitoes, so Winegard recommends keeping yourself as cool as possible. This applies to your wardrobe, too. 'Dark clothes retain relatively more heat,' he said, so it's best to opt for lighter-colored, long-sleeved attire to keep mosquitoes at bay. Applying insect repellent is the gold standard for mosquito management, but if you're not careful when applying it, you can leave yourself vulnerable to bites. 'I know people who lather themselves in it, but they miss this little spot on the back of their calf and she'll find the chink in our armor,' Winegard told Gupta, referring to the female mosquito, who is the bloodsucking hunter. Mosquito repellent isn't like perfume, in which a few spritzes can cover your whole body. If you're spraying, make sure to be thorough. 'DEET (a chemical repellent) is still the gold standard, while oil of lemon eucalyptus is a plant-derived option,' Winegard said. For an added boost of security, he noted some clothes come pretreated with a mosquito-targeted insecticide called permethrin. Pool days and cool drinks outdoors offer a respite from the heat for humans, but they are equally as attractive to mosquitoes. Female mosquitoes lay their eggs in still water — and they don't need much. 'From a pond or stream to a minuscule collection in the bottom of an old container, used tire, or backyard toy — even a bottle cap full — any will suffice,' Winegard said via email. Even waterlogged soil is enough for mom-to-be mosquitoes to lay their eggs in, he added. Winegard recommended eliminating standing water around your home and yard to keep potential mosquito breeding grounds to a minimum. Another way to fight the swarms this summer is to consider skipping a shower or two. 'It's better to be stinky!' Winegard said. 'Being pungently rancid is a good thing, for it increases bacterial levels on the skin, which makes you less alluring to mosquitoes.' While this may offend others, Winegard says to skip the scented products: Deodorants, soaps and other applied fragrances are all enticing to mosquitoes. The one exception is your feet. 'Clean your feet,' he told Gupta. 'The bacteria on our feet, which is the same one that ripens a lot of cheeses, is an aphrodisiac to mosquitoes.' Winegard noted that this is the reason many of us get bitten around our ankles and feet. 'So, wash your feet!' he urged. Mosquitoes don't care about most personal characteristics you can objectively see. 'There is absolutely no truth to the persistent myths that mosquitoes fancy females over males, that they prefer blondes and redheads over those with darker hair, or that the darker or more leathery your skin, the safer you are from her bite,' Winegard said. But he noted that 'she does play favorites and feasts on some more than others.' What might entice a mosquito? 'Blood type O seems to be the vintage of choice over types A and B or their blend,' he said. 'People with blood type O get bitten twice as often as those with type A, with type B falling somewhere in between.' The creators of the 1998 movie 'A Bug's Life,' he noted, must have 'done their homework when portraying a tipsy mosquito ordering a 'Bloody Mary, O-positive.'' Maybe it's a mosquito's world, Winegard suggests, and people are just living in it. We hope these five tips help you keep mosquitoes at bay. Listen to the full episode here. And join us next week for a new episode of the Chasing Life podcast.

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