Image Animation What is prion disease?

Prion diseases belong to group of progressive conditions that affect the nervous system in humans and animals. In people, prion diseases impair brain function, causing memory changes, personality changes, a decline in intellectual function (dementia), and problems with movement that worsen over time. The signs and symptoms of these conditions typically begin in adulthood, and these disorders lead to death within a few months to several years.

Familial prion diseases of humans include classic Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal insomnia (FI). These conditions form a spectrum of diseases with overlapping signs and symptoms.

Scientists have shown for the first time that “lifeless” prion proteins, devoid of all genetic material, can evolve just like higher forms of life.

How does something evolve when its not even alive? Prions are the scariest nasties on earth.

dairy cow in California is the fourth known American case of mad cow disease, which is caused by prions, infectious agents composed only of protein (the story hit the press the day after my lecture on this type of illness). Unlike viruses, prions have no nucleic acid and no protective coat. But virologists know all about them because, as Stanley Prusiner once said, there was a time when only virologists believed that they existed.

Prions are found in mammals and in fungi, but only in mammals are they infectious and pathogenic. All mammals make normal forms of the prion protein (PrPc) which is found in many tissues including the nervous system. The pathogenic form, called PrPSc, is a structurally altered form of PrPc. The PrPSc protein, named after the first prion disease studied, scrapie in sheep, causes PrPc to undergo a structural transformation to the pathogenic form. The PrPSc protein becomes deposited in amyloid fibrils in the brain, leading to neurodegenerative diseases known as transmissible spongiform encephalopathies (TSE), after the sponge-like appearance of the brain observed in afflicted animals (image).

There are three different ways to acquire a TSE. One is by infection: a human consumes meat that contains PrPSc, or receives a corneal transplant from a donor with an undiagnosed TSE . The PrPSc proteins make their way to the brain where they cause the host’s PrPc to misfold and become the pathogenic PrPSc. The more PrPSc that is made, the more the normal PrPc is converted to the pathogenic form. After an incubation period of many years, the host develops an invariably fatal neurodegenerative disease characterized by dementia in humans. There is also a familial form, in which mutations in the gene encoding PrPc are inherited; these cause the PrPc protein to misfold to form the pathogenic form. In the sporadic form PrPc spontaneously converts to PrPSc without any known mutation or infection.

TSEs occur in different forms with varied symptoms and pathology. There are TSEs of humans (Creutzfeld-Jacob disease, fatal familial insomnia, Gerstmann-­Sträussler syndrome, Kuru) cows (bovine spongiform encephalopathy or mad cow disease), sheep and goats (scrapie), deer, elk, and moose (chronic wasting disease), and of a variety of other mammals.

This brings us back to the mad American cow, the first in the US since 2006. It died on a dairy farm and was tested for BSE as are 40,00o other cows each year in this country. The reason why this is big news is that back in the 1990s there was an outbreak of human TSE in the United Kingdom caused by consuming beef from animals with BSE. The cows acquired BSE by being fed processed animal byproducts as protein supplements, which unknowingly contained pathogenic prions. Bt the time the disease was detected in cows, contaminated meat had already entered the human food chain. Cows are routinely tested for BSE precisely to avoid a similar outbreak of human TSE.

The dead cow apparently had atypical BSE – that is, it was not a consequence of eating contaminated meat and it was not an inherited disease. Atypical BSE is caused by strains of prions distinct from other forms. This is good news because it means that the feed that the cow was receiving was not contaminated with pathogenic prions. Furthermore, the cow was not destined for meat production; it was a dairy cow that had died and was selected for random sampling.

Could the milk produced by this cow and consumed by humans pose a risk for transmission of a TSE to humans? It is known that ewes with scrapie shed infectious and pathogenic prions in their milk. However cows with BSE have  much less PrPSc accumulation in peripheral tissues, and in particular lymphoid tissues which include the mammary glands. It seems unlikely that cow milk contains prions, but it is a question worth revisiting. Pathogenic prions are highly resistant to heat, ultraviolet irradiation and other extreme conditions, so would certainly survive the pasteurization process.

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The flexible tail of the prion protein poisons brain cells (University of Zurich)

For decades, there has been no answer to the question of why the altered prion protein is poisonous to brain cells. Neuropathologists from the University of Zurich and University Hospital Zurich have now shown that it is the flexible tail of the prion protein that triggers cell death. These findings have far-reaching consequences: only those antibodies that target the tail of the prion protein are suitable as potential drugs for combating prion diseases.

Proteins behind mad-cow disease also help brain to develop

Since the discovery of prions (infectious misfolded proteins) decades ago scientists have been at a loss as to what the normally-folded versions of the proteins were doing in cells. If they are so dangerous and prone to awful neurological problems when misfolded and aggregated, why has evolution kept them around? New research discussed here in Nature suggests what the normal prion proteins may be doing in helping brain development:

"The team reports in the Journal of Neuroscience that prions are involved in developmental plasticity, the process by which the structure and function of neurons in the growing brain is shaped by experience. “

A prion, pictured above, is an infectious agent comprised only of a protein in misfolded form. It lies in stark contrast to all other known infectious agents; even the simplest bacterium or virus contains nucleic acids (either DNA, RNA, or both) but amazingly, prions seem to have neither. Instead, they propagate by transmitting a misfolded protein state - meaning that when a prion enters a healthy organism, it induces existing, properly folded proteins to convert into the disease-associated, prion form. The prion essentially acts as a template to guide the misfolding of more cellular proteins; newly formed prions can then go on to convert more other proteins, triggering a chain reaction that produces the prion form in exponentially large numbers.

Prions are responsible for the transmissible spongiform encephalopathies in a variety of mammals, including bovine spongiform encephalopathy (BSE, also known as “mad cow disease”) in cattle and Creutzfeldt–Jakob disease (CJD) in humans. All known prion diseases affect the structure of the brain or other neural tissue, and all are currently untreatable and universally fatal.

What is a Prion?

Jonathan Simms was born in 1984 in Northern Ireland. He grew up as any normal teenager does and became a talented football player. He had a bright future ahead of him. In 2001 Simms was awarded a try out for the Northern Ireland national football team, something he and his family dreamed about for ages. Unfortunately for Simms that’s when his symptoms first manifested; he was clumsy, appeared disinterested and didn’t make the cut. Two weeks later Jonathan was at home and got up to leave the room when he had to reach out and steady himself with the door frame. His father asked if he had been drinking and when Simms responded his speech was slurred. To vindicate himself Simms agreed to a drug test for his parents. While at the clinic he failed a basic neurological exam before they could even test for drugs. The following tests did not bode well for Simms. He had variant Creutzfeldt-Jakob disease, more commonly known as ‘Mad Cow Disease,’ the result of an infectious agent known as a prion. Very rapidly Simms’ condition deteriorated, leaving him locked into a decaying shell that left him comatose and twitching until he died in 2011.

Prions are one of the biggest medical mysteries facing modern science. They aren’t viruses, bacteria or fungi; they’re just proteins. These rogue, misfolded proteins hijack normal proteins of the same type in the brain causing them to misfold, accumulate and cause neuronal death leaving a hole in the brain tissue. These proteins can be inherited, or they can be acquired through external means. In Simms’ case he ate contaminated beef. There the protein waited for possibly decades before attacking his brain mercilessly.

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There is no cure for prions, and they’re very hard to destroy (this lead to recent transmission in New England due to contaminated surgical instruments). There are many promising treatments in the works, but nothing definite yet.

The early symptoms of prion disease appear vaguely as insomnia, depression and confusion. Some people report altered perception or hallucinations. Eventually there’s deterioration in speech, the ability to walk and memory. Conditions continue to spiral downward robbing people of their lives and leaving them quivering husks of their former selves.

Today we know more about prions than we did when Simms was diagnosed. There are many different strains of prion, some effect humans and some don’t. Some have a genetic mechanism, others are spread by various (and somewhat unknown) vectors. They loom like a shadow over the medical world because we don’t know the extent of how many people are infected. In the UK it’s estimated that 1 in 2,000 people harbor the vCJD proteins in their brains, a ticking time bomb waiting to go off when the time is right. We don’t have any estimations of how many might be infected here in the US.

Prion protein hints at role in aiding learning and memory

Research has found that prion helps our brains to absorb zinc, which is believed to be crucial to our ability to learn and the wellbeing of our memory.

The findings published in Nature Communications show that prion protein regulates the amount of zinc in the brain by helping cells absorb it through channels in the cell surface. It is already known that high levels of zinc between brain cells are linked with diseases such as Alzheimer’s and Parkinson’s.

Professor Nigel Hooper from the University’s Faculty of Biological Sciences explains: “With ageing, the level of prion protein in our brains falls and less zinc is absorbed by brain cells, which could explain why our memory and learning capabilities change as we get older. By studying both their roles in the body, we hope to uncover exactly how prion and zinc affect memory and learning. This could help us better understand how to maintain healthy brain cells and limit the effects of ageing on the brain.”

Whilst the abnormal infectious form of prion - which causes Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE) in cattle - has been extensively studied, the Leeds team is among the first to investigate the role of the ‘normal’ form of the protein.

Lead researcher, Dr Nicole Watts, says: “Zinc is thought to aid signalling in the brain as it’s released into the space between brain cells. However, when there’s too much zinc between the brain cells it can become toxic.  High levels of zinc in this area between the brain cells are known to be a factor in neurodegenerative diseases, so regulating the amount of absorption by the cells is crucial.”

The research, funded by the Medical Research Council, Wellcome Trust and Alzheimer’s Research UK, may have implications for how we treat - and possibly prevent - neurodegenerative diseases in the future.

Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, said: “We’re pleased to have helped support this study, which has uncovered new information that could one day aid the development of new treatments for Alzheimer’s. One next step would be to understand how regulating zinc levels may affect the progress of the disease. Results like these have the potential to lead to new and effective treatments - but for that to happen, we must build on these results and continue investing in research.”

Language of Life

Prion - an infectious agent made mostly of protein (no nucleic acids). To date, all such agents are capable of propagating through the manipulation of their shape and the shape of surrounding proteins, essentially transmitting a misfolded protein state to their neighbors. The mis-folded form of the prion protein has been implicated in a number of diseases of mammals, including bovine spongiform encephalopathy (BSE, “mad cow disease”). All known prion diseases affect the structure of the brain or other neural tissue, and all are currently untreatable and are always fatal. In general usage, prion refers to the theoretical unit of infection.

All known prions induce the formation of an amyloid fold, in which the protein polymerises into an aggregate consisting of tightly packed beta sheets. This altered structure is extremely stable and accumulates in infected tissue, causing tissue damage and cell death. This stability means that prions are resistant to denaturation by chemical and physical agents, making disposal and containment of these particles difficult.

The word prion is a compound word derived from the initial letters of the words proteinaceous” and infectious”, with -on added by analogy to the word virion.

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Shaking Death

In the 1950s and 60s, a fatal epidemic called kuru swept through the South Fore tribe of Papua New Guinea, killing over 1,000 people. Kuru means “shaking death” which is consistent to the first symptoms of the victims: tremors, headaches and loss of motor skills, since the disease affected the cerebellum, which is responsible for co-ordinarting movement. Soon the victims weren’t able to stand or eat, they sometimes lost speech and developed open sores, and then finally died six to twelve months later. It was discovered that the epidemic was linked to the tribe’s ritual of mortuary cannibalism—consuming the brains of the recently deceased. Kuru began to disappear when cannibalism was outlawed, and yet a few cases still occurred up into the 2000s, suggesting that the disease has an incubation period of up to 50 years. Kuru belongs to a class of neurodegenerative diseases that also includes what is commonly known as “Mad Cow Disease,” and is caused by abnormally folded proteins called prions. These proteins are present in all cells in their normal form, but the abnormal ones are infectious agents, able to ‘flip’ other proteins into the abnormal prion shape that then flip others, and on and on like dominoes. They gradually cause nerve cells to degenerate and die—and since nerve cells cannot be replaced, the brain tissue takes on a sponge-like appearance as it slowly dies. So, Kuru was originally caused by the victims consuming infected brain material, which then infected their own brain tissue and turned it to spongy mush.

(Image Credit)

A photograph of a brain suffering from a TSE compared to a normal brain.
Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of progressive conditions that affect the brain and nervous system of many animals, including humans. According to the most widespread hypothesis they are transmitted by prions, though some other data suggest an involvement of a Spiroplasma infection. Mental and physical abilities deteriorate and myriad tiny holes appear in the cortex causing it to appear like a sponge (hence ‘spongiform’) when brain tissue obtained at autopsy is examined under a microscope. The disorders cause impairment of brain function, including memory changes, personality changes and problems with movement that worsen over time.
Prion diseases of humans include classic Creutzfeldt–Jakob disease, new variant Creutzfeldt–Jakob disease (nvCJD, a human disorder related to mad cow disease), Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia and kuru. These conditions form a spectrum of diseases with overlapping signs and symptoms.
 
Unlike other kinds of infectious disease which are spread by microbes, the infectious agent in TSEs is a specific protein called prion protein. Misshaped prion proteins carry the disease between individuals and cause deterioration of the brain. TSEs are unique diseases in that their aetiology may be genetic, sporadic or infectious via ingestion of infected foodstuffs and via iatrogenic means (e.g. blood transfusion).  Most TSEs are sporadic and occur in an animal with no prion protein mutation. Inherited TSE occurs in animals carrying a rare mutant prion allele, which expresses prion proteins that contort by themselves into the disease-causing conformation. Transmission occurs when healthy animals consume tainted tissues from others with the disease. In recent times a type of TSE called bovine spongiform encephalopathy (BSE) spread in cattle in an epidemic fashion. This occurred because cattle were fed the processed remains of other cattle, a practice now banned in many countries. The epidemic could have begun with just one cow with sporadic disease.
 
Prions cannot be transmitted through the air or through touching or most other forms of casual contact. However, they may be transmitted through contact with infected tissue, body fluids, or contaminated medical instruments. Normal sterilization procedures such as boiling or irradiating materials fail to render prions non-infective.

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"A Unifying Role for Prions in Neurodegenerative Diseases"

This morning I attended a keynote talk by the Nobel laureate Stanley Prusiner, the man credited with piecing together the data indicating a new infectious agent consisting only of protein and coined the phrase “prion.” The talk is part of an ongoing conference this week called “Expanding Prion Horizons,” the focus of which is “Where is prion research headed?” The outline presented by Dr. Prusiner was mind blowing compared to the brief information presented to me in undergrad and medical school. The field is moving fast and expanding into areas we typically don’t associate with prions. Here were some highlights:

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The distinctions between prion diseases and neurodegenerative diseases have been broken down. Recently researchers have been able to demonstrate that Alzheimer’s, Parkinson’s and other dementias are actually prion diseases.

How did they reach these conclusions? That’s a twofold answer: the first is by looking at what we know about those diseases and recognizing a familiar pattern. Alzheimer’s is the result of what Prusiner calls a “double prion” infection. A-beta proteins and Tau proteins aggregate in neurons to form neurofibrillary tangles leading to neuronal death and dementia, which is what a prion does.

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Parkinson’s is the accumulation of a protein called alpha-synuclein forming Lewy Bodies in the Substantia Nigra, leading to cell death and stopping production of dopamine.

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But these proteins also spread, they just don’t form and stay in one place, they infect other neurons around them. Alzheimer’s starts in areas like the hippocampus and then spreads all over the cortex. In an experiment where fetal substantia nigra cells where implanted in locations of the brain of people diagnosed with Parkinson’s, the fetal cells were infected with Lewy Bodies regardless of being far away from the substantia nigra. Researchers have “one-upped” this and taken brain homogenate from humans that died from Alzheimer’s and inoculated mice who then later died from Alzheimer’s. What are the implications of this? Alzheimer’s and Parkinson’s behave in a manner similar to prion diseases, and are now demonstrated to be infectious.

All of this research has also solidified the existence of various prion strains. This is one of the reasons why it’s so difficult to develop treatments and cures. Prusiner also pointed out another difficulty they’re having with developing effective treatments: it seems that prions have a 100% mutation rate, making them highly resistant to drug therapies.

All in all, the keynote presentation was highly informative and engaging. In undergrad and medical school we often just learn a blurb about prions because of how novel they are. It turns out that they’re more than just this novel protein that changed how we view contagion and the implications of this are still being worked out.

What Makes Memories Last?

Prions can be notoriously destructive, spurring proteins to misfold and interfere with cellular function as they spread without control. New research, published in the open access journal PLOS Biology on February 11, 2014, from scientists at the Stowers Institute for Medical Research reveals that certain prion-like proteins, however, can be precisely controlled so that they are generated only in a specific time and place. These prion-like proteins are not involved in disease processes; rather, they are essential for creating and maintaining long-term memories.

“This protein is not toxic; it’s important for memory to persist,” says Stowers researcher Kausik Si, Ph.D., who led the study. To ensure that long-lasting memories are created only in the appropriate neural circuits, Si explains, the protein must be tightly regulated so that it adopts its prion-like form only in response to specific stimuli. He and his colleagues report on the biochemical changes that make that precision possible.

Si’s lab is focused on finding the molecular alterations that encode a memory in specific neurons as it endures for the days, months, or years—even as the cells’ proteins are degraded and renewed. Increasingly, their research is pointing toward prion-like proteins as critical regulators of long-term memory.

In 2012, Si’s group demonstrated that prion formation in nerve cells is essential for the persistence of long-term memory in fruit flies. Prions are a fitting candidate for this job because their conversion is self-sustaining: once a prion-forming protein has shifted into its prion shape, additional proteins continue to convert without any additional stimulus.

Si’s team found that in fruit flies, the prion-forming protein Orb2 is necessary for memories to persist. Flies that produce a mutated version of Orb2 that is unable to form prions learn new behaviors, but their memories are short-lived. “Beyond a day, the memories become unstable. By three days, the memory has completely disappeared,” Si explains.

In the new study, Si wanted to find out how this process could be controlled so that memories form at the right time. “We know that all experiences do not form long-term memory—somehow the nervous system has a way to discriminate. So if prion-formation is the biochemical basis of memory, it must be regulated.” Si says. “But prion formation appears to be random for all the cases we know of so far.”

Si and his colleagues knew that Orb2 existed in two forms—Orb2A and Orb2B. Orb2B is widespread throughout the fruit fly’s nervous system, but Orb2A appears only in a few neurons, at extremely low concentrations. What’s more, once it is produced, Orb2A quickly falls apart; the protein has a half-life of only about an hour.

“When Orb2A binds to the more abundant form, it triggers conversion to the prion state, acting as a seed for the conversion. Once conversion begins, it is a self-sustaining process; additional Orb2 continues to convert to the prion state, with or without Orb2A. By altering the abundance of the Orb2A seed”, Si says, “cells might regulate where, when, and how the conversion process is engaged”. But how do nerve cells control the abundance of the Orb2A seed?

Their experiments revealed that when a protein called TOB associates with Orb2A , it becomes much more stable, with a new half-life of 24 hours. This step increases the prevalence of the prion-like state and explains how Orb2’s conversion to the prion state can be confined in both time and space.

The findings raise a host of new questions for Si, who now wants to understand what happens when Orb2 enters its prion-like state, as well as where in the brain the process occurs. While unraveling these mechanisms will likely be more accessible in the fruit fly than in more complex organisms, Si points out that proteins related to Orb2 and TOB have also been found in the brains of mice and humans. He has already shown that in the sea snail Aplysia, conversion to a prion-like state facilitates long-term change in synaptic strength. “This basic mechanism appears to be conserved across species,” he notes.

unlike viruses, Prions reproduce without genes.

a prion is an infectious entity and pathogen. proteins, as you may know (or not), are made of chains of amino-acids. composition dictates how these chains bend and curl, and form dictates function. now, a prion is a mal-formed protein, which causes other, similar proteins similarly denature: thus “reproducing”. they do this without DNA or other reproductive structures.

a common example of a prion infection is mad cow disease, and all prion diseases have similar prognosis: affecting the nervous system and being fatal.

http://en.wikipedia.org/wiki/Prion

Prion-Like Proteins Drive Several Diseases of Aging (Emory Health Sciences)

Two leading neurology researchers have proposed a theory that could unify scientists’ thinking about several neurodegenerative diseases and suggest therapeutic strategies to combat them.The theory and backing for it are described in the September 5, 2013 issue of Nature.

Mathias Jucker and Lary Walker outline the emerging concept that many of the brain diseases associated with aging, such as Alzheimer’s and Parkinson’s, are caused by specific proteins that misfold and aggregate into harmful seeds. These seeds behave very much like the pathogenic agents known as prions, which cause mad cow disease, chronic wasting disease in deer, scrapie in sheep, and Creutzfeldt-Jakob disease in humans.

In Nature, Walker and Jucker describe how prion-like protein aggregates drive the progression of several neurodegenerative diseases. A. Amyloid-beta plaques in Alzheimers B. Neurofibrillary tangles (tau) in Alzheimer’s C. Lewy bodies (alpha-synuclein) in Parkinson’s D. TDP-43 inclusions in motor neurons in ALS (Credit: Image courtesy of Emory Health Sciences)


Mathias Jucker, Lary C. Walker. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature, 2013; 501 (7465): 45 DOI: 10.1038/nature12481

Prions

Firstly, the term prion comes from the words protein and infection, which already gives some insight into what they’re all about. So basically, it’s an infectious agent made up of proteins in misfolded form.

Put in much simpler terms, prions are a microorganism, much like a virus or bacteria, that cause disease in the organism it’s hosting. It’s composed of proteins, which are little fibrous forms that control biological function, and while normally they kind of fold up into this little coil, when they are misfolded they can cause diseases. Which is exactly what prions do.

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Because of their structure, unlike other infectious agents, prions lack nucleic acids (DNA, RNA etc)

Prions increase in numbers by serving as a template for healthy proteins. So the prion enters into a healthy organism, like the new kid at school, and is sort of like, “Hey healthy proteins! You suck and I’m cool, so I’m here to f*ck shit up.” And all the healthy proteins are all, “Wow prion! You are so cool! We want to be just like you!” And so the healthy, normal proteins physically change to look just like the prion, in all it’s misfolded protein glory. Then, this gang of newly misfolded proteins go on to more healthy cells and peer pressure them into misfolding too. This chain reaction is how prions increase their numbers and spread.

So that’s why you don’t succumb to peer pressure, kids.

The screwed up structure of all these prions are incredibly stable and hard to contain. These prions accumulate in infected tissue causing disease and death. Fun stuff.

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09 March 2014

Prion Prevalance

Variant Creutzfeldt-Jakob disease (vCJD) is a rare and invariably fatal brain-wasting condition. It’s the human form of bovine spongiform encephalopathy (BSE), commonly known as ‘mad-cow disease’. At the root of both diseases are prion proteins – misfolded proteins that coax other proteins to misfold as well. This self-amplifying process results in an accumulation of toxic protein clumps (the large, fibrous blobs seen here) that destroy neurons. A BSE outbreak in the 1980s led to a surge of vCJD cases in the UK, and a recent study found that 1 in every 2,000 people there carries the disease-causing prion protein. But that doesn’t necessarily mean they will develop vCJD, because prion proteins were only found in the lymphoid system – including the spleen and tonsils – which is more easily infected than the brain. Nevertheless, scientists will be watching closely as it’s still not clear if the infection can spread from the lymphoid system.

Written by Daniel Cossins

Image courtesy of Theresa Hammett
Public Health Image Library
This image is in the public domain and can be freely reused
Research published in Biomedical Journal, October 2013

Vacuole in brain tissue caused by prion disease. A vacuole is basically just a hole, and that’s what prions do to your brain; cause cellular death on such a large scale that holes form in your brain.

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