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MCG scientists find copper transporter as potential therapeutic target for cardiovascular diseases – News-Medical.Net

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An internal transporter that enables us to use the copper we consume in foods like shellfish and nuts to enable a host of vital body functions also has the essential role of protecting the receptor that enables us to grow new blood vessels when ours become diseased, Medical College of Georgia scientists report.

The findings published in the journal Nature Communications point toward the copper transporter ATP7A as a potential new therapeutic target in treating cardiovascular diseases like heart attack, peripheral artery disease and stroke.

“Our paper is talking about a newly discovered function of ATP7A,” says Dr. Masuko Ushio-Fukai, vascular biologist in MCG’s Vascular Biology Center. “Our paper shows that ATP7A directly binds to the receptor for vascular endothelial growth factor, called VEGFR2, to stabilize it, to regulate the receptor itself,” she says of the receptor that enables us to produce new blood vessels from our existing ones in a process called angiogenesis.

They’ve already shown that in diseases like diabetes, a major risk factor for cardiovascular disease, ATP7A expression is down, degradation of VEGFR2 is up and a healthy copper balance lost, which contributes to many of the problems these patients experience like heart attacks and impaired wound healing, says Dr. Tohru Fukai, vascular biologist and cardiologist in the VBC.

It was those findings that got the co-corresponding authors on the new paper thinking there might be a direct link between ATP7A and VEGF’s receptor.

Endothelial cells line our blood vessels, and VEGF stimulates the proliferation and movement of these cells, which lay the foundation and stimulation for restorative new blood vessels. VEGF receptors on endothelial cells are a starting point for angiogenesis, says Fukai.

In healthy humans, angiogenesis occurs to some extent throughout life, but in conditions like diabetes, when this ability is probably needed most, it’s impaired, the scientists say.

They suspect and are further pursuing that the essential crosstalk they have now discovered between transporter and receptor occurs in aging as well when, as with many body functions and factors, levels of ATP7A naturally begin to decrease.

Next steps in their work include identifying drugs that would increase and stabilize ATP7A levels and consequently the VEGF receptor, Ushio-Fukai says.

The reddish metal copper, an essential micronutrient, has long been known to stimulate the proliferation and migration of endothelial cells — copper prompts new blood vessel growth, and removing copper reduces tumor growth in animal models — and copper concentrations are increased in tissue forming new blood vessels, the scientists say. But just how copper stimulates new blood vessel formation has been unknown, they say.

ATP7A typically resides in the cell’s trans-Golgi network — a sort of bus station inside the cell that sends new proteins out where needed — where it delivers copper to enzymes that need the micronutrient to be activated and functional. These enzymes include superoxide dismutase, which breaks down the harmful byproducts of oxygen use like reactive oxygen species, which play a key role in a variety of conditions like cardiovascular disease and diabetes, as well as lysyl oxidase, which is critical to producing connective tissue in the body and essential to healthy bones, hair and more, Fukai says.

When too much copper accumulates inside the cells, as they have seen in conditions like diabetes, ATP7A also has the job of removing the excess because both too much or too little can be destructive. “Copper is both very toxic and essential,” Fukai notes.

Now the MCG scientists have shown that VEGF coaxes ATP7A out of the trans-Golgi network to the cell membrane where it binds to and stabilizes VEGF’s receptor. They also have shown that loss of ATP7A in endothelial cells promotes formation of autophagosomes, which basically cast a membrane net around whatever items are about to be consumed, and which now target VEGFR2 for degradation. The excess copper that begins to accumulate inside the cell can further hamper helpful angiogenesis.

Essential copper enzymes cannot be activated and also excessive amounts of copper cannot be exported. ATP7A would be one of the therapeutic targets to help correct this.”

Dr. Masuko Ushio-Fukai, Vascular Biologist, MCG’s Vascular Biology Center

The collective findings mean that copper transporter ATP7A is required for new blood vessel formation and for restoring blood flow in ischemic cardiovascular disease, they write.

The fact that copper is essential to angiogenesis was shown decades ago, when it was found that just applying copper to endothelial cells stimulates angiogenesis, Ushio-Fukai says.

There has been some indication copper’s role in angiogenesis worked through ATP7A’s delivery of copper to copper containing enzymes like superoxide dismutase. “Our paper changes this concept,” she says.

Conditions that can trigger ATP7A to move out of the trans-Golgi network are signals like a lot of copper being present in the cytoplasm, a fluid-filled pocket in the cell that holds most its contents including the trans-Golgi network; inadequate oxygen, called hypoxia, being supplied to a tissue, like what occurs in heart and peripheral artery disease; and insulin.

Too much copper inside cells is definitely bad, where it can work like what Fukai calls an “atomic weapon” to vigorously produce destructive free radicals. Without sufficient work by ATP7A to keep copper levels balanced, levels of the metal keep going up while the essential activities of copper containing enzymes decrease.

Although our cells naturally make copper receptors, we have to consume the essential micronutrient itself. Foods high in copper include oysters and other shellfish like lobster and small clams, shitake mushrooms, tofu and soybeans, sweet potatoes, sesame seeds and nuts like cashews and walnuts as well as leafy greens like spinach and kale.

Journal reference:

Ash, D., et al. (2021) The P-type ATPase transporter ATP7A promotes angiogenesis by limiting autophagic degradation of VEGFR2. Nature Communications. doi.org/10.1038/s41467-021-23408-1.

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Here’s how Helene and other storms dumped a whopping 40 trillion gallons of rain on the South

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More than 40 trillion gallons of rain drenched the Southeast United States in the last week from Hurricane Helene and a run-of-the-mill rainstorm that sloshed in ahead of it — an unheard of amount of water that has stunned experts.

That’s enough to fill the Dallas Cowboys’ stadium 51,000 times, or Lake Tahoe just once. If it was concentrated just on the state of North Carolina that much water would be 3.5 feet deep (more than 1 meter). It’s enough to fill more than 60 million Olympic-size swimming pools.

“That’s an astronomical amount of precipitation,” said Ed Clark, head of the National Oceanic and Atmospheric Administration’s National Water Center in Tuscaloosa, Alabama. “I have not seen something in my 25 years of working at the weather service that is this geographically large of an extent and the sheer volume of water that fell from the sky.”

The flood damage from the rain is apocalyptic, meteorologists said. More than 100 people are dead, according to officials.

Private meteorologist Ryan Maue, a former NOAA chief scientist, calculated the amount of rain, using precipitation measurements made in 2.5-mile-by-2.5 mile grids as measured by satellites and ground observations. He came up with 40 trillion gallons through Sunday for the eastern United States, with 20 trillion gallons of that hitting just Georgia, Tennessee, the Carolinas and Florida from Hurricane Helene.

Clark did the calculations independently and said the 40 trillion gallon figure (151 trillion liters) is about right and, if anything, conservative. Maue said maybe 1 to 2 trillion more gallons of rain had fallen, much if it in Virginia, since his calculations.

Clark, who spends much of his work on issues of shrinking western water supplies, said to put the amount of rain in perspective, it’s more than twice the combined amount of water stored by two key Colorado River basin reservoirs: Lake Powell and Lake Mead.

Several meteorologists said this was a combination of two, maybe three storm systems. Before Helene struck, rain had fallen heavily for days because a low pressure system had “cut off” from the jet stream — which moves weather systems along west to east — and stalled over the Southeast. That funneled plenty of warm water from the Gulf of Mexico. And a storm that fell just short of named status parked along North Carolina’s Atlantic coast, dumping as much as 20 inches of rain, said North Carolina state climatologist Kathie Dello.

Then add Helene, one of the largest storms in the last couple decades and one that held plenty of rain because it was young and moved fast before it hit the Appalachians, said University of Albany hurricane expert Kristen Corbosiero.

“It was not just a perfect storm, but it was a combination of multiple storms that that led to the enormous amount of rain,” Maue said. “That collected at high elevation, we’re talking 3,000 to 6000 feet. And when you drop trillions of gallons on a mountain, that has to go down.”

The fact that these storms hit the mountains made everything worse, and not just because of runoff. The interaction between the mountains and the storm systems wrings more moisture out of the air, Clark, Maue and Corbosiero said.

North Carolina weather officials said their top measurement total was 31.33 inches in the tiny town of Busick. Mount Mitchell also got more than 2 feet of rainfall.

Before 2017’s Hurricane Harvey, “I said to our colleagues, you know, I never thought in my career that we would measure rainfall in feet,” Clark said. “And after Harvey, Florence, the more isolated events in eastern Kentucky, portions of South Dakota. We’re seeing events year in and year out where we are measuring rainfall in feet.”

Storms are getting wetter as the climate change s, said Corbosiero and Dello. A basic law of physics says the air holds nearly 4% more moisture for every degree Fahrenheit warmer (7% for every degree Celsius) and the world has warmed more than 2 degrees (1.2 degrees Celsius) since pre-industrial times.

Corbosiero said meteorologists are vigorously debating how much of Helene is due to worsening climate change and how much is random.

For Dello, the “fingerprints of climate change” were clear.

“We’ve seen tropical storm impacts in western North Carolina. But these storms are wetter and these storms are warmer. And there would have been a time when a tropical storm would have been heading toward North Carolina and would have caused some rain and some damage, but not apocalyptic destruction. ”

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Follow AP’s climate coverage at https://apnews.com/hub/climate

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Follow Seth Borenstein on Twitter at @borenbears

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Associated Press climate and environmental coverage receives support from several private foundations. See more about AP’s climate initiative here. The AP is solely responsible for all content.

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‘Big Sam’: Paleontologists unearth giant skull of Pachyrhinosaurus in Alberta

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It’s a dinosaur that roamed Alberta’s badlands more than 70 million years ago, sporting a big, bumpy, bony head the size of a baby elephant.

On Wednesday, paleontologists near Grande Prairie pulled its 272-kilogram skull from the ground.

They call it “Big Sam.”

The adult Pachyrhinosaurus is the second plant-eating dinosaur to be unearthed from a dense bonebed belonging to a herd that died together on the edge of a valley that now sits 450 kilometres northwest of Edmonton.

It didn’t die alone.

“We have hundreds of juvenile bones in the bonebed, so we know that there are many babies and some adults among all of the big adults,” Emily Bamforth, a paleontologist with the nearby Philip J. Currie Dinosaur Museum, said in an interview on the way to the dig site.

She described the horned Pachyrhinosaurus as “the smaller, older cousin of the triceratops.”

“This species of dinosaur is endemic to the Grand Prairie area, so it’s found here and nowhere else in the world. They are … kind of about the size of an Indian elephant and a rhino,” she added.

The head alone, she said, is about the size of a baby elephant.

The discovery was a long time coming.

The bonebed was first discovered by a high school teacher out for a walk about 50 years ago. It took the teacher a decade to get anyone from southern Alberta to come to take a look.

“At the time, sort of in the ’70s and ’80s, paleontology in northern Alberta was virtually unknown,” said Bamforth.

When paleontogists eventually got to the site, Bamforth said, they learned “it’s actually one of the densest dinosaur bonebeds in North America.”

“It contains about 100 to 300 bones per square metre,” she said.

Paleontologists have been at the site sporadically ever since, combing through bones belonging to turtles, dinosaurs and lizards. Sixteen years ago, they discovered a large skull of an approximately 30-year-old Pachyrhinosaurus, which is now at the museum.

About a year ago, they found the second adult: Big Sam.

Bamforth said both dinosaurs are believed to have been the elders in the herd.

“Their distinguishing feature is that, instead of having a horn on their nose like a triceratops, they had this big, bony bump called a boss. And they have big, bony bumps over their eyes as well,” she said.

“It makes them look a little strange. It’s the one dinosaur that if you find it, it’s the only possible thing it can be.”

The genders of the two adults are unknown.

Bamforth said the extraction was difficult because Big Sam was intertwined in a cluster of about 300 other bones.

The skull was found upside down, “as if the animal was lying on its back,” but was well preserved, she said.

She said the excavation process involved putting plaster on the skull and wooden planks around if for stability. From there, it was lifted out — very carefully — with a crane, and was to be shipped on a trolley to the museum for study.

“I have extracted skulls in the past. This is probably the biggest one I’ve ever done though,” said Bamforth.

“It’s pretty exciting.”

This report by The Canadian Press was first published Sept. 25, 2024.

The Canadian Press. All rights reserved.

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The ancient jar smashed by a 4-year-old is back on display at an Israeli museum after repair

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TEL AVIV, Israel (AP) — A rare Bronze-Era jar accidentally smashed by a 4-year-old visiting a museum was back on display Wednesday after restoration experts were able to carefully piece the artifact back together.

Last month, a family from northern Israel was visiting the museum when their youngest son tipped over the jar, which smashed into pieces.

Alex Geller, the boy’s father, said his son — the youngest of three — is exceptionally curious, and that the moment he heard the crash, “please let that not be my child” was the first thought that raced through his head.

The jar has been on display at the Hecht Museum in Haifa for 35 years. It was one of the only containers of its size and from that period still complete when it was discovered.

The Bronze Age jar is one of many artifacts exhibited out in the open, part of the Hecht Museum’s vision of letting visitors explore history without glass barriers, said Inbal Rivlin, the director of the museum, which is associated with Haifa University in northern Israel.

It was likely used to hold wine or oil, and dates back to between 2200 and 1500 B.C.

Rivlin and the museum decided to turn the moment, which captured international attention, into a teaching moment, inviting the Geller family back for a special visit and hands-on activity to illustrate the restoration process.

Rivlin added that the incident provided a welcome distraction from the ongoing war in Gaza. “Well, he’s just a kid. So I think that somehow it touches the heart of the people in Israel and around the world,“ said Rivlin.

Roee Shafir, a restoration expert at the museum, said the repairs would be fairly simple, as the pieces were from a single, complete jar. Archaeologists often face the more daunting task of sifting through piles of shards from multiple objects and trying to piece them together.

Experts used 3D technology, hi-resolution videos, and special glue to painstakingly reconstruct the large jar.

Less than two weeks after it broke, the jar went back on display at the museum. The gluing process left small hairline cracks, and a few pieces are missing, but the jar’s impressive size remains.

The only noticeable difference in the exhibit was a new sign reading “please don’t touch.”

The Canadian Press. All rights reserved.

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