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Calidi Biotherapeutics Announces Exclusive License Agreement with City of Hope and the University of Chicago for Novel Oncolytic Virotherapy…

Posted: August 18, 2021 at 1:53 am

DetailsCategory: DNA RNA and CellsPublished on Monday, 16 August 2021 17:11Hits: 496

LA JOLLA, CA, USA I August 16, 2021 I Calidi Biotherapeutics, Inc., a clinical-stage biotechnology company with novel allogeneic stem cell platforms for delivery of oncolytic viruses, together with the University of Chicago and City of Hope, a world renowned NCI-Designated Comprehensive Cancer Center, based in Duarte, California, have entered into an exclusive worldwide licensing agreement for patents covering cutting edge therapies using an oncolytic adenovirus in combination with a clinical grade allogeneic neural stem cell line.

City of Hope (COH) scientists, led by Dr. Karen Aboody in collaboration with Dr. Maciej Lesniak's team at University of Chicago, and later Northwestern University, have used COHs exclusive GMP grade immortalized, clonal human neural stem cell line, to selectively deliver an oncolytic adenovirus to tumor sites. Dr. Aboody and Dr. Lesniak, together with Dr. Rachael Mooney at COH, have spent 13 years in a passionate effort to translate promising pre-clinical results into the clinic, attaining FDA approval for commencing a first-in-human Phase-1 trial in recurrent glioma patients.

We are very excited about the partnership and collaboration with Calidi Biotherapeutics. Their deep understanding and expertise using allogeneic stem cells as a delivery platform to protect, deliver, amplify, and potentiate oncolytic virotherapy, can potentially result in a significantly more effective treatment for cancer patients with invasive tumors, commented Dr. Karen Aboody, Professor, Department of Developmental and Stem Cell Biology, City of Hope National Medical Center & Beckman Research Institute.

The first wave of Oncolytic Viruses were novel, but lacked the ability to efficiently deliver the virus to tumor sites, due to the human complement immune system inactivating the viruses, usually within one hour of patient injection, thus resulting in a lack of efficacy, stated Allan Camaisa, Co-Founder, Chairman and CEO of Calidi Biotherapeutics. We believe this collaboration with City of Hope will allow us to implement Calidis proprietary techniques together with City of Hopes novel approach to glioblastoma and other malignant tumors, using neural stem cells combined with an oncolytic adenovirus. This FDA approved Investigational New Drug (IND), planned for patient trials in the first quarter of 2022, increases Calidis drug pipeline and gives our company a tumor-tropic stem cell line to use for oncolytic virus delivery in cancer patients.

This exclusive license agreement, which was executed by the University of Chicagos Polsky Center for Entrepeneurship and Innovation, transferred the COH/University of Chicago IND to Calidi for the commercial development of a licensed product. The agreement grants to Calidi commercial exclusivity in using neural stem cells with the adenovirus known as CRAd-pk-S-7 for oncolytic virotherapy.

Calidis scientific and medical teams are very excited to contribute in the development of this promising technology that has significant potential to help many patients with advanced tumors, said Boris Minev, MD, President, Medical and Scientific Affairs at Calidi Biotherapeutics. We are delighted to collaborate with the outstanding researchers and clinicians who developed this novel oncolytic virotherapy approach.

About Calidi Biotherapeutics

Calidi Biotherapeutics is a clinical-stage immuno-oncology company with proprietary technology that is revolutionizing the effective delivery of oncolytic viruses protected by stem cells for targeted therapy against difficult-to-treat cancers. Calidi Biotherapeutics is advancing a potent allogeneic stem cell and oncolytic virus combination for use in multiple oncology indications. Calidis off-the-shelf, universal cell-based delivery platform is designed to protect, amplify, and potentiate oncolytic viruses currently in development leading to enhanced efficacy and improved patient safety. Calidi Biotherapeutics is headquartered in San Diego, California. For more information, please visit http://www.calidibio.com.

About University of Chicago

The University of Chicago is a leading academic and research institution that has driven new ways of thinking since its founding in 1890. As an intellectual destination, the University draws scholars and students from around the world to its campuses and centers around the globe. The University provides a distinctive educational experience and research environment, empowering individuals to challenge conventional thinking and pursue field-defining research that produces new understanding and breakthroughs with global impact.

The Polsky Center for Entrepreneurship and Innovation applies world-class business expertise from the University of Chicago Booth School of Business to bring new ideas and breakthrough innovations to market. Home of the Universitys technology transfer office, the Polsky Centers dedicated team of professionals with deep technical expertise enabling technology commercialization perform market analysis, manage intellectual property, identify partners, and negotiate partnerships and licenses for discoveries and inventions developed by faculty, researchers, and staff. Learn more at polsky.uchicago.edu and follow us on Twitter @polskycenter.

About City of Hope

City of Hope is an independent biomedical research and treatment center for cancer, diabetes and other life-threatening diseases. Founded in 1913, City of Hope is a leader in bone marrow transplantation and immunotherapy. City of Hopes translational research and personalized treatment protocols advance care throughout the world. Human synthetic insulin, monoclonal antibodies, and numerous breakthrough cancer drugs are based on technology developed at the institution. Translational Genomic research (TGen) became a part of City of Hope in 2016. AccessHope, a wholly owned subsidiary, was launched in 2019, dedicated to serving employers and their health care partners by providing access to City of Hopes exceptional cancer expertise. A National Cancer Institute-designated comprehensive cancer center and a founding member of the National Comprehensive Cancer Network, City of Hope is ranked among the nations Best Hospitals by U.S. News & World Report. Its main campus is located in Pasadena, California, near Los Angeles, with additional locations throughout Southern California and in Arizona. For more information about City of Hope, follow us on Facebook, Twitter, YouTube, or Instagram.

SOURCE: Calidi Biotherapeutics

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Calidi Biotherapeutics Announces Exclusive License Agreement with City of Hope and the University of Chicago for Novel Oncolytic Virotherapy...

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Jim McMahon broke his neck playing for Vikings, and found out about it 17 years later – TwinCities.com-Pioneer Press

Posted: December 23, 2020 at 11:56 am

In 2010, Jim McMahon was getting results from what he thought was a routine examination for workers compensation. The doctor asked him, When did you break your neck?

Suddenly, the former quarterbacks mind shot back to when he played one season for the Vikings in 1993. In a 17-10 playoff loss to the Giants in New York on Jan. 9, 1994, McMahon was battered and knocked out of the game twice but returned each time.

I said, I have a pretty good idea, McMahon said in a phone interview.

On the second play of the third quarter, with the Vikings leading 10-3, McMahon was sandwiched by defensive linemen Mike Fox and Keith Hamilton, the latter belting him in the head. McMahon was down on the field for nearly two minutes, and CBS play-by-play announcer Pat Summerall later said on the air he had been diagnosed with a mild concussion.

I believe thats the game that I broke my neck, McMahon said. I remember lying on the field for quite a while. I had all my senses but I was like, Dont touch me. I cant feel my legs.

McMahon eventually was able to get up and slowly walked off the field. He was replaced by Sean Salisbury but returned on Minnesotas next series.

I remember rolling out to throw a pass and (Fox) jumped up to block the pass, McMahon said of a play late in the third quarter. He brushed against my helmet, and then my legs went numb again.

McMahon was down again for more than a minute, and again was replaced by Salisbury. But McMahon returned with five minutes left in the game after CBS analyst John Madden had said on the air he should sit out the rest of the afternoon.

McMahon went on to play three more NFL seasons.

After that game, you go back to Minnesota and you see the coach (Dennis Green), and he says, Have a good summer, and then you leave, McMahon said. I guess they never caught (the neck injury) with any X-rays the next three years because I passed every physical. They told me (in 2010) that the C6 and C7 vertebrae were cracked and compressed, which means they were squished together and cracked at the ends.

McMahon was beaten up plenty while playing in the NFL from 1982-96, suffering other neck injuries, numerous concussions and shoulder injuries. He had 12 knee surgeries and suffering bruised ribs and a lacerated kidney. In 2012, McMahon, who now lives in Scottsdale, Ariz., was diagnosed as being in the early stages of dementia but said he has felt better in recent years.

McMahon, 61, goes to a chiropractor in New York every three months to have his neck aligned to help the flow of spinal fluid. And last December he went to Columbia University Irving Medical Center in New York to have 275 million stem cells added into both shoulders, both elbows, both knees, and his neck, spine and brain.

McMahon helped lead the Chicago Bears to a 15-1 record in 1985, and a resounding 46-10 win over New England in Super Bowl XX. Had he not been sidelined by injuries in three Chicago seasons after that, the Bears might have won another Super Bowl or two.

McMahon doesnt watch the NFL much now. The Bears will face the Vikings on Sunday at U.S. Bank Stadium, and McMahon isnt expected to watch. But he likely will check out the score.

Even though he played just one season with the Vikings and it didnt end well, McMahon has fond memories of Minnesota. He has returned to the Twin Cities twice in the past two years for autograph shows and to play golf.

I enjoy Minnesota, he said. I like to go up there and see some old teammates and have a beer and have some laughs.

McMahons latest visit was in September, when he stayed at the Blaine home of Buddy Becker, a friend and real-estate agent. Becker is friends with Tommy Kramer, a Vikings quarterback from 1977-89 who has been living at his home. Former NFL quarterback Jim McMahon, right, who played with the Minnesota Vikings in 1993, visits with Tommy Kramer, a Vikings quarterback from 1977-89, at an autograph signing at Route 47 Pub & Grub in Fridley in September 2020. (Courtesy of Buddy Becker)

McMahon and Kramer got to know each other a bit when their teams faced each other twice a season in the old NFC Central Division. A few years ago, they started tweeting at one another, and since have become much closer.

Theyre golf, drinking and singing buddies, Becker said. When Jim was here in September, I have a video of him and Tommy singing the Waylon Jennings song, Good Hearted Woman. They were singing to their exes.

McMahon and Kramer faced off in what was perhaps the most memorable regular-season game of McMahons career. Entering the Sept. 19, 1985, game at the Metrodome, the Bears and the Vikings were both 2-0.

The game was played on a Thursday night and televised nationally by ABC with its Monday Night Football broadcasting team of Frank Gifford, Joe Namath and O.J. Simpson. McMahon had been in the hospital for two days during the week with a pinched nerve in his neck and head coach Mike Ditka had announced that Steve Fuller would start at quarterback.

I had been in the hospital in Chicago in traction, and Ditka told me I wasnt going to play, McMahon said. The night before the game, I was sitting in my (Twin Cities hotel) room icing my shoulder, my back and my neck. Then one of the coaches comes up and says, Ditkas ticked off. Why arent you at (a team) meeting? So, I had to go down and listen to Ditka rant and rave about me, and I said, Why do I have to be here? You told me Im not playing.

McMahon said he was given painkillers before the game, and that once the game got underway, he started bugging Ditka the whole first half that you better let me play.

With the Bears trailing 17-9 midway through the third quarter and Fuller ineffective, Ditka finally inserted McMahon. The quarterback joked that he probably did so because Ditka was tired of being pestered on the sideline.

On the first play, a screen pass was called, McMahon said. I was a little wobbly when I dropped back because of all the painkillers I had taken. But I saw a blitz, and downfield Willie Gault was 10 yards past his man, so I threw it to him instead.

The speedy wide receiver scored on a 70-yard reception to cut the deficit to 17-16. But Ditka wasnt happy.

When I came off the field, he grabbed me and said, What play did you call? Why did you throw it to (Gault)? I said, Because he was open.

On Minnesotas next possession, Kramer threw an interception. On the next play, McMahon tossed a 25-yard touchdown pass to Dennis McKinnon for a 23-17 Bears lead.

Later in the third quarter, McMahon threw a 43-yard touchdown pass to McKinnon for a 30-17 lead. That made it three TD passes in a span of 6 minutes, 40 seconds, and the Bears were on their way to a 33-24 win.

We should have won that game, Kramer said. McMahon hadnt even been on the field and then comes in and nobodys guarding Willie Gault. Willie Teal was supposed to be on him.

The win helped springboard the Bears to a 12-0 start before they lost their only game of the season, 38-24 at Miami. McMahon completed 8 of 15 passes for 236 yards.

It was a fun third quarter, McMahon said. It was awesome. People got to see that we were more than just a defensive football team.

Between 1985-88, McMahon was 29-3 as Chicagos starting quarterback but missed about as many games as he played. So, the Bears traded him to San Diego, where he played one forgettable season.

McMahon then went to Philadelphia to serve as Randall Cunninghams backup from 1990-92 but had 12 starts. Then it was on to Minnesota in 1993. There, he started a career-most 12 games and went 8-4. He missed four games due to a dislocated shoulder, and the Vikings finished 9-7. Minnesota Vikings quarterback Jim McMahon reacts after a third-down pass intended for Quadry Ismail falls incomplete, forcing Minnesota to punt in an NFL football game against the Green Bay Packers at the Metrodome in Minneapolis on Sept. 26, 1993. Vikings placekicker Fuad Reveiz kicked a 22-yard field goal his fifth of the game with four seconds left to lift Minnesota to a 15-13 victory. (Jean Pieri / Pioneer Press)

We had a pretty good defense, and offensively we had some weapons in Cris Carter and Anthony Carter, McMahon said. My biggest memory that season was beating the Packers twice and the Bears twice.

The Vikings beat the Bears 10-7 at the Metrodome in Week 2 and 19-12 in Week 8 on Monday Night Football at Chicago. It marked the only times in McMahons career he defeated the Bears as a starter.

It was nice to play back home, McMahon said of the win at Soldier Field. They gave me a nice ovation. The fans always treated me well in Chicago. But the sweetest revenge was getting a victory.

During his 1982-88 Chicago tenure, McMahon had the image of being a punk rocker, which he attributed to one bad haircut. He said he didnt write any lyrics for The Super Bowl Shuffle video in which he sang, Im the punky QB known as McMahon. And he said the sunglasses he regularly wore were for medical reasons.

McMahon said his image with the Bears was a media creation, and Minnesota teammates never saw it.

He had that image of wearing sunglasses and the headband and all those kind of things, but he was just a normal guy, said Brad Johnson, Minnesotas third-string quarterback in 1993. Wed go over to his house and play darts and cards. I remember him as just a really good guy, a good teammate.

That season marked the only time McMahon led a team other than Chicago to the playoffs. He completed 60.4 percent of his passes, a career best as a starter, and threw for 1,968 yards with nine touchdowns and eight interceptions.

He was tough, like a Scott Studwell playing quarterback, said former Vikings cornerback Carl Lee, referring to the rugged former linebacker. He got beaten up a lot, but he never wanted to miss a play.

That attitude was on display to start the playoffs at Giants Stadium, when the temperature was 20 degrees with a 21-mph wind that made the wind-chill factor 4 degrees. Going against a rugged defense that featured legendary linebacker Lawrence Taylor, McMahon completed 12 of 25 passes for 145 yards and a touchdown.

He got knocked around a lot in that game, but I didnt know he broke his neck, said Roger Craig, then a Vikings running back. Thats crazy. Thats wild. He was a tough, tough guy, and he was great leader. If I broke my neck, man, that would have made me retire right away.

Of course, McMahon didnt know it then and played three more seasons.

After the Vikings opted to bring in quarterback Warren Moon in 1994, McMahon spent that year as backup in Arizona. He then moved on to Green Bay to serve as Brett Favres backup in 1995 and 1996. In his final NFL game, he watched from the sidelines as the Packers beat New England 35-21 in Super Bowl XXXI, earning McMahon a second championship ring.

McMahon still keeps up with Favre. He reached out to him when he saw that Beckers home has a urinal in a basement bathroom with a Packers logo at the bottom of the bowl.

Jim got a kick out of it, and the first thing he did was send a picture of it to Brett Favre, and Brett sent a text back laughing, Becker said. Former NFL quarterback Jim McMahon, who played with the Minnesota Vikings in 1993, on the beach in Cabo, Mexico on Dec. 17, 2020. (Courtesy of Jim McMahon)

McMahon spends much of his time now at his Arizona home, and recently bought a house in Mexico. He said he still at times gets bad headaches because the spinal fluid is acting up and must go into a dark room for relief. But hes been able to keep that mostly under control by going regularly to Rock Hill, N.Y., to have adjustments made by chiropractor Scott Rosa.

McMahon said he also has been helped by the visit to a clinic last December in Medellin, Colombia, when the stem cells were added, and by having a medical prescription for marijuana. McMahon said hes looking himself to get into the cannabis business.

My body is actually feeling a heck of a lot better now, he said.

McMahon was battered plenty in the NFL, most famously when Packers defensive end Charles Martin body slammed him to the turf in Week 12 in 1986. That ended his season due to a shoulder injury.

Not as well documented has been the beating he took seven years later with the Vikings in the playoffs. Any regrets?

I went back in, like an idiot, he said.

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Jim McMahon broke his neck playing for Vikings, and found out about it 17 years later - TwinCities.com-Pioneer Press

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Want to Know Where The Best Fall Colors Are in Your Area? Check Out This Interactive US Map – Good News Network

Posted: October 5, 2020 at 2:52 pm

Across the northern hemisphere, leaves are currently turning from deep summer green to the most brilliant shades of red and orange, yellow and gold.

Its quite the show, and for leaf peepers in the Lower 48, its possible to take a look at a virtual, interactive map to see just where the tree leaves are at their brilliant best.

At SmokyMountains.com, publicly accessible data such as National Oceanic and Atmospheric Administration precipitation forecasts, temperature forecasts, and average daylight exposure gets collated and synthesized in order to create a map that changes color according to where the most colorful scenes might be seen across the States.

Co-founder of the map, David Angotti, noted that its predictions arentquite perfect. It might show amazing fall colors happened in the middle of Arizona, but if there are no deciduous trees in that areaof course there wont be much of a show.

I wish I could make fall happen in South Florida or in the desert, Angotti told the Washington Post, but at the end of the day, the math is basically showing when the temperature and precipitation trendswouldcause peak fall to occur in each of these areas.

RELATED: Stunning Aerial Video of Icelands Green VolcanoCan Soothe Your Lockdown Stress

So just why do leaves change their color? According to SmokyMountains.com, As the fall days begin to get shorter and shorter, the production of chlorophyll slows to a halt, eventually giving way to the true color of the leaf.

When it gets cold, the trees then slowly close off the veins that carry water and nutrients to and from the leaves with a layer of new cells that form at the base of the leaf stem, protecting the limbs and body of the tree.

MORE: Americans Say COVID-19 Has Given Them a Newfound Appreciation of Nature

Once the process of new cell creation is complete, water and nutrients no longer flow to and from the leafthis enables the leaf to die and weaken at the stem, eventually falling gracefully to the ground.

Graceful is the word. We hope its beautiful where you are right now.

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‘Were not your slaves’: Alternative health providers bristle at warning letters about their coronavirus treatments – USA TODAY

Posted: September 4, 2020 at 1:55 am

The Bill and Melinda Gates Foundation have invested $350 million to fund treatment and vaccine research to fight coronavirus. USA TODAY

Operation Quack Hack, the federal governments initiative to clamp down on fake coronavirus medications and cures, has exposed a health underground in America brimming with distrust not only of mainstream medicinebut the government itself.

Its a Tea Party for COVID-times.

Its members are angry at government warning letters that many perceive as an infringement on their right to free speech, free trade and people's control over their health care and some are ready to fight back.

A common refrain: How can we trust the same government that signed off onopioids?

The most radical believe that wealthy globalists including Bill Gates and Anthony Fauci created the coronavirus, unleashed it from Wuhan, China, along with immune-system-weakening 5G wireless technology; and intend to install digital ID chips in our bodies at the same time they give us the vaccine.

For them, the two agencies behind Operation Quack Hack the Food and Drug Administration and the Federal Trade Commission are sinister organizations. Their objective is to force everyone to take the vaccine, and the only way to do that is to convince ustheres no other choice.

Were not your slaves, were not in your cult, right-wing talk show host Alex Jones shouted in June at an anti-mask rally in Austin. If you want war, you'd better believe you got war.

Info Wars founder Alex Jones joins nearly 150 anti-mask protesters.(Photo: RICARDO B. BRAZZIELL/AMERICAN-STATESMAN)

False claims: Fact check: 'Plandemic' sequel makes false claims about Bill Gates

COVID-5G: https://www.mcgill.ca/oss/article/covid-19-pseudoscience-technology/how-distrust-and-coinc

Jones got in trouble with the FDA in April for peddling a line of silver products, including silver-laced toothpaste, as a COVID-19 cure.

The majority of alternative health providers that received warning letters are less extreme, but many still think the FDA and FTC are out to get them. The goal as they see it? To protect Big Pharma from competition as their market share grows.

The healthcare system in this country is rigged against inexpensive, safe, and effective natural remedies in favor of expensive pharmaceutical drugs, saidClark Hansen, anaturopathic medical doctor in Arizona,in an email message to USA TODAY. "The US medical system is ignoring any treatment that is not patentable and therefore cannot provide a multi-billion profit for some giant healthcare company.

The FTC warned Hansenin May to stop implying that a combination of elderberry, echinacea and the herb andrographis could prevent coronavirus infection.

In an email to USA TODAY, the FDA said its goalactually isto protect consumers from scammers and products that harm them. The agency added that it doesnt want consumers wasting their time on remedies that may lead to delays in getting proper diagnosis and medical care for COVID-19 and other potentially serious diseases and conditions.

Its sister agency was more succinct.

The FTC has taken aggressive action against marketers who want to take advantage of the anxiety caused by the current health crisis, the agency said in an email.We have done so to prevent consumer injury.There is no other motivation.

Under the law, supplement suppliers are not allowed to use some words "cure," "treat," "prevent," "mitigate" or "diagnose" in promotional materials.

Though many providers openly declare their products wont cure COVID-19, the mention of treat or prevent in the same sentence as "coronavirus" has been enough to trigger a letter from the FTC and FDA.

Recognizing the power of these agencies, mostof the more than 300 companies and individuals that got warning letters have responded by removing or changingmarketing materials on their websites, then they've quietly gotten back to the business of addressing customer ailments.

Theres plenty of money to be made in the herbal remedies and alternative health care market even without a pandemic. Revenueis expected to reach nearly $18 billion in the United States this year, according to IBISWorld, a global economic research firm.

Nevertheless, frustration lies just beneath the surface.

Kate Tietje, who runs the Modern Alternative Mama website and ran afoul of the government for touting Elderberry Elixir, vitamin C and vitamin D as remedies for the coronavirus, had this to say about government regulators in a post she later removed from her website:

Seeing that the FDA allows approved drugs to harm and even kill millions of people, while badgering natural companies that have fewer than 10 reports of unproven adverse effect claims, shows us definitively that its not about keeping people healthy.

Since the onset of the pandemic seven months ago, the FDA and the FTC have sent out an average of 13letters a weekwarning companies and individualsto stop making false claims about their ability to prevent or cure COVID-19.

Many of the recipients have a history of fraud and malfeasance.

They include televangelist JimBakker, who spent five years in prison for defrauding his own ministry back in the 1980s;Gordon Pedersen, who wears a lab coat and stethoscope and calls himself a doctor even though he holds no medical degree; and Matthew Martinez, who agreed to give up his chiropractor'slicense in 2016 after being accused of having sex with clients and suggesting that a patient with multiple sclerosis could be cured by drinking breast milk.

Both Bakker and Pedersen told their followers that Silver Solution was the antidote to COVID-19 and were sued by the government for failing to address allegedly false claims outlined in warning letters.

If the government does not receive an adequate response to its warning letter it can file suit, seek arestraining order to shutdown the company's web sites and operations, commandit to recall and destroy its products and raw materials and refund its customers.

Pedersen refused to participate in court proceedings and could not be reached for comment. Bakker battled back, claiming religious exemption. Court documents filed on his behalf state that his product is a sacrament, as important to his ministry as solicitingdonations and preaching the second coming of Christ.

As for Martinez, the FTC faulted him for claiming that high doses of vitamin C "havea significant impacton treating coronavirus" and that stem cells helpin the healing process.After receiving his warning letter from the FTC, he also boasted that the ultraviolet light in his companys octagon-shaped Blue Room provided virus-killing benefits.

Another warning letter recipient with a history of breaking the law was Richard Marschall. A naturopathic physician, he got busted twice between 2011 and 2017 for introducing misbranded drugs into interstate commerce and spent 60 days in jail. That didnt stop him from marketing a product called the dynamic duo that he said could crush 30 different viral infections including those in the Corona family.

On Aug. 5, Marschall was indicted for the third time on the same charge: introducing misbranded drugs into interstate commerce.

An insistence to keep selling supposed coronavirus cures after being told not to is also what got Marc White Eagle Travalino in trouble.

A self-proclaimed medicine man and shaman who runs website and folksy trading post in Fort Davis, Texas, Travalino got nabbed by the FDA for saying his Kolon Kleen, Maska Miakoda and Shar Mar products were proven to work and destroy the coronavirus. Instead of ceasing his marketing activities after receiving his warning letter, he tried to sell more treatments this time to an undercover agent.

The government responded by shutting down all Travalinos operations, both online and brick-and-mortar.

Some coronavirus treatments exposed by Operation Quack Hack were more outlandish.

Face Vital LLC swore by a battery-powered silicon brush used for cleaning facial pores. Mypurmist argued that its hand-held steam machine was the answer. BioElectric Shield offered a golf-ball-sized pendant to block immune-system-sapping 5G electromagnetic waves.

5G appears to be the straw that broke the camels back when it comes to the spread of the Coronavirus, the company said on its website.An extremely intense rollout of 5G was launched initially in Wuhan City, China.

Is it a coincidence that this is also where the coronavirus outbreak started? the company asked. "We are urging you to get protection from EMF radiation."

At least four makers of electric pulse machines, used by chiropractors to reduce muscle tension, stated online that their devices boost the immune system. Electric pulse therapy is like a power up for your cells akin to giving your cells a cup of coffee to energize and speed up their job, said BioBalance, a Maryland-based company.

Three morecompanies suggested sound waves or music could defeat the virus. Musical Medicine, headed by Dr. Suzanne Jonas, advertised new music "designed to boost your immune system. Spooky2 Scalar, a New York company headed by Matt Forrest, said its new sounds would protect you and your family, andBioenergy Wellness in Miami said it had found a COVID-attacking frequency and that sound frequencies were better at penetrating cells than chemicals.

These treatments and others subject to the warning letters have no ability to help anyone with COVID-19, said professor Arthur Caplan, who heads the medical ethics division at the NYU School of Medicine.

Arthur L. Caplan Ph.D. of New York University's Langone Medical Center.(Photo: John Abbott Photography)

Theyre just emptying our pockets for their own gain and greed, he said.

Caplan added that if companies receiving warning letters had any real virus fighting abilities, Dr. Fauci,director of the National Institute of Allergy and Infectious Diseases, would be talking about them on TV.

If Im going to bet on the future, Caplan said. Im still betting on the infectious disease guys over the vitamin purveyors to work our way out of this,

Peddling potions, balmsand tinctures for ailments asvaried as erectile disfunction and Parkinson's disease, alternative health providers targeted by Operation Quack Hack do most of their business over the Internet.

About four in 10 also operate naturopathic, holistic, acupuncture or chiropractic clinics where practitioners meet with clients to help with pain management or plan healthy alternatives for living on an increasingly toxic planet.

For nearly a third, go-to products for fighting coronavirus virus have been simple the kind of thing any mother might suggest to ward off the flu: vitamin C, vitamin D and zinc. Another 26% offered some mixture of herbs or essential oils that might include elderberries, echinacea, ginger, garlic, licorice, turmeric, peppermint, astragalus root, reishi mushrooms, blackseed oil, olive leaf, dandelion.

In a nod to the New Testament, some even recommend frankincense and myrrh.

Corey Basch, associate professor in the Department of Public Health at William Paterson University in Wayne, N.J., said that vitamins, minerals and other micronutrients are a needed element for maintaining health, including immune function.

But its not always clear for whom these supplements will work and under what circumstances.To Basch and others, that alone justifies the government clamping down on those thatmake a definitive statement about the a cure or treatment forCOVID-19.

They need to have competent scientific evidence that something works and no one has that, said Mitchell Katz, spokesman for the FTC.

Alternative health care providers say that doesnt mean they should be silenced. Thats where Dr. David Brownstein, who believes in the basic mission of the FDA and FTC, says the two agencies have gone too far.

Dr. David Brownstein, of West Bloomfield MI, a AARM member.(Photo: Steven M. Herppich)

A medical doctor who got interested in holistic medicine nearly 30 years ago when his father was suffering from heart disease, Brownstein said he found a new way of looking at health care less centered on medications than on treatments that support the immune system.

Brownstein said one of his patients gave him a book on nutrition, which led him to wean his father off nitroglycerin pills in favor of natural supplements. Within 30 days, he said, his fathers cholesterol fell from 300 to 200, his 20-year history of angina endedand his skin turned from pasty gray to pink.

That led Brownstein to seek out natural therapies for his patients, including an anti-viral strategy that he regularly turns to during flu season. The regimen involves high doses of vitamins A, C, D and iodine for four days, followed, if necessary, by nebulizer treatments of hydrogen peroxide and iodine, then intravenous treatments of hydrogen peroxide, vitamin C and ozone.

Brownstein said he used the same regimen every year for more than 20 yearsand on more than 100 COVID-19 patients during the outbreak in the Detroit suburbs in March and April.

Dr. Brownstein administering viral treatment to patients in April.(Photo: Courtesy)

My partners, nurses and I were going out to see patients in their cars in the parking lot in 30-degree weather in March, Brownstein said. We were giving them IVs in their cars, and as soon as we started treating them they got better. We saw 107 patients. Only one was hospitalized. No one died and no one had to be ventilated.

Instead of drawing praise, Brownstein said he got in trouble with the FTC for posting the results of his 107-person study on his website and including YouTube testimonials from patients who recovered. Brownstein said the FTC faulted his study because it wasnt randomized, meaning he had no untreated control group.

I just couldnt sleep at night if I did that, he said. How could I not have people receive a therapy that I thought could help them?

Dr. Brownstein administering to patients during the onset of the pandemic in April.(Photo: Courtesy)

Brownsteins study was peer-reviewed by three medical doctors and an academicand contained more than 90 citations to scholarly articles and texts. But the FTC still made him pull it off his website. The cost of doing that, he said, is that the general public and fellow doctors around the world didnt get the benefit of what he saw on the front lines of the crisis.

It sends a chill out that you cant report anything about COVID thats positive, Brownstein said. You cant report anything that doesnt fit the narrative that all you can do is wear a mask, social-distance and wait for a vaccine.

The pushback against the governments orders is that they represent an unnecessary overstep against alternative health companies that are doing no harmand may even be providing peace of mind at a difficult time.

Rosalee De la Foret, a best-selling author and herbalist, acknowledged that regulators had a legal right to cite her for mentioning the forbidden word "prevent" in promotional materials about herbal products. But she believes the FDA and FTC are too heavy-handed in applying the law.

Best selling author and herbalist Rosalee De la Foret(Photo: Courtesy)

De la Foret, who mentioned the benefits of an herb called astragalus in one of her articles, maintained that she was very careful to point out that the root was not a cure forCOVID-19 or anything else.

I was trying to be open and honest, De la Foret said. But they were saying that I was wink wink implying that the product could be used to cure the virus.

That interpretation, De la Foret said, prevents people from discussing remedies that might be useful.

Heaven forbid that something in nature might be more effective than a drug, agreedHansen, the Arizona naturopathic doctor.

Ralph Fucetola, a retired lawyer and co-trustee of the Natural Solutions Foundation, also echoed that sentiment.

This Deep State attack on good medicine is particularly outrageous because during a declared pandemic it is ethical, according to the (World Health Organization), to use even unapproved remedies that may offer help, Fucetola said in an article posted in April on OpenSourceTruth.com, a website that pushesback against the mass media. Once again, the Federal authorities are putting themselves squarely against common sense in order to maintain the fiction that the government is here to help.

Ralph Fucetola(Photo: Courtesy)

Fucetola told USA TODAY that theres a distinction between treatment ofa disease, which drug companies provide, and therapies that may benefit a patient, which alternative health companies offer.

Theyre trying to subject us to the treatment of disease standard, Fucetola said. People in the health freedom world, in the natural remedies world, are not trying to treat diseases, were trying to help people achieve a healthy status.

Fucetola said he still hopes to reach an understanding with the FDA and FTC regarding what can be said about Nano Silver, a nutrient he says supports a healthy immune system.

Like most other alternative health providers, he has taken down all allegedly offending documents from his website.Even Jones, the founder of Info Wars, has taken steps to comply.

But some letter recipients, including televangelist JimBakker, silver solution salesman Gordon Pederson non-religious church founder Mark Grenon,and investigative journalist Maryam Henein, are defiant.

Investigative journalist Maryam Henein, who edited the movie "Vanishing of the bees."(Photo: Courtesy)

Henein, who directed the filmVanishing of the Beesand foundedHoneyColony.com, a natural-remedies website, said she drew a warning letter by suggesting that the best coronavirus treatment is prevention and recommending that customers take chelated silver, vitamin C and magnesium.

I know in my heart I did not do anything wrong Henein told USA TODAY. The FDA and FTC are using the coronavirus to attack natural remedies. Theres a reason we call them the medical mafia.

So far, the FDA and FTC have ignored Henein because she made required changes to her website, but they went after Pedersen and Grenon when bothmen refused to play by the rules.

Sued in late April and accused of tryingto defraud consumers by claiming his liquid silver product will destroy all forms of viruses, Pedersen declined to accept any mail from the U.S. attorneys office andchose to represent himself as a sovereign citizen.

He declared that the court had no jurisdiction over him as a private living, flesh and blood man.

U.S.attorneys swiftly responded by persuading the court to impose a restraining order and then shut down Pedersons websites. That, in turn, persuaded Pedersens partners to push him out of his company and agree to reimburse any customers who believed they had been defrauded.

Grenon, who declined to talk to USA TODAY, deployed similar tactics, refusing to recognize the authority of the U.S. government over Genesis II Church of Health and Healing, which offered church members Miracle Mineral Solution a bleach-like substance as a sacrament, in return for donations.

Mark Grenon(Photo: YouTube)

He went further, too, threatening the government and the judge presiding over his case.

In July, law enforcement officials raided his familys headquarters and distribution facility in Bradenton, Florida. They arrested two of his sons, Jonathan and Jordan, who are still being held without bail. They seized cash and goldfrom the company safeand carted off all the companys computers, electronic equipment, files and documents. They also confiscated all raw materials used to make MMS.

Grenon, who was at his familys compound in Colombia at the time of the raid, said in a Youtube video interview with Henein that hes determined to face his accusers. He's certain he will prevail.

Experts say his legal position is not enviable. Its not a good idea to get in a fight with the FDA and the FTC, they say, no matter how righteous you think your cause.

Theyre like the IRS, said Caplan, the NYU medical ethics professor. Flout them, challenge them, dont cooperate and they come down hard.

Read or Share this story: https://www.usatoday.com/story/news/investigations/2020/09/03/government-coronavirus-crackdown-angers-alternative-health-providers/5660997002/

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'Were not your slaves': Alternative health providers bristle at warning letters about their coronavirus treatments - USA TODAY

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Neogene precipitation, vegetation, and elevation history of the Central Andean Plateau – Science Advances

Posted: at 1:55 am

Abstract

Andean uplift played a fundamental role in shaping South American climate and species distribution, but the relationship between the rise of the Andes, plant composition, and local climatic evolution is poorly known. We investigated the fossil record (pollen, leaves, and wood) from the Neogene of the Central Andean Plateau and documented the earliest evidence of a puna-like ecosystem in the Pliocene and a montane ecosystem without modern analogs in the Miocene. In contrast to regional climate model simulations, our climate inferences based on fossil data suggest wetter than modern precipitation conditions during the Pliocene, when the area was near modern elevations, and even wetter conditions during the Miocene, when the cordillera was around ~1700 meters above sea level. Our empirical data highlight the importance of the plant fossil record in studying past, present, and future climates and underscore the dynamic nature of high elevation ecosystems.

A major uncertainty in climate modeling is how future precipitation will change over the Central Andean Plateau (CAP) and Amazon Basin (1). While some model outputs suggest feedbacks that will lead to massive drying (2, 3), others suggest wetter-than-modern conditions (46). Ongoing changes in temperature and atmospheric CO2 concentration (pCO2) will, by the end of this century, provide similar conditions to those found in the late Miocene and early Pliocene (7). Between ca. 10 million years ago (Ma) (late Miocene) and 5 Ma (early Pliocene), the northernmost part of the CAP (NCAP) doubled in elevation (8, 9). Mechanistic models (e.g., RegCM3 and ECHAM) project that this uplift increased precipitation over the CAP, creating essentially modern climate patterns (Fig. 1) (5, 911). The CAP paleobotanical record provides physical evidence that can be used to reconstruct paleoprecipitation, providing elements for testing the validity of climate models of the geologic past and for refining predictions of future climates. Here, we provide both Miocene and Pliocene paleobotanical evidence to document the effects that uplift of the NCAP had on regional ecosystems and climates.

Geographic location of the CAP, summary of paleoprecipitation estimates from previous studies. (A) Topographic map showing the location of the CAP and the location of the Descanso-Yauri Basin (black triangle) in the Peruvian Andes. Gray triangles indicate the geographic location of sites from the modern palynological dataset and their environmental distribution (elevation and mean annual precipitation). m.a.s.l., meters above sea level. (B) Simulated precipitation based on the ECHAM model when the CAP had 100% (600 to 700 mm/year) and 40% (100 to 200 mm/year) of its current elevation [figure taken from (9)].

The modern NCAP sits at ~4000 m of elevation and has a mean annual temperature (MAT) ~8 to 9C and a mean annual precipitation (MAP) ~500 to 800 mm. The CAP is characterized by cold and strong winds throughout the year, and it experiences extreme diurnal and nocturnal temperature changes reaching up to 30C (12). Most precipitation in the CAP falls during the austral summer as a result of easterly winds bringing moisture from the Atlantic Ocean via Amazonia (13). The modern high-elevation vegetation types of the NCAP are grasslands and shrublands, known locally as puna.

Here, we studied the Neogene paleobotanical record from the NCAP (Fig. 1) aiming to (i) estimate regional paleoelevation and paleoprecipitation and (ii) reconstruct its paleovegetation. The plant fossil material was collected in the Descanso Formation, Descanso-Yauri Basin, southern Peru. This basin has an approximate area of 2000 km2. We studied two members (or lithostratigraphic units) from the Descanso Formation that were previously dated using radiometric methods: Member B, dated to ca. 18.7 to 9.1 Ma (middle to late Miocene) (8, 14), and Member C, dated to ca. 4.8 to 3.9 Ma [Fig. 2; early Pliocene; (8)]. Exposed along most of the basin, Member B is the thickest unit of the Descanso Formation and was deposited in a braided-river environment (8). There is an angular unconformity (time gap) between members B and C of approximately 4 Ma during which an uplift of ca. 2500 m has been inferred on the basis of isotopic data (8). Member C is a thin unit deposited in a fluvial-lacustrine system at a similar elevation as it is found today (8, 15).

(A) Geologic map for the Descanso-Yauri Basin, showing where the samples were collected [modified from (8)]. (B) Stratigraphic column for El Descanso Formation, including members A, B, and C [modified from (8)]. Bars next to the samples correspond to the uncertainty in the stratigraphic depth for the sample or group of samples. Undulating line represents the unconformity between members B and C. (C) Photographs of some of the macro- and microfossils collected for this study. From top to bottom: Fossil log with 7 m of length, legume fossil wood anatomy (scale bar, 1 mm), Ribes sp. leaf (scale bar, 10 mm), and Podocarpus sp. pollen (scale bar, 10 m). Photo credits: First and second rows: C. Martnez, Cornell University and Smithsonian Tropical Research Institute (STRI); third row: A. Aliaga, Museo de Historia Natural de Lima; fourth row: J. E. Moreno, STRI.

The plant fossil record from the Descanso-Yauri Basin studied here included palynological (pollen and spores) and macrofossil samples (permineralized wood and compressions and impressions of leaves and fruits) of Neogene age (Fig. 2). The age of the fossiliferous localities was determined using previously published stratigraphic information (8), together with new zircon U-Pb geochronologic analyses of two tuff samples from the Member B that yielded ages of 10.03 0.16/0.18 Ma and 12.07 0.73/0.74 Ma (fig. S1 and the Supplementary Materials). A total of 187 paleobotanical samples were collected from 88 localities from members B and C. Seventy-five palynological samples were analyzed, containing 168 palynomorph taxa in 5389 individual occurrences (table S1 and the Supplementary Materials for raw counts). From those, 154 palynomorphs were described (see the Supplementary Materials for descriptions and plates for each palynomorph). Thirteen samples of permineralized wood were assigned to four morphotypes. Ninety-nine samples consisted of macrofossil compressions and impressions of leaves and fruits and were assigned to eight morphotypes (see the Supplementary Materials for descriptions and plates for each macrofossil morphotype).

Wood samples were preserved as silica permineralizations and were only found at the top of Member B (Fig. 2). Eight specimens had taxonomic affinities with Fabaceae and one with the fossil genus Anacardioxylon (Anacardiaceae). Within Fabaceae, two samples were identified within the Tribe Ingeae, five samples within the mimosoid clade, and one as the fossil genus Andiroxylon sp. (see the Supplementary Materials). Tree height was estimated for the Andiroxylon sp. sample based on its diameter, and estimates ranged from 29.8 to 34.6 m. In tropical high-elevation ecosystems, plant growth is dependent on the number of hours of freezing per day (16). A correlation between tree height and elevation across six modern Andean elevation transects shows that trees taller than 30 m are not found above ~1100 m of elevation in the Andean region (17). Nevertheless, assuming that plants shift their distribution upward when the temperature increases (18), a temperature correction for the late Miocene would produce higher estimates. On the basis of these observations, we infer that trees of the size found in Member B would not be found above ~1750 m during the late Miocene. This provides a maximum likely paleoelevation for Member B at the time of deposition.

The traits of woody plants found in Member B are consistent with a warm and wet setting. All wood samples had simple perforation plates. Twelve of the 13 samples collected had diffuse porous wood and nondistinct growth rings. Six of the seven samples identified had large vessel diameters (>150 and up to 270 m) and high proportions of axial parenchyma cells. Diffuse porosity, nondistinct growth rings, vessels of large diameter, simple perforation plates, and a large proportion of axial parenchyma cells were dominant wood anatomical characters in our fossil assemblage. That combination of characters is commonly found in trees of large size, having lowland affinities, and growing in sites with high MAP regimes and low seasonality (19, 20).

Leaves were found in both members; Member B only had palm leaf fragments (Arecaceae), whereas Member C had leaves with taxonomic affinities to five genera and one family that are today present in the Puna: Ribes (Grossulariaceae), Berberis (Berberidaceae), Polylepis (Rosaceae), Polystichum (Dryopteridaceae), Equisetum (Equisetaceae), and Juncaceae (see the Supplementary Materials for descriptions and photographs of each morphotype). The palynological record shows that the floristic composition of Member B is dominated (>50 counts) by the families: Podocarpaceae, Cyatheaceae, Polygonaceae, Poaceae, Polypodiaceae, Chenopodiaceae, Chloranthaceae, Malvaceae, Asteraceae, Lycopodiceae, Araceae, Solanaceae and Caryophyllaceae, while Member C is dominated by Poaceae and Cyatheaceae (table S3). Studies across modern Andean transects have shown that altitudinal vegetation gradients are accurately reflected by modern pollen rain data and thus that fossil palynological assemblages can be used to reconstruct aspects of past Andean ecosystems (21).

Taking the sum of the paleobotanical data, we developed a new quantitative coexistence analysis to reconstruct paleoprecipitation and paleoelevation. This coexistence analysis uses climate and elevation information associated with the nearest living relatives of the identified palynomorphs and macrofossil taxa to estimate a mutual climate and altitudinal range (table S3). Although climate tolerances of species could have shifted since the Miocene, no substantial changes seem likely to have occurred given physiological uniformitarianism (22). Two distribution datasets (palynological and macrofossil) were described through bivariate probability density distributions of modern taxon occurrence along elevation and precipitation gradients. Global temperatures during both, middle to late Miocene and early Pliocene times, were warmer than preindustrial temperatures. Therefore, we performed a correction of temperature estimates that resulted in average displacements of the elevation by ~650 and 440 m for members B and C, respectively, using modern lapse rate for the Central Andes (fig. S3) (23). Each distribution dataset (palynological and macrofossil) was first analyzed independently, and later after a mixture sensitivity analysis was applied (fig. S4), final estimations were weighted equally for precipitation and for the elevation of Member C (1 = 2 = 0.5). However, an unequal weight was assigned for elevation estimates for Member B due to the high sensitivity found in our analysis depending on the dataset used (1 = 0.615). For Member B, the median elevation based on the mixture model (palynological and macrofossil data) was 1636 m (interquartile range, 971 to 2850 m), whereas for Member C, the median estimated elevation was 3780 m (interquartile range, 3340 to 4140 m). These corrected elevation estimates are congruent with previous paleoelevation estimates based on isotopic data for the NCAP (fig. S5) (8). Median annual precipitation for Member B based on the mixture model was 1671 mm/year. (interquartile range, 1265 to 2077 mm/year), whereas for Member C, it was 862 mm/year (interquartile range, 620 to 1121 mm/year; Fig. 3). These estimates of environmental space show a trend that progressed in time toward ascending elevation and decreasing precipitation (Fig. 3). An additional comparison with environmental space from Holocene records from the CAP shows that changes in the environmental space from Miocene to Pliocene were much greater than those transitioning from Pliocene to Holocene (Fig. 3). It is worth noting that nonanalog assemblages can still be used to provide quantitative paleoclimate reconstructions. Analogs rely on the co-occurrence of species in their realized niche space, but the fundamental niche (sensu Hutchinson, 1957) (24) of species is broader than their observed realized niche. By using the range tolerance of the genera, probabilities can be generated for overlapping environmental characteristics, even if the genera do not co-occur today (25).

Estimated environmental space for the middle to late Miocene (Member B; gray), the early Pliocene (Member C; red), and the Holocene (blue) at Descanso-Yauri Basin, showing probability density functions for precipitation (right) and elevation (bottom). These estimations are based on a mixture of micro- and macrofossil sets.

Our reconstructions for the middle to late Miocene indicate that when the southern Peruvian Andes were at half of their modern elevation (~1600 m), MAP was about three times higher (~1700 mm/year) than today. In contrast, regional climate models (ECHAM, GENESIS, PLASIM, and RegCM3) predict that half-modern CAP elevations would lead to much-drier-than-modern conditions (3, 5, 10, 11, 26, 27). For example, the global ECHAM model indicates that when the Andes were at 40% of their modern elevation, MAP was 100 to 200 mm, or about ~80% drier than today (Fig. 1B) (9). Previous paleobotanical studies also suggest that, during the middle to late Miocene, the CAP had a paleoelevation between 1200 and 2000 m, a MAT of ~20 to 22C, and a MAP ranging from 550 to 1500 mm (fig. S5) (28, 29). Although other MAP estimates based on paleobotanical data from other CAP localities suggest lower precipitation ranges for the Miocene (30, 31), these values are never lower than modern records. The incongruence between the paleobotanical evidence from the middle to late Miocene and climate models for the CAP is a major question that needs to be addressed to predict the impact of future climate change in South America.

Our early Pliocene reconstructions indicate that, around 4.8 Ma, the NCAP had already attained near-modern elevations (~3800 m) and had a MAP slightly higher than modern (~850 mm). This higher-than-modern MAP is also supported by the fossil lacustrine biota (diatoms and ostracods) (15), stratigraphic (15), and isotopic data (8, 32). Given that ferns have higher water requirements than angiosperms (33), the high proportion of fern taxa present in Member C of the Descanso Basin compared with the modern puna (fig. S6B) offers additional evidence to support the high MAP estimations for the early Pliocene. The time spanned by Member C overlaps with the early Pliocene warm period (4.6 to 3.1 Ma). Our inferred wetter conditions for the NCAP during the early Pliocene contradict some global climate models that report permanent El Niolike conditions during the early Pliocene warm periodwhich implies lower-than-modern precipitation for the CAP(34, 35). However, whether these wetter conditions correspond to a large scale or a permanent state for the Altiplano during the Pliocene is unknown as numerous high-magnitude regional sea surface temperature (SST) excursions (36) and short-term climate perturbations (37) have also been reported for the Pliocene.

Separately, when comparing Pleistocene with Pliocene climate data, evidence from Pleistocene cores in the Altiplano suggest that glacial (interglacial) periods were wetter (drier) than modern (3840). Considering that SSTs for the Peru margin show that the early Pliocene was 3.3C warmer than the late Pleistocene (36) and that the elevation of the CAP has not changed substantially since the early Pliocene, paleoprecipitation would be expected to follow the interglacial pattern with drier regional conditions. However, our wetter CAP estimates for the early Pliocene suggest that this time period does not represent an extended interglacial period.

To address the similarities of paleofloras in members B and C to modern ecosystems, we used the Chaos dissimilarity index (CDI). We first calculate CDI for all extant sites in four elevation ranges (lowlands, lower montane, upper montane, and puna) to estimate the overall heterogeneity of the ecosystem, and then we compared the extant sites with the fossil palynological record from each member (Table 1). For Member B, the median CDI between palynoflora and extant lower montane sites was 0.8. This value is considerably higher than the median CDI of 0.3 obtained by all pairs of extant lower montane modern sites, suggesting high dissimilarity (Fig. 4A and Table 1). The median CDI between the Member B palynoflora and all extant upper montane sites was 0.7. This value differs substantially from the median CDI of 0.17 obtained by all pairs of extant upper montane modern sites, also suggesting high dissimilarity (Fig. 4B and Table 1). Thus, our results suggest that the palynoflora of Member B is not similar to extant Andean montane sites. This Miocene palynoflora is composed of common montane forest indicators such as Podocarpus, Hedyosmum, Bocconia, Mutisia, and Cyatheaceae, as well as higher elevation taxa such as Calamagrostis, Polylepis, and Valeriana. However, the oddity of this flora is emphasized by the co-occurrence of plants with traits of lowland ecosystems (e.g., 30-m legume trees and palms). Therefore, we propose that the Member B paleoflora does not have a modern analog and that it was more heterogeneous than modern montane ecosystems.

Floristic comparison of pollen records from members B and C and modern pollen records from sites located along the Central and Northern Andes (Fig. 1A). The altitudinal gradient includes sites from lowland, lower montane, upper montane, and puna ecosystems. The comparison was done using the CDI (0 = least dissimilar; 1 = most dissimilar).

Comparison of palynofloras from members B and C with extant pollen data from South America. The density plots show the probability distribution of the CDI (0 = least dissimilar; 1 = most dissimilar). Green curves represent CDI for within-biome comparison for modern altitudinal ranges (lower montane, upper montane, and puna). (A) Comparison for lower montane sites: Gray curve represents CDI between the fossil assemblage from the Miocene Member B and the modern lower montane sites. (B) Comparison for upper montane sites: Gray curve represents CDI between the fossil assemblage from the Miocene Member B and the modern upper montane sites. (C) Comparison for puna sites: Red curve represents CDI between the fossil assemblage from the Pliocene Member C and the modern puna sites.

For Member C, the median CDI between the palynoflora and all extant sites from the Puna was 0.2. This value was similar to the mean CDI of 0.16 obtained by all pairs of puna modern sites, suggesting low dissimilarity (Fig. 4C and Table 1). The macrofossil record of Member C also indicates a puna biome by the combined presence of Polylepis, Berberis, Ribes, and Polystichum. The Member C flora, therefore, represents the earliest record of the Puna, appearing shortly after the landscape is inferred to have reached near-modern elevations. This early puna differs from the modern puna by having a higher diversity and abundance of ferns (fig. S6B).

Late Miocene uplift shaped modern ecology: The rise of the Tibetan Plateau gave rise to the Asiatic monsoon system (41), while the uplift of the Andes created the South American Summer Monsoon (6). Moisture-laden winds flowing across Amazonia started to be deflected southward by the rising Andes between the Miocene and the Pliocene, drying out the highlands. This Andean uplift created new Neotropical niches for highland and dryland (Peruvian coastal rain shadow) species, while markedly reducing the area available to mid-montane species. Our data indicate that there would also have been a substantial reduction in potential biomass as forests supporting large trees were replaced by grasslands. The fact that current climate models underestimate Miocene precipitation so severely leads to underestimates of carbon storage and overestimates of the grasslands available to Miocene megafauna. Capturing the topographic effects of the Andes on atmospheric circulation accurately is essential to modeling both past and future climate change.

The coexistence approach proposed here offers a novel way to analyze macrofossil and palynological data and improves reconstructions of past climates and ecosystems. Our paleoelevation estimations calculated on the basis of the Neogene plant fossil record of the NCAP support evidence from previous studies based on isotopic data (8, 9) that proposed rapid surface uplift of approximately 2500 m in elevation between ~9.1 and 4.8 Ma. In contrast, our paleoprecipitation estimations strongly differ from those predicted by regional and global precipitation simulations for the Miocene and Pliocene [e.g., (3, 5, 29, 38)], revealing a marked precipitation decrease over the NCAP with the Andean uplift. Understanding the origin of these discrepancies can help reveal the driving forces controlling the climate of the Altiplano and ultimately the overall climate of South America. The uplift of the CAP shaped the biome distribution and climate of the region: Our reconstructions of a montane forest ecosystem without modern analogs in the Miocene and of a puna-like ecosystem in the early Pliocene highlight the dynamic nature of high elevation ecosystems and how these can change and evolve as a response to extreme modifications in elevation and climate.

Fieldwork. The Descanso-Yauri Basin, southern Peru, was explored during three field trips done during the dry season of years 2014, 2015, and 2016. We collected as many samples as possible during those field trips. All the samples were collected from members B and C. During the collection process, we kept a stratigraphic control by visiting the localities previously described by Kar et al. (8) and then by correlating stratigraphically the new localities found. We collected palynological samples, tuffs, and compressions and impressions of fossil leaves and fertile parts and permineralized wood. To correlate stratigraphically two of the new localities, we used radiometric dating of volcanic horizons (tuffs) present near the fossiliferous region.

Zircon U-Pb geochronology methods. Two tuff samples with abundant pumaceous fragments were collected to correlate two wood localities of the Colpamayo and San Miguel regions using U-Pb geochronology (Fig. 2). The sample from the Colpamayo region (STRI-MUSM 44449) was collected from a 60-cm conglomerate rich in pumaceous fragments, and the sample from the San Miguel region (STRI-MUSM 44448) was collected from a 50-cm-thick ashfall tuff. Zircon separates were performed by standard magnetic and gravity-based methods at the University of Rochester using a Frantz LB-1 separator and methylene iodide. Before U-Pb analysis by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), zircons were mounted in 1 epoxy plugs and characterized by cathodoluminescence (CL) imaging using a JEOL JSM-7100 electron microscope equipped with a field-emission gun and a Deben Centaurus CL detector at the Mackay Microbeam Laboratory, University of Nevada, Reno. All U-Pb isotopic measurements were performed by LA-ICP-MS at the Arizona Laserchron Center, University of Arizona using a Photon Machines Analyte-G2 Excimer laser system coupled to a Thermo Finnigan Element2 single collector ICP-MS. Analytical methods for the U-Pb analyses are outlined in Ibez-Mejia et al. (42) and Pullen et al. (43) (see the Supplementary Materials for detailed methods and reference material).

Palynological data. Palynological sample preparation included digestion of 10 g of rock in hydrochloric acid for 12 hours, addition of water, and decantation after 12 hours, followed by digestion in hydrofluoric acid for at least 24 hours, addition of water, and decantation of the acid solution after 24 hours. Sieving of the dissolved mineral fraction was initially done with a 250-m mesh to eliminate the thick fraction, followed by sieving through to 10-m mesh. Panning of the >10-m fraction was done in an ultrasonic equipment for recovery of the less dense organic matter fraction. This residue was cleaned in the ultrasonic equipment for some seconds, and the organic residue was concentrated by centrifugation, followed by mounting of a first cover slide in a solution of polyvinyl alcohol. Mounting of a second cover slide was done after oxidation with nitric acid, sealing with Canada balsam. Samples were processed at the laboratory of Paleoflora, Bucaramanga, Colombia. Palynomorphs were counted aiming for a minimum of 300 specimens per slide. Transects of all slides were made at 40 magnification using an Olympus BH-2 binocular scope to identify all pollen types. Bright-field microphotographs were obtained at 100 magnification using a Pixera Camera System attached to the Olympus scope.

All the taxonomic affinities proposed for the palynomorphs are reported in alphabetical order by family and then by genus (file S5). The proposed botanical affinities at the family, genus, and species level were proposed by comparing the fossil taxa with pollen atlases of extant taxa of the region and the pollen reference collection of A. Graham at the Center for Tropical Paleoecology and Archaeology, from the Smithsonian Tropical Research Institute, Panama (see the Supplementary Materials for reference material). The taxonomic status of botanical names was updated consulting the Tropicos database. Some associated organisms and those undetermined palynomorphs are included as assemblage of possible indicators of environmental conditions.

Macrofossil data. Macrofossil compressions and impressions were studied at the Paleontological Collection of the Museo de Historia Natural de la Universidad Nacional Mayor de San Marcos, Lima, Peru (DPV-MHN-UNMSM). Sediment was carefully removed using an air scriber to expose possible attachments and the maximum number of features. Specimens were observed using a Leica EZ4 HD coupled to an integrated camera of 5.0-megapixel with a complementary metal-oxide semiconductor sensor. Photographs were taken with varied low-angle light. Each leaf morphotype was described following the terminology of the Manual of Leaf Architecture (44). Comparisons with extant taxa were made with herbarium material from the San Marcos Herbarium (MHN-UNMSM, Lima, Peru), and virtual collections were accessed through the JSTOR Global Plants database and literature.

Permineralized wood was initially cut with diamond saws at the Museum of Natural History of Universidad de San Marcos of Lima (MUSM). Thin sections were prepared following the standard techniques described in detail by Boonchai (45). The anatomy of the samples was described following the International Association of Wood Anatomists (IAWA) list of microscopic features for hardwood identification (46). Preliminary comparisons with modern and fossil wood were done using the InsideWood database (47), and additional comparisons were done on the basis of literature.

Using linear regression models that account for the allometric relation between stem diameter and tree height in modern trees, we estimated the approximate height of one complete fossil sample (48, 49). Four different regression models were used for the calculation, one that uses a global dataset (48), while the other three used large tropical datasets from west Amazonia, tropical South America, and the pantropical region (49).

Macrofossil compressions and impressions and permineralized wood were organized and described by morphotypes following the method described by Peppe et al. (50). Each morphotype has a three-letter prefix (DSB or DSC) based on the name of the formation and the member from which they belong to, plus a number starting from one. A systematic affinity was proposed for each morphotype. Species names were not proposed for any of the morphotypes described because this required extensive research into the nomenclature of the taxon, previous fossil descriptions, and phylogenetic relationships (50), which were topics out of the scope of this paper.

A new coexistence method was developed here to estimate paleoelevation and paleoprecipitation using the macrofossil and palynological data collected in this study. Climate and elevation information associated with the nearest living relatives of the identified palynomorphs and macrofossil taxa was used to estimate a mutual climate and altitudinal range. Two distribution datasets (palynological and macrofossil) were described through bivariate probability density distributions of modern taxon occurrence both of our variables of interest.

Given that palynological counts were uneven because of differential preservation of samples and also aiming to make palynology and macrofossil estimates comparable, palynological relative abundance was not considered representative of environmental conditions, and the dataset was therefore transformed to presence-absence. Palynological samples were filtered to consider only samples that met the following criteria: (i) The sample was composed of taxa that were represented in the modern pollen and spore dataset, (ii) at least three taxa were represented in the sample, and (iii) at least one of the taxa present in the sample was identified at the genus level. For macrofossil material, taxonomic identifications at the family and genus level were used for the paleoclimatic analysis, and in instances of taxonomic uncertainty in the identifications, the probability density distributions were based on the modern distribution of multiple taxa that were phylogenetically related.

The distribution of taxa found in the fossil datasets (palynology and macrofossils) was described through bivariate probability density distributions (PDD) of modern taxon occurrence along elevation and precipitation gradients. These distributions were described through a bivariate Gaussian kernel density estimator (51) defined byf(x;H)=1ni=1nKH(xXi)where f(x;H) defines the probability density at a point x = (x1, x2)T; Xi = (Xi1, Xi2)T is the vector of realizations at points i = 1,2, , n, for variables X1 (elevation) and X2 (precipitation).

H=|h100h2| is a matrix of bandwidths; in our case, h1 = h2 = 250.

K(x)=12e12xTx is the Gaussian kernel smoother.

Georeferenced occurrences of the nearest living relatives of both palynological and macrofossil records were extracted from the BIEN R package (52) and were described in terms of the elevation and MAP at the occurrence points (data from WordClim) (53). Thus, two reference libraries of bivariate environmental distributions were built: one for palynology (PDFpaly) and one for macrofossils (PDFmacro). In instances of taxonomic uncertainty in the identification of macrofossils, PDFmacro was based on the modern distribution of multiple taxa that were phylogenetically related. The paleoenvironmental reconstruction for a given fossil palynology sample consisted of PDFfossil palyj derived from a nonweighted finite mixture (54) of the modern PDFpaly of sj pollen and spore taxa present in the fossil sample j. Individual sample estimates from the same stratigraphic member (T) were, in turn, mixed to obtain a PDFTPDFfossil palyj=k=1sjPDFpalykleadsPDFT=j=1nTPDFfossil palyjwhere PDFfossil palyj is the probability density function (PDF) of sample j composed of sj pollen taxa; PDFpalyk is the PDF of modern pollen taxon k with k = 1,2, , s.; PDFT is the PDF of stratigraphic member T, represented by nT samples.

The paleoenvironmental reconstruction based on macrofossils consisted of a single PDF for each stratigraphic member (PDFmacroB and PDFmacroC), as followsPDFmacro=i=1sPDFmacrokwhere PDFmacrok is the PDF of modern pollen taxon k with k = 1,2, , s. PDFpaly and PDFmacro of each sample represent the probability distribution of data pairs of precipitation and elevation conditioned to the presence of a given set of taxa s. The credible environmental area within each PDF was obtained by trimming the margins of the bivariate surface, keeping the area of the distribution associated with a cumulative probability higher than 0.5. On the basis of the probability densities of this area, the marginal distribution of elevation and precipitation for each sample was extracted, obtaining one macrofossil-based marginal distribution per variable per stratigraphic member and nB and nC palynology-based marginal distributions per variable. For summarizing palynology-based estimates, marginal distributions were subsequently mixed.

Marginal distributions of elevation estimates based on palynology and macrofossils were corrected taking into account the global temperature within the estimated age range for each stratigraphic member between 12.87 and 8.4 Ma for Member B and 5.3 and 4.3 Ma for Member C, global temperature anomaly data from Hansen et al. (55). Observed global temperature anomalies within the time period of each stratigraphic member were randomly sampled, converted to elevation using a lapse rate of 0.6C (56), and added to our estimates (global temperature was warmer).

Final estimates of both elevation and precipitation per stratigraphic member resulted from mixing palynology- and macrofossil-based marginal distributions. Modern estimates were based on mixing palynology-based, cross-validated estimates with distributions of modern climatic data (this latter step was necessary because of the lack of macrofossils for the Holocene). Such mixture resulted from an addition of individual densities weighted by a proportion factor, as followsMDparameter=1*MDpaly+2*MDmacrowhere MDparameter is the marginal distribution of temperature or precipitation; MDpaly is the pollen-based marginal distribution of temperature or precipitation; MDmacro is the macrofossil-based marginal distribution of temperature or precipitation; 1 and 2 are the representation factors for palynology and macrofossil data, respectively, with 1 + 2 = 1.

This mixture model was developed to evaluate the proportion or weight that each proxy (palynological versus macrofossil) should be given to better estimate paleoclimatic conditions because this information was unknown from the literature. 1 was set to vary from zero (estimation based exclusively on macrofossils) to one (estimation based exclusively on palynology) aiming to evaluate the stability of estimates. When estimates varied monotonically with , we selected a solution based on a completely proportional mixture (i.e., 2= 1= 0.5), whereas when the estimation was notoriously affected by the selection of , the inflection point was preferred. The environmental space for each time period was represented as the conjunction of the interquartile range of elevation and precipitation.

Fossil palynological data from members B and C were used for a comparison with modern pollen data. The modern pollen dataset consisted of palynological counts grouped by family from South American sites that span an elevation gradient from 100 to 4700 m. We used the CDI (57) to estimate similarities between modern data and modern versus fossil palynological data. The parameters used to estimate the CDI here were the asymmetric Sorensen-type using probability estimations and taxa abundance data. This analysis was implemented in R using the CommEcol package (58).

Because the modern pollen dataset did not include spore counts, we also did a comparison of the proportion of angiosperms and ferns present in the palynological record from Member C and modern data from the Global Biodiversity Information Facility (59) using relative abundances. Modern data were extracted from a polygon that included the Altiplano region and the eastern and western flanks of the Andes. The polygon was between 17 and 11 of latitude and 74 and 69 of longitude. Within the analysis, a quaternary sample that was collected in the Espinar region was also included in the comparison. Last, the inferred habit from the taxa represented in the fossil palynological samples was also compared to evaluate changes in the ecosystems.

Acknowledgments: We thank R. Salas-Gismondi, J. Tejada, and M. Arakaki for providing help in the field and space at the Museum of Natural History of Lima, Peru; G. Umasi for valuable help in the field and the Espinar community for welcoming us; D. Caballero for help with a palynological analysis; N. Jud for helpful discussions about the wood samples; T. Jordan, M. A. Gandolfo, and K. Nixon for providing guidance and reviewing the manuscript multiple times; N. Kar for providing geological information for the region; J. Houston for providing photo rights for the cover photo; and C. Hoorn and an anonymous reviewer for insightful comments on this manuscript. Funding: C.M. thanks the Fulbright-Colciencias Doctoral Fellowship, from Colombia; the College of Agriculture and Life Sciences, the Plant Biology Section, the Harold E. Moore, Jr. Memorial and Endowment Funds, and the Cornell Graduate School Research Travel Grant, Cornell University, USA, for providing facilities, travel and research support. C.J. was funded by the Smithsonian Institution, the National Geographic Society (NGS 2014 9537-14), the Anders Foundation, the 1923 Fund, and the Gregory D. and Jennifer Walston Johnson. A.C.-M. was supported by Programa de Apoyos para la Superacin del Personal Acadmico de la UNAM (PASPA, DGAPA). M.I.-M. acknowledges funding by NSF-EAR 1926124. Author contributions: C.M. and C.J. led the writing and had significant contributions from W.C., M.B.B., and M.I.-M. C.M., and C.J., designed the study and organized and conducted fieldwork. W.C. contributed to project design. A.C.-M. and C.M. contributed to the paleoprecipitation and paleoelevation analyses. C.M. described and analyzed wood fossil samples. J.E.M. and C.J. contributed to palynological analyses. F.M., C.J., and C.M. contributed to the stratigraphic analyses and fieldwork. A.A. and C.M. prepared and described the leaf macrofossils. M.I.-M. and F.M. conducted the zircon U-Pb geochronologic analyses. M.B., A.C.-M., C.M., and C.J. contributed to the comparison with modern pollen. C.J and C.M. provided financial support. All authors contributed to the manuscript and figure preparation. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested to the authors.

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Research Roundup: Lasting Immunity to COVID-19 and More – BioSpace

Posted: August 21, 2020 at 8:57 pm

Every week there are numerous scientific studies published. Heres a look at some of the more interesting ones.

Multiple Studies Suggest Lasting Immunity to COVID-19 After Infection

Although probably not enough time has passed to know definitively, several studies are now suggesting that even mild cases of COVID-19 stimulate lasting immune responses, not only in disease-fighting antibodies, but in B- and T-cells.

Things are really working as theyre supposed to, Deepta Bhattacharya, an immunologist at the University of Arizona, and an author of one of the studies, told The New York Times.

Its difficult, probably impossible, to predict how long those immune responses will last, but many of the researchers believe the results are promising for long-term protection.

This is exactly what you would hope for, Marion Pepper, an immunologist at the University of Washington and an author of a study currently being reviewed by the journal Nature. All the pieces are there to have a totally protective immune response.

Pepper notes that the protective effects cant be completely evaluated until there is proof that people exposed to the virus a second time can fight it off. But the data suggests the immune system is indeed able to fight resistance a second time. Some of this qualification comes from unconfirmed reports of people being reinfected by the virus.

Antibody responses are typically relatively short-lived, disappearing from the blood weeks or months after being produced. Generally, the majority of the B-cells that produce antibodies die off, too. But the body keeps some longer-lived B-cells that are able to manufacture virus-fighting antibodies should the immune system be triggered by re-exposure to the virus. Some stay in the bloodstream while others wait in the bone marrow where they manufacture small numbers of antibodies that can sometimes be observed years, even decades later. Several studies, some by Bhattacharya and Pepper, have identified antibodies at low levels in the blood months after people recovered from COVID-19.

The antibodies decline, but they settle in what looks like a stable nadir, Bhattacharya said. These have been observed about three months after symptoms show up. The response looks perfectly durable.

Additional studies, including one published in the journal Cell, have isolated T-cells from recovered patients that can attack SARS-CoV-2. In laboratory studies, the T-cells produced signals to fight the virus and cloned themselves in large numbers to fight the potential infection.

This is very promising, said Smita Iyer, an immunologist at the University of California, Davis, who was not involved in the new studies, but has researched immune responses to the novel coronavirus in rhesus macaques. This calls for some optimism about herd immunity, and potentially a vaccine.

It's still has not been definitely determined if milder cases of COVID-19 will lead to long-term or even medium-term immunity. There have been some studies that suggest it does not and some newer studies suggesting it does. Iyer notes that the recent paper indicates, You can still get durable immunity without suffering the consequences of infection.

This idea is reinforced by Eun-Hyung Lee, an immunologist at Emory University who was not involved in these studies. He told The New York Times, Yes, you do develop immunity to this virus, and good immunity to this virus. Thats the message we want to get out there.

Why Seasonal Flu Vaccines Only Last a Year

As most everyone knows, flu vaccines only last about a year. Some of this is related to viral mutations. But in fact, the actual immunity itself caused by the vaccine does not appear to last longer than a year, even though the flu vaccine increases the number of antibody-producing cells specific for the flu in the bone marrow. Researchers out of Emory Vaccine Center found that for most newly-generated plasma cell lineages, between 70 and 99% of the cells were gone after one year, but that the levels of antibody-secreting cells in blood correlated with long-term response in the bone marrow.

Gut Bacteria Can Help Immuno-Oncology Therapies

Researchers with the University of Calgary identified gut bacteria that help our immune system fight cancerous tumors. This also helped provide more information about why immunotherapy works in some cases, but not others. By combining immunotherapy with specific microbial therapy, they believe they can help the immune system and immunotherapy be more effective in treating three types of cancer: melanoma, bladder and colorectal cancers. They found that specific bacteria were essential for immunotherapy to work in colorectal cancer tumors in germ-free mice. The bacteria produced a small molecule called inosine that interacts directly with T-cells and together with immunotherapy.

An Online Calculator to Predict Stroke Risk

Scientists at the University of Virginia Health System developed an online tool that measures the severity of a patients metabolic syndrome, a mix of conditions that includes high blood pressure, abnormal cholesterol levels and excess body fat. With it, they can then predict the patients risk for ischemic stroke. The study discovered that stroke risk increased consistently with metabolic syndrome severity even in patients that did not have diabetes. The tool is available for free at https://metscalc.org/.

A Link Between Autism and Cholesterol

Researchers at Harvard Medical School, Massachusetts Institute of Technology (MIT) and Northwestern University identified a subtype of autism that is the result of a cluster of genes that regulate cholesterol metabolism and brain development. They believe this information can help design precision-targeted therapies for this specific type of autism and improve screening efforts for earlier diagnosis of autism. They analyzed the DNA from brain samples that they then confirmed with the medical records of autistic individuals. They found that children with autism and their parents had significant alterations in lipid blood. However, there is much more to be understood, emphasizing the complexity of autism, which is affected by a variety of genetic and environmental factors.

Researchers Grow First Functioning Mini Human Heart Model

Investigators with Michigan State University grew the first miniature human heart model in the laboratory that is complete with all primary heart cell types and a functioning structure of chambers and vascular tissue. They utilized induced pluripotent stem cells which were obtained from consenting adults and created a functional mini heart in a few weeks. The primary value was in giving them an unprecedented view into how a fetal heart develops.

In the lab, we are currently using heart organoids to model congenital heart diseasethe most common birth defect in humans affecting nearly 1% of the newborn population, said Aitor Aguirre, senior author and assistant professor of biomedical engineering at MSUs Institute for Quantitative Health Science and Engineering. With our heart organoids, we can study the origin of congenital heart disease and find ways to stop it.

Another area of focus is that improving on the final organoid will help with future research. Current heart organoids are not identical yet to human hearts and so are flawed in their use as research models.

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Research Roundup: Lasting Immunity to COVID-19 and More - BioSpace

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What in the world is ‘Project Carpaccio’ and which Israeli company is doing business in Abu Dhabi? – CTech

Posted: at 8:57 pm

Employee surveillance tools emerge as a serious side effect of Covid-19. Dystopian products that track workers' every move have become hot commodities for managers who had to transition to supervise remote teams. Read more

Israeli-based Pluristem and Abu Dhabi Stem Cells Center sign deal to collaborate in development of cell therapies. Agreement comes just days after Israel and the United Arab Emirates (UAE) announce intention to fully normalize diplomatic relations. Read more

Israel-based Fintica extends R&D collaboration with Nikko Global Wrap after a successful trial. Fintica, a spinoff of Cortica, leverages next-generation AI to understand volatile market and steer investment decisions. Read more

The '5 Key Forces shaping the future of organizations, according to CEO of freelance workforce tool Stoke Talent. Freelancing, Millennials, and Remote Working: everything shaping the future of organizations after Covid-19. Read more

Opinion | Predictive analytics takes center stage in the fight against Covid-19 and the critically ill. Clew Medical's Gal Salomon discusses Covid-19 and how the pandemic has revealed vulnerabilities in healthcare systems around the world. Read more

First-ever AI-based autonomous traffic management platform unveiled in Phoenix, Arizona, thanks to Israeli-founded company. NoTraffic uses its AI to optimize traffic management systems and improve traffic flow in urban areas. Read more

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What in the world is 'Project Carpaccio' and which Israeli company is doing business in Abu Dhabi? - CTech

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Viruses have big impacts on ecology and evolution as well as human health – The Economist

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Aug 20th 2020

IThe outsiders inside

HUMANS ARE lucky to live a hundred years. Oak trees may live a thousand; mayflies, in their adult form, a single day. But they are all alive in the same way. They are made up of cells which embody flows of energy and stores of information. Their metabolisms make use of that energy, be it from sunlight or food, to build new molecules and break down old ones, using mechanisms described in the genes they inherited and may, or may not, pass on.

It is this endlessly repeated, never quite perfect reproduction which explains why oak trees, humans, and every other plant, fungus or single-celled organism you have ever seen or felt the presence of are all alive in the same way. It is the most fundamental of all family resemblances. Go far enough up any creatures family tree and you will find an ancestor that sits in your family tree, too. Travel further and you will find what scientists call the last universal common ancestor, LUCA. It was not the first living thing. But it was the one which set the template for the life that exists today.

And then there are viruses. In viruses the link between metabolism and genes that binds together all life to which you are related, from bacteria to blue whales, is broken. Viral genes have no cells, no bodies, no metabolism of their own. The tiny particles, virions, in which those genes come packagedthe dot-studded disks of coronaviruses, the sinister, sinuous windings of Ebola, the bacteriophages with their science-fiction landing-legs that prey on microbesare entirely inanimate. An individual animal, or plant, embodies and maintains the restless metabolism that made it. A virion is just an arrangement of matter.

The virus is not the virion. The virus is a process, not a thing. It is truly alive only in the cells of others, a virtual organism running on borrowed hardware to produce more copies of its genome. Some bide their time, letting the cell they share the life of live on. Others immediately set about producing enough virions to split their hosts from stem to stern.

The virus has no plan or desire. The simplest purposes of the simplest lifeto maintain the difference between what is inside the cell and what is outside, to move towards one chemical or away from anotherare entirely beyond it. It copies itself in whatever way it does simply because it has copied itself that way before, in other cells, in other hosts.

That is why, asked whether viruses are alive, Eckard Wimmer, a chemist and biologist who works at the State University of New York, Stony Brook, offers a yes-and-no. Viruses, he says, alternate between nonliving and living phases. He should know. In 2002 he became the first person in the world to take an array of nonliving chemicals and build a virion from scratcha virion which was then able to get itself reproduced by infecting cells.

The fact that viruses have only a tenuous claim to being alive, though, hardly reduces their impact on things which are indubitably so. No other biological entities are as ubiquitous, and few as consequential. The number of copies of their genes to be found on Earth is beyond astronomical. There are hundreds of billions of stars in the Milky Way galaxy and a couple of trillion galaxies in the observable universe. The virions in the surface waters of any smallish sea handily outnumber all the stars in all the skies that science could ever speak of.

Back on Earth, viruses kill more living things than any other type of predator. They shape the balance of species in ecosystems ranging from those of the open ocean to that of the human bowel. They spur evolution, driving natural selection and allowing the swapping of genes.

They may have been responsible for some of the most important events in the history of life, from the appearance of complex multicellular organisms to the emergence of DNA as a preferred genetic material. The legacy they have left in the human genome helps produce placentas and may shape the development of the brain. For scientists seeking to understand lifes origin, they offer a route into the past separate from the one mapped by humans, oak trees and their kin. For scientists wanting to reprogram cells and mend metabolisms they offer inspirationand powerful tools.

IIA lifestyle for genes

THE IDEA of a last universal common ancestor provides a plausible and helpful, if incomplete, answer to where humans, oak trees and their ilk come from. There is no such answer for viruses. Being a virus is not something which provides you with a place in a vast, coherent family tree. It is more like a lifestylea way of being which different genes have discovered independently at different times. Some viral lineages seem to have begun quite recently. Others have roots that comfortably predate LUCA itself.

Disparate origins are matched by disparate architectures for information storage and retrieval. In eukaryotescreatures, like humans, mushrooms and kelp, with complex cellsas in their simpler relatives, the bacteria and archaea, the genes that describe proteins are written in double-stranded DNA. When a particular protein is to be made, the DNA sequence of the relevant gene acts as a template for the creation of a complementary molecule made from another nucleic acid, RNA. This messenger RNA (mRNA) is what the cellular machinery tasked with translating genetic information into proteins uses in order to do so.

Because they, too, need to have proteins made to their specifications, viruses also need to produce mRNAs. But they are not restricted to using double-stranded DNA as a template. Viruses store their genes in a number of different ways, all of which require a different mechanism to produce mRNAs. In the early 1970s David Baltimore, one of the great figures of molecular biology, used these different approaches to divide the realm of viruses into seven separate classes (see diagram).

In four of these seven classes the viruses store their genes not in DNA but in RNA. Those of Baltimore group three use double strands of RNA. In Baltimore groups four and five the RNA is single-stranded; in group four the genome can be used directly as an mRNA; in group five it is the template from which mRNA must be made. In group sixthe retroviruses, which include HIVthe viral RNA is copied into DNA, which then provides a template for mRNAs.

Because uninfected cells only ever make RNA on the basis of a DNA template, RNA-based viruses need distinctive molecular mechanisms those cells lack. Those mechanisms provide medicine with targets for antiviral attacks. Many drugs against HIV take aim at the system that makes DNA copies of RNA templates. Remdesivir (Veklury), a drug which stymies the mechanism that the simpler RNA viruses use to recreate their RNA genomes, was originally developed to treat hepatitis C (group four) and subsequently tried against the Ebola virus (group five). It is now being used against SARS-CoV-2 (group four), the covid-19 virus.

Studies of the gene for that RNA-copying mechanism, RdRp, reveal just how confusing virus genealogy can be. Some viruses in groups three, four and five seem, on the basis of their RdRp-gene sequence, more closely related to members of one of the other groups than they are to all the other members of their own group. This may mean that quite closely related viruses can differ in the way they store their genomes; it may mean that the viruses concerned have swapped their RdRp genes. When two viruses infect the same cell at the same time such swaps are more or less compulsory. They are, among other things, one of the mechanisms by which viruses native to one species become able to infect another.

How do genes take on the viral lifestyle in the first place? There are two plausible mechanisms. Previously free-living creatures could give up metabolising and become parasitic, using other creatures cells as their reproductive stage. Alternatively genes allowed a certain amount of independence within one creature could have evolved the means to get into other creatures.

Living creatures contain various apparently independent bits of nucleic acid with an interest in reproducing themselves. The smallest, found exclusively in plants, are tiny rings of RNA called viroids, just a few hundred genetic letters long. Viroids replicate by hijacking a host enzyme that normally makes mRNAs. Once attached to a viroid ring, the enzyme whizzes round and round it, unable to stop, turning out a new copy of the viroid with each lap.

Viroids describe no proteins and do no good. Plasmidssomewhat larger loops of nucleic acid found in bacteriado contain genes, and the proteins they describe can be useful to their hosts. Plasmids are sometimes, therefore, regarded as detached parts of a bacterias genome. But that detachment provides a degree of autonomy. Plasmids can migrate between bacterial cells, not always of the same species. When they do so they can take genetic traits such as antibiotic resistance from their old host to their new one.

Recently, some plasmids have been implicated in what looks like a progression to true virus-hood. A genetic analysis by Mart Krupovic of the Pasteur Institute suggests that the Circular Rep-Encoding Single-Strand-DNA (CRESS-DNA) viruses, which infect bacteria, evolved from plasmids. He thinks that a DNA copy of the genes that another virus uses to create its virions, copied into a plasmid by chance, provided it with a way out of the cell. The analysis strongly suggests that CRESS-DNA viruses, previously seen as a pretty closely related group, have arisen from plasmids this way on three different occasions.

Such jailbreaks have probably been going on since very early on in the history of life. As soon as they began to metabolise, the first proto-organisms would have constituted a niche in which other parasitic creatures could have lived. And biology abhors a vacuum. No niche goes unfilled if it is fillable.

It is widely believed that much of the evolutionary period between the origin of life and the advent of LUCA was spent in an RNA worldone in which that versatile substance both stored information, as DNA now does, and catalysed chemical reactions, as proteins now do. Set alongside the fact that some viruses use RNA as a storage medium today, this strongly suggests that the first to adopt the viral lifestyle did so too. Patrick Forterre, an evolutionary biologist at the Pasteur Institute with a particular interest in viruses (and the man who first popularised the term LUCA) thinks that the RNA world was not just rife with viruses. He also thinks they may have brought about its end.

The difference between DNA and RNA is not large: just a small change to one of the letters used to store genetic information and a minor modification to the backbone to which these letters are stuck. And DNA is a more stable molecule in which to store lots of information. But that is in part because DNA is inert. An RNA-world organism which rewrote its genes into DNA would cripple its metabolism, because to do so would be to lose the catalytic properties its RNA provided.

An RNA-world virus, having no metabolism of its own to undermine, would have had no such constraints if shifting to DNA offered an advantage. Dr Forterre suggests that this advantage may have lain in DNAs imperviousness to attack. Host organisms today have all sorts of mechanisms for cutting up viral nucleic acids they dont like the look ofmechanisms which biotechnologists have been borrowing since the 1970s, most recently in the form of tools based on a bacterial defence called CRISPR. There is no reason to imagine that the RNA-world predecessors of todays cells did not have similar shears at their disposal. And a virus that made the leap to DNA would have been impervious to their blades.

Genes and the mechanisms they describe pass between viruses and hosts, as between viruses and viruses, all the time. Once some viruses had evolved ways of writing and copying DNA, their hosts would have been able to purloin them in order to make back-up copies of their RNA molecules. And so what began as a way of protecting viral genomes would have become the way life stores all its genesexcept for those of some recalcitrant, contrary viruses.

IIIThe scythes of the seas

IT IS A general principle in biology that, although in terms of individual numbers herbivores outnumber carnivores, in terms of the number of species carnivores outnumber herbivores. Viruses, however, outnumber everything else in every way possible.

This makes sense. Though viruses can induce host behaviours that help them spreadsuch as coughingan inert virion boasts no behaviour of its own that helps it stalk its prey. It infects only that which it comes into contact with. This is a clear invitation to flood the zone. In 1999 Roger Hendrix, a virologist, suggested that a good rule of thumb might be ten virions for every living individual creature (the overwhelming majority of which are single-celled bacteria and archaea). Estimates of the number of such creatures on the planet come out in the region of 1029-1030. If the whole Earth were broken up into pebbles, and each of those pebbles smashed into tens of thousands of specks of grit, you would still have fewer pieces of grit than the world has virions. Measurements, as opposed to estimates, produce numbers almost as arresting. A litre of seawater may contain more than 100bn virions; a kilogram of dried soil perhaps a trillion.

Metagenomics, a part of biology that looks at all the nucleic acid in a given sample to get a sense of the range of life forms within it, reveals that these tiny throngs are highly diverse. A metagenomic analysis of two surveys of ocean life, the Tara Oceans and Malaspina missions, by Ahmed Zayed of Ohio State University, found evidence of 200,000 different species of virus. These diverse species play an enormous role in the ecology of the oceans.

A litre of seawater may contain 100bn virions; a kilogram of dried soil perhaps a trillion

On land, most of the photosynthesis which provides the biomass and energy needed for life takes place in plants. In the oceans, it is overwhelmingly the business of various sorts of bacteria and algae collectively known as phytoplankton. These creatures reproduce at a terrific rate, and viruses kill them at a terrific rate, too. According to work by Curtis Suttle of the University of British Columbia, bacterial phytoplankton typically last less than a week before being killed by viruses.

This increases the overall productivity of the oceans by helping bacteria recycle organic matter (it is easier for one cell to use the contents of another if a virus helpfully lets them free). It also goes some way towards explaining what the great mid-20th-century ecologist G. Evelyn Hutchinson called the paradox of the plankton. Given the limited nature of the resources that single-celled plankton need, you would expect a few species particularly well adapted to their use to dominate the ecosystem. Instead, the plankton display great variety. This may well be because whenever a particular form of plankton becomes dominant, its viruses expand with it, gnawing away at its comparative success.

It is also possible that this endless dance of death between viruses and microbes sets the stage for one of evolutions great leaps forward. Many forms of single-celled plankton have molecular mechanisms that allow them to kill themselves. They are presumably used when one cells sacrifice allows its sister cellswhich are genetically identicalto survive. One circumstance in which such sacrifice seems to make sense is when a cell is attacked by a virus. If the infected cell can kill itself quickly (a process called apoptosis) it can limit the number of virions the virus is able to make. This lessens the chances that other related cells nearby will die. Some bacteria have been shown to use this strategy; many other microbes are suspected of it.

There is another situation where self-sacrifice is becoming conduct for a cell: when it is part of a multicellular organism. As such organisms grow, cells that were once useful to them become redundant; they have to be got rid of. Eugene Koonin of Americas National Institutes of Health and his colleagues have explored the idea that virus-thwarting self-sacrifice and complexity-permitting self-sacrifice may be related, with the latter descended from the former. Dr Koonins model also suggests that the closer the cells are clustered together, the more likely this act of self-sacrifice is to have beneficial consequences.

For such profound propinquity, move from the free-flowing oceans to the more structured world of soil, where potential self-sacrificers can nestle next to each other. Its structure makes soil harder to sift for genes than water is. But last year Mary Firestone of the University of California, Berkeley, and her colleagues used metagenomics to count 3,884 new viral species in a patch of Californian grassland. That is undoubtedly an underestimate of the total diversity; their technique could see only viruses with RNA genomes, thus missing, among other things, most bacteriophages.

Metagenomics can also be applied to biological samples, such as bat guano in which it picks up viruses from both the bats and their food. But for the most part the finding of animal viruses requires more specific sampling. Over the course of the 2010s PREDICT, an American-government project aimed at finding animal viruses, gathered over 160,000 animal and human tissue samples from 35 countries and discovered 949 novel viruses.

The people who put together PREDICT now have grander plans. They want a Global Virome Project to track down all the viruses native to the worlds 7,400 species of mammals and waterfowlthe reservoirs most likely to harbour viruses capable of making the leap into human beings. In accordance with the more-predator-species-than-prey rule they expect such an effort would find about 1.5m viruses, of which around 700,000 might be able to infect humans. A planning meeting in 2018 suggested that such an undertaking might take ten years and cost $4bn. It looked like a lot of money then. Today those arguing for a system that can provide advance warning of the next pandemic make it sound pretty cheap.

IVLeaving their mark

THE TOLL which viruses have exacted throughout history suggests that they have left their mark on the human genome: things that kill people off in large numbers are powerful agents of natural selection. In 2016 David Enard, then at Stanford University and now at the University of Arizona, made a stab at showing just how much of the genome had been thus affected.

He and his colleagues started by identifying almost 10,000 proteins that seemed to be produced in all the mammals that had had their genomes sequenced up to that point. They then made a painstaking search of the scientific literature looking for proteins that had been shown to interact with viruses in some way or other. About 1,300 of the 10,000 turned up. About one in five of these proteins was connected to the immune system, and thus could be seen as having a professional interest in viral interaction. The others appeared to be proteins which the virus made use of in its attack on the host. The two cell-surface proteins that SARS-CoV-2 uses to make contact with its target cells and inveigle its way into them would fit into this category.

The researchers then compared the human versions of the genes for their 10,000 proteins with those in other mammals, and applied a statistical technique that distinguishes changes that have no real impact from the sort of changes which natural selection finds helpful and thus tries to keep. Genes for virus-associated proteins turned out to be evolutionary hotspots: 30% of all the adaptive change was seen in the genes for the 13% of the proteins which interacted with viruses. As quickly as viruses learn to recognise and subvert such proteins, hosts must learn to modify them.

A couple of years later, working with Dmitri Petrov at Stanford, Dr Enard showed that modern humans have borrowed some of these evolutionary responses to viruses from their nearest relatives. Around 2-3% of the DNA in an average European genome has Neanderthal origins, a result of interbreeding 50,000 to 30,000 years ago. For these genes to have persisted they must be doing something usefulotherwise natural selection would have removed them. Dr Enard and Dr Petrov found that a disproportionate number described virus-interacting proteins; of the bequests humans received from their now vanished relatives, ways to stay ahead of viruses seem to have been among the most important.

Viruses do not just shape the human genome through natural selection, though. They also insert themselves into it. At least a twelfth of the DNA in the human genome is derived from viruses; by some measures the total could be as high as a quarter.

Retroviruses like HIV are called retro because they do things backwards. Where cellular organisms make their RNA from DNA templates, retroviruses do the reverse, making DNA copies of their RNA genomes. The host cell obligingly makes these copies into double-stranded DNA which can be stitched into its own genome. If this happens in a cell destined to give rise to eggs or sperm, the viral genes are passed from parent to offspring, and on down the generations. Such integrated viral sequences, known as endogenous retroviruses (ERVs), account for 8% of the human genome.

This is another example of the way the same viral trick can be discovered a number of times. Many bacteriophages are also able to stitch copies of their genome into their hosts DNA, staying dormant, or temperate, for generations. If the cell is doing well and reproducing regularly, this quiescence is a good way for the viral genes to make more copies of themselves. When a virus senses that its easy ride may be coming to an end, thoughfor example, if the cell it is in shows signs of stressit will abandon ship. What was latent becomes lytic as the viral genes produce a sufficient number of virions to tear the host apart.

Though some of their genes are associated with cancers, in humans ERVs do not burst back into action in later generations. Instead they have proved useful resources of genetic novelty. In the most celebrated example, at least ten different mammalian lineages make use of a retroviral gene for one of their most distinctively mammalian activities: building a placenta.

The placenta is a unique organ because it requires cells from the mother and the fetus to work together in order to pass oxygen and sustenance in one direction and carbon dioxide and waste in the other. One way this intimacy is achieved safely is through the creation of a tissue in which the membranes between cells are broken down to form a continuous sheet of cellular material.

The protein that allows new cells to merge themselves with this layer, syncytin-1, was originally used by retroviruses to join the external membranes of their virions to the external membranes of cells, thus gaining entry for the viral proteins and nucleic acids. Not only have different sorts of mammals co-opted this membrane-merging trickother creatures have made use of it, too. The mabuya, a long-tailed skink which unusually for a lizard nurtures its young within its body, employs a retroviral syncytin protein to produce a mammalian-looking placenta. The most recent shared ancestor of mabuyas and mammals died out 80m years before the first dinosaur saw the light of day, but both have found the same way to make use of the viral gene.

This is not the only way that animals make use of their ERVs. Evidence has begun to accumulate that genetic sequences derived from ERVs are quite frequently used to regulate the activity of genes of more conventional origin. In particular, RNA molecules transcribed from an ERV called HERV-K play a crucial role in providing the stem cells found in embryos with their pluripotencythe ability to create specialised daughter cells of various different types. Unfortunately, when expressed in adults HERV-K can also be responsible for cancers of the testes.

As well as containing lots of semi-decrepit retroviruses that can be stripped for parts, the human genome also holds a great many copies of a retrotransposon called LINE-1. This a piece of DNA with a surprisingly virus-like way of life; it is thought by some biologists to have, like ERVs, a viral origin. In its full form, LINE-1 is a 6,000-letter sequence of DNA which describes a reverse transcriptase of the sort that retroviruses use to make DNA from their RNA genomes. When LINE-1 is transcribed into an mRNA and that mRNA subsequently translated to make proteins, the reverse transcriptase thus created immediately sets to work on the mRNA used to create it, using it as the template for a new piece of DNA which is then inserted back into the genome. That new piece of DNA is in principle identical to the piece that acted as the mRNAs original template. The LINE-1 element has made a copy of itself.

In the 100m years or so that this has been going on in humans and the species from which they are descended the LINE-1 element has managed to pepper the genome with a staggering 500,000 copies of itself. All told, 17% of the human genome is taken up by these copiestwice as much as by the ERVs.

Most of the copies are severely truncated and incapable of copying themselves further. But some still have the knack, and this capability may be being put to good use. Fred Gage and his colleagues at the Salk Institute for Biological Studies, in San Diego, argue that LINE-1 elements have an important role in the development of the brain. In 2005 Dr Gage discovered that in mouse embryosspecifically, in the brains of those embryosabout 3,000 LINE-1 elements are still able to operate as retrotransposons, putting new copies of themselves into the genome of a cell and thus of all its descendants.

Brains develop through proliferation followed by pruning. First, nerve cells multiply pell-mell; then the cell-suicide process that makes complex life possible prunes them back in a way that looks a lot like natural selection. Dr Gage suspects that the movement of LINE-1 transposons provides the variety in the cell population needed for this selection process. Choosing between cells with LINE-1 in different places, he thinks, could be a key part of the process from which the eventual neural architecture emerges. What is true in mice is, as he showed in 2009, true in humans, too. He is currently developing a technique for looking at the process in detail by comparing, post mortem, the genomes of different brain cells from single individuals to see if their LINE-1 patterns vary in the ways that his theory would predict.

VPromised lands

HUMAN EVOLUTION may have used viral genes to make big-brained live-born life possible; but viral evolution has used them to kill off those big brains on a scale that is easily forgotten. Compare the toll to that of war. In the 20th century, the bloodiest in human history, somewhere between 100m and 200m people died as a result of warfare. The number killed by measles was somewhere in the same range; the number who died of influenza probably towards the top of it; and the number killed by smallpox300m-500mwell beyond it. That is why the eradication of smallpox from the wild, achieved in 1979 by a globally co-ordinated set of vaccination campaigns, stands as one of the all-time-great humanitarian triumphs.

Other eradications should eventually follow. Even in their absence, vaccination has led to a steep decline in viral deaths. But viruses against which there is no vaccine, either because they are very new, like SARS-CoV-2, or peculiarly sneaky, like HIV, can still kill millions.

Reducing those tolls is a vital aim both for research and for public-health policy. Understandably, a far lower priority is put on the benefits that viruses can bring. This is mostly because they are as yet much less dramatic. They are also much less well understood.

The viruses most prevalent in the human body are not those which infect human cells. They are those which infect the bacteria that live on the bodys surfaces, internal and external. The average human microbiome harbours perhaps 100trn of these bacteria. And where there are bacteria, there are bacteriophages shaping their population.

The microbiome is vital for good health; when it goes wrong it can mess up a lot else. Gut bacteria seem to have a role in maintaining, and possibly also causing, obesity in the well-fed and, conversely, in tipping the poorly fed into a form of malnutrition called kwashiorkor. Ill-regulated gut bacteria have also been linked, if not always conclusively, with diabetes, heart disease, cancers, depression and autism. In light of all this, the question who guards the bacterial guardians? is starting to be asked.

The viruses that prey on the bacteria are an obvious answer. Because the health of their hosts hostthe possessor of the gut they find themselves inmatters to these phages, they have an interest in keeping the microbiome balanced. Unbalanced microbiomes allow pathogens to get a foothold. This may explain a curious detail of a therapy now being used as a treatment of last resort against Clostridium difficile, a bacterium that causes life-threatening dysentery. The therapy in question uses a transfusion of faecal matter, with its attendant microbes, from a healthy individual to reboot the patients microbiome. Such transplants, it appears, are more likely to succeed if their phage population is particularly diverse.

Medicine is a very long way from being able to use phages to fine-tune the microbiome. But if a way of doing so is found, it will not in itself be a revolution. Attempts to use phages to promote human health go back to their discovery in 1917, by Flix dHrelle, a French microbiologist, though those early attempts at therapy were not looking to restore balance and harmony. On the basis that the enemy of my enemy is my friend, doctors simply treated bacterial infections with phages thought likely to kill the bacteria.

The arrival of antibiotics saw phage therapy abandoned in most places, though it persisted in the Soviet Union and its satellites. Various biotechnology companies think they may now be able to revive the traditionand make it more effective. One option is to remove the bits of the viral genome that let phages settle down to a temperate life in a bacterial genome, leaving them no option but to keep on killing. Another is to write their genes in ways that avoid the defences with which bacteria slice up foreign DNA.

The hope is that phage therapy will become a backup in difficult cases, such as infection with antibiotic-resistant bugs. There have been a couple of well-publicised one-off successes outside phage therapys post-Soviet homelands. In 2016 Tom Patterson, a researcher at the University of California, San Diego, was successfully treated for an antibiotic-resistant bacterial infection with specially selected (but un-engineered) phages. In 2018 Graham Hatfull of the University of Pittsburgh used a mixture of phages, some engineered so as to be incapable of temperance, to treat a 16-year-old British girl who had a bad bacterial infection after a lung transplant. Clinical trials are now getting under way for phage treatments aimed at urinary-tract infections caused by Escherichia coli, Staphylococcus aureus infections that can lead to sepsis and Pseudomonas aeruginosa infections that cause complications in people who have cystic fibrosis.

Viruses which attack bacteria are not the only ones genetic engineers have their eyes on. Engineered viruses are of increasing interest to vaccine-makers, to cancer researchers and to those who want to treat diseases by either adding new genes to the genome or disabling faulty ones. If you want to get a gene into a specific type of cell, a virion that recognises something about such cells may often prove a good tool.

The vaccine used to contain the Ebola outbreak in the Democratic Republic of Congo over the past two years was made by engineering Indiana vesiculovirus, which infects humans but cannot reproduce in them, so that it expresses a protein found on the surface of the Ebola virus; thus primed, the immune system responds to Ebola much more effectively. The World Health Organisations current list of 29 covid-19 vaccines in clinical trials features six versions of other viruses engineered to look a bit like SARS-CoV-2. One is based on a strain of measles that has long been used as a vaccine against that disease.

Viruses engineered to engender immunity against pathogens, to kill cancer cells or to encourage the immune system to attack them, or to deliver needed genes to faulty cells all seem likely to find their way into health care. Other engineered viruses are more worrying. One way to understand how viruses spread and kill is to try and make particularly virulent ones. In 2005, for example, Terrence Tumpey of Americas Centres for Disease Control and Prevention and his colleagues tried to understand the deadliness of the influenza virus responsible for the pandemic of 1918-20 by taking a more benign strain, adding what seemed to be distinctive about the deadlier one and trying out the result on mice. It was every bit as deadly as the original, wholly natural version had been.

The use of engineered pathogens as weapons of war is of dubious utility, completely illegal and repugnant to almost all

Because such gain of function research could, if ill-conceived or poorly implemented, do terrible damage, it requires careful monitoring. And although the use of engineered pathogens as weapons of war is of dubious utilitysuch weapons are hard to aim and hard to stand down, and it is not easy to know how much damage they have doneas well as being completely illegal and repugnant to almost all, such possibilities will and should remain a matter of global concern.

Information which, for billions of years, has only ever come into its own within infected cells can now be inspected on computer screens and rewritten at will. The power that brings is sobering. It marks a change in the history of both viruses and peoplea change which is perhaps as important as any of those made by modern biology. It is constraining a small part of the viral world in a way which, so far, has been to peoples benefit. It is revealing that worlds further reaches in a way which cannot but engender awe.

Editors note: Some of our covid-19 coverage is free for readers of The Economist Today, our daily newsletter. For more stories and our pandemic tracker, see our hub

This article appeared in the Essay section of the print edition under the headline "The outsiders inside"

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Encouraging News About Coronavirus Immunity | In the Pipeline – Science Magazine

Posted: at 8:57 pm

Weve had some good news on coronavirus immunity recently good because it gives us some more clarity on the whole situation, and because it suggests that both people who have already recovered from the infection and people who will be getting vaccinated can have good protection.

We have this preprint from several of the Boston/Cambridge area institutions, comparing antibody levels in 259 infected patients (out to 75 days post-symptoms) with 1548 pre-pandemic samples. Theyre looking specifically at IgM, IgG, and IgA comparisons. IgM is the first antibody type to appear in response to an infection theyre the ones I mentioned in this post as being five of the Y-shaped units put together. IgG are the ones that most people are talking about when they talk about antibodies in the blood, and IgA are secreted mucosal antibodies, found in the saliva and nasal/lung tissues.That mucosal immunity is surely an important factor in a disease that appears to be spread largely by inhaled airborne droplets.

They estimate that it takes about 11 days to seroconvert after infection, that is, to show evidence that your immune system has raised these new antibodies to the coronavirus. Looking at hospitalized individuals versus milder cases, the former actually seroconverted a couple of days earlier, and their IgM response tended to drop off a bit more quickly. One limitation of this paper is that the coronavirus patient cohort was skewed towards the hospitalized patients, rather than mild infections. But overall they found that IgG antibodies were still detectable in serum 75 days out (the last time point measured) and were a very useful marker for infection, although IgM and IgA had mostly gone back down by then. The paper concludes that although we dont yet know the optimum levels of antibodies for protection (and were still collecting later time points!), the association between RBD-IgG with neutralizing titers and the persistence of these antibodies at late time points is encouraging.

Heres a reporton the same topic from a multicenter team in Canada thats comparing antibody level both in the blood and in saliva. In contrast to the report just mentioned, the authors here found IgA against the coronavirus persisting for at least three months after infection, and correlating well with IgG in the blood. Not every study has shown that sort of persistence, but the authors believe that this might be due to the techniques used for detection. They also found that several of their negative controls samples banked from people pre-pandemic, who had definitely not been exposed to coronavirus also showed IgA titers in saliva, presumably cross-reactive antibodies that were raised from some other infection. It is tempting to speculate, they write,that these preexisting IgA antibodies may provide some stop-gap protection against SARS-CoV-2 in the oral cavity, and if so, it is essential to ascertain their original antigenic specificity.

Then theres this preprint from a team in Arizona, which confirms these results by finding that antibodies against the RBD part of the coronavirus Spike protein persisted for at least three months. In contrast to other reports, they say, we conclude that immunity is durable for at least several months after SARS-CoV-2 infection. They also checked antibodies to the nucleocapsid protein (N) as well as to the spike and found that the N response was more variable. One possibility they raise is that there are cross-reactive antibodies to other coronavirus N proteins (which is a more conserved domain across the various types than the Spike), and that these were raised by previous infections with different viruses.

Moving past antibodies, we have this paper on T-cell responses. The authors, a multinational team led out of the Karolinska Institute in Sweden, have put in a lot of work looking at the T-cell situation in unexposed individuals, people with acute coronavirus infections and those who have recovered, and family members of those patients as well. The acute phase subjects had just the sort of cellular profile youd expect: highly activated and cytotoxic, out there killing virus-infected cells as T-cells were born to do. In the convalescent patients this had calmed down, as its supposed to, and they detected stem-memory-type cells, which is just what youd want to see. Importantly, these were also found in people who had recovered from much milder infections and in the asymptomatic family members tested as well. (The paper provides a great deal of detail on the exact sorts of responses in the various T-cell types that Im not going into, but its valuable information).

They also detected potentially cross-reactive T cells in 28% of people who had donated blood before the pandemic even hit, which is consistent with several other reports. 41% of the overall patients who were seronegative in antibody tests were still positive for T-cells (CD4+ and CD8+ alike) against coronavirus proteins (Spike, nucleocapsid, and membrane). They conclude that the T-cell response is indeed non-redundant and apparently an important part of immunity to this virus, and that using seroprevalence (antibody levels) as a marker for exposure in a population will almost certainly underestimate the real situation. Thats good news, since it would mean that more people have already been exposed (and are to some good degree immune) than we would think. But that doesnt mean that we can blow the all-clear whistle, either, as the various surges in infection around the world have shown: the situation may be better than feared, but we dont seem to be anywhere near herd immunity levels yet. And we would be killing off an awful lot more people to get there without a vaccine.

And finally, we have this report from the University of Washington, which is about as direct a measure of immune protection as were likely to get before the vaccine efficacy trials read out. The authors studied the crew of a fishing vessel, before and after its voyage. Three crew members showed a positive antibody response beforehand, indicating that they had been infected earlier in the epidemic they were not positive in RT-PCR testing, though, indicating that they did not have active infections. In fact, none of the other 120 crew members tested (out of 122 total) had such a positive reading on departure.

But an outbreak occurred on the ship anyway someone was early enough in the infection that they hadnt shown positive yet. This crewmember became sick and the vessel returned to port on Day 18 of the voyage. (Sequencing of viral samples from a number of crew members confirmed that the outbreak seemed to originate from a single source). Testing then and over the next few days showed that 104 of the 120 crew members were now positive for the coronavirus but not the three who had antibodies beforehand. This high attack rate (!) and apparent protection makes a strong case for protective immunity, because God knows everyone on board had plenty of chances to catch the disease.

How long this protection lasts, what part of it is due to antibody response and what part to T cells, and what the exact cutoffs are for those these are the important things we dont quite know yet. But the picture is becoming clearer. And what were seeing is that this virus, which it has definitely has some unusual features, is also something that our immune systems are dealing with in the just the way that you would hope to see. That gives us hope that the vaccines are in turn going to raise protective, lasting responses. We just have to see the details!

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Scientists are seeing signs of lasting immunity to COVID-19, among survivors with even mild infections – Firstpost

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The New York TimesAug 19, 2020 14:24:20 IST

To the immune system, not all germs are equally memorable. But our bodys cells seem to be seriously studying up on the coronavirus.

Scientists who have been monitoring immune responses to the virus are now starting to see encouraging signs of strong, lasting immunity, even in people who developed only mild symptoms of COVID-19, a flurry of new studies suggests. Disease-fighting antibodies, as well as immune cells, called B cells and T cells that are capable of recognizing the virus, appear to persist months after infections have resolved an encouraging echo of the bodys enduring response to other viruses.

Things are really working as theyre supposed to, said Deepta Bhattacharya, an immunologist at the University of Arizona and an author on one of the new studies, which has not yet been peer-reviewed.

Although researchers cannot forecast how long these immune responses will last, many experts consider the data a welcome indication that the bodys most studious cells are doing their job and will have a good chance of fending off the coronavirus, faster and more fervently than before, if exposed to it again.

This is exactly what you would hope for, said Marion Pepper, an immunologist at the University of Washington and an author on another of the new studies, which is currently under review at the journal Nature. All the pieces are there to have a totally protective immune response.

Protection against reinfection cannot be fully confirmed until there is proof that most people who encounter the virus a second time are actually able to keep it at bay, Pepper said. But the findings could help quell recent concerns over the viruss ability to dupe the immune system into amnesia, leaving people vulnerable to repeat bouts of disease.

Researchers have yet to find unambiguous evidence that coronavirus reinfections are occurring, especially within the few months that the virus has been rippling through the human population. The prospect of immune memory helps to explain that, Pepper said.

Face shields and masks for sale in New York on March 23, 2020. The clear plastic guards may be easier to wear, disinfect and reuse than cloth or surgical face coverings, although they dont entirely replace the need for masks. (Marian Carrasquero/The New York Times)

In discussions about immune responses to the coronavirus, much of the conversation has focused on antibodies Y-shaped proteins that can latch onto the surfaces of pathogens and block them from infecting cells. But antibodies represent just one wing of a complex and coordinated squadron of immune soldiers, each with its own unique modes of attack. Viruses that have already invaded cells, for instance, are cloaked from antibodies but are still vulnerable to killer T cells, which force infected cells to self-destruct. Another set of T cells, nicknamed helpers, can coax B cells to mature into antibody-making machines.

(Yet another sector of the immune system assails pathogens within minutes of their arrival while sending out signals called cytokines to mobilize forces from elsewhere in the body. Some evidence suggests that severe cases of COVID-19 may stem from this early process going awry.)

Antibodies also come with an expiration date: Because they are inanimate proteins and not living cells, they cant replenish themselves, and so disappear from the blood just weeks or months after they are produced. Hoards of antibodies appear shortly after a virus has breached the bodys barriers, then wane as the threat dissipates. Most of the B cells that produce these early antibodies die off as well.

But even when not under siege, the body retains a battalion of longer-lived B cells that can churn out virus-fighting antibodies en masse, should they prove useful again. Some patrol the bloodstream, waiting to be triggered anew; others retreat into the bone marrow, generating small amounts of antibodies that are detectable years, sometimes decades, after an infection is over. Several studies, including those led by Bhattacharya and Pepper, have found antibodies capable of incapacitating the coronavirus lingering at low levels in the blood months after people have recovered from COVID-19.

The antibodies decline, but they settle in what looks like a stable nadir, which is observable about three months after symptoms start, Bhattacharya said. The response looks perfectly durable.

Seeing antibodies this long after infection is a strong indication that B cells are still chugging away in the bone marrow, Pepper said. She and her team were also able to pluck B cells that recognize the coronavirus from the blood of people who have recovered from mild cases of COVID-19 and grow them in the lab.

Multiple studies, including one published Friday in the journal Cell, have also managed to isolate coronavirus-attacking T cells from the blood of recovered individuals long after symptoms have disappeared. When provoked with bits of the coronavirus in the lab, these T cells pumped out virus-fighting signals, and cloned themselves into fresh armies ready to confront a familiar foe. Some reports have noted that analyses of T cells could give researchers a glimpse into the immune response to the coronavirus, even in patients whose antibody levels have declined to a point where they are difficult to detect.

This is very promising, said Smita Iyer, an immunologist at the University of California, Davis, who is studying immune responses to the coronavirus in rhesus macaques but was not involved in the new studies. This calls for some optimism about herd immunity, and potentially a vaccine.

Notably, several of the new studies are finding these powerful responses in people who did not develop severe cases of COVID-19, Iyer added. Some researchers have worried that infections that take a smaller toll on the body are less memorable to the immune systems studious cells, which may prefer to invest their resources in more serious assaults. In some cases, the body could even jettison the viruses so quickly that it fails to catalog them. This paper suggests this is not true, Iyer said. You can still get durable immunity without suffering the consequences of infection.

A resident wears a mask to curb the spread of the coronavirus, while browsing meat products at a Beijing supermarket on 15 June 2020. The capital is bracing for a resurgence of the coronavirus after more than 100 new cases were reported in recent days in the city, which hadnt seen a case of local transmission in more than a month. Image: AP

What has been observed in people who fought off mild cases of COVID-19 might not hold true for hospitalized patients, whose bodies struggle to marshal a balanced immune response to the virus, or those who were infected but had no symptoms at all. Research groups around the world are continuing to study the entire range of responses. But the vast majority of the cases are these mild infections, said Jason Netland, an immunologist at the University of Washington and an author on the paper under review at Nature. If those people are going to be protected, thats still good.

This new spate of studies could also further assuage fears about how and when the pandemic will end. On Friday, updated guidance released by the Centers for Disease Control and Prevention was misinterpreted by several news reports that suggested immunity against the coronavirus might last only a few months. Experts quickly responded, noting the dangers of propagating such statements and pointing to the wealth of evidence that people who previously had the virus are probably at least partly protected from reinfection for at least three months, if not much longer.

Considered with other recent reports, the new data reinforce the idea that, Yes, you do develop immunity to this virus, and good immunity to this virus, said Dr. Eun-Hyung Lee, an immunologist at Emory University who was not involved in the studies. Thats the message we want to get out there.

Some illnesses, like the flu, can plague populations repeatedly. But that is at least partly attributable to the high mutation rates of influenza viruses, which can quickly make the pathogens unrecognizable to the immune system. Coronaviruses, in contrast, tend to change their appearance less readily from year to year.

Still, much remains unknown. Although these studies hint at the potential for protectiveness, they do not demonstrate protection in action, said Cheong-Hee Chang, an immunologist at the University of Michigan who was not involved in the new studies. Its hard to predict whats going to happen, Chang said. Humans are so heterogeneous. There are so many factors coming into play.

Research in animals could help fill a few gaps. Small studies have shown that one bout of the coronavirus seems to protect rhesus macaques from contracting it again.

But tracking long-term human responses will take time, Pepper said. Good immune memory, she added, requires molecules and cells to be abundant, effective and durable and scientists cannot yet say that all three conditions have been definitively met.

As peoples bodies settle into their post-coronavirus state, were just now hitting the point of relevance to take the long view on immunity, Bhattacharya said. Things may change a few months or years down the line. Or they may not.

Theres no shortcuts here, Bhattacharya said. We just have to follow it out.

Katherine J. Wuc.2020 The New York Times Company

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