Prion - Knowledge

1882:, an RNA-binding protein, has been found in ALS/MND patients, and mutations in the genes coding for these proteins have been identified in familial cases of ALS/MND. These mutations promote the misfolding of the proteins into a prion-like conformation. The misfolded form of TDP-43 forms cytoplasmic inclusions in affected neurons, and is found depleted in the nucleus. In addition to ALS/MND and FTLD-U, TDP-43 pathology is a feature of many cases of Alzheimer's disease, Parkinson's disease and Huntington's disease. The misfolding of TDP-43 is largely directed by its prion-like domain. This domain is inherently prone to misfolding, while pathological mutations in TDP-43 have been found to increase this propensity to misfold, explaining the presence of these mutations in familial cases of ALS/MND. As in yeast, the prion-like domain of TDP-43 has been shown to be both necessary and sufficient for protein misfolding and aggregation. 1858:

then aggregates like a known prion. Similarly, removing the prion domain from a fungal prion protein inhibits prionogenesis. This modular view of prion behaviour has led to the hypothesis that similar prion domains are present in animal proteins, in addition to PrP. These fungal prion domains have several characteristic sequence features. They are typically enriched in asparagine, glutamine, tyrosine and glycine residues, with an asparagine bias being particularly conducive to the aggregative property of prions. Historically, prionogenesis has been seen as independent of sequence and only dependent on relative residue content. However, this has been shown to be false, with the spacing of prolines and charged residues having been shown to be critical in amyloid formation.

671:-linked glycans, when present, project outward from the lateral surfaces of the fiber cores. Often PrP is bound to cellular membranes, presumably via its array of glycolipid anchors, however, sometimes the fibers are dissociated from membranes and accumulate outside of cells in the form of plaques. The end of each fiber acts as a template onto which free protein molecules may attach, allowing the fiber to grow. This growth process requires complete refolding of PrP. Different prion strains have distinct templates, or conformations, even when composed of PrP molecules of the same 1587:, and in the process, preserve the information corresponding to different strains of the prion state. It has also shed some light on prion domains, which are regions in a protein that promote the conversion into a prion. Fungal prions have helped to suggest mechanisms of conversion that may apply to all prions, though fungal prions appear distinct from infectious mammalian prions in the lack of cofactor required for propagation. The characteristic prion domains may vary between species – e.g., characteristic fungal prion domains are not found in mammalian prions. 719: 396: 205: 114: 612: 826: 834: 2083: 2069: 63: 1862:

particularly enriched in PrLD's, compared to other classes of protein. In particular, 29 of the known 210 proteins with an RNA recognition motif also have a putative prion domain. Meanwhile, several of these RNA-binding proteins have been independently identified as pathogenic in cases of ALS, FTLD-U, Alzheimer's disease, and Huntington's disease.

493:', the prototypic prion disease, occurring in sheep. PrP can also be induced to fold into other more-or-less well-defined isoforms in vitro; although their relationships to the form(s) that are pathogenic in vivo is often unclear, high-resolution structural analyses have begun to reveal structural features that correlate with prion infectivity. 2041:, announced that his team had purified the hypothetical infectious protein, which did not appear to be present in healthy hosts, though they did not manage to isolate the protein until two years after Prusiner's announcement. The protein was named a prion, for "proteinacious infectious particle", derived from the words 2018:" (1970): While asserting that the flow of sequence information from protein to protein, or from protein to RNA and DNA was "precluded", he noted that Griffith's hypothesis was a potential contradiction (although it was not so promoted by Griffith). The revised hypothesis was later formulated, in part, to accommodate 1301:(CWD) was buried, the hamsters became ill with CWD, suggesting that prions can bind to plants, which then take them up into the leaf and stem structure, where they can be eaten by herbivores, thus completing the cycle. It is thus possible that there is a progressively accumulating number of prions in the environment. 2052:

Following the discovery of the same protein in different form in uninfected individuals, the specific protein that the prion was composed of was named the prion protein (PrP), and Griffith's second hypothesis that an abnormal form of a host protein can convert other proteins of the same type into its

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prions degrade over time, while soil-bound prions remain at stable or increasing levels, suggesting that prions likely accumulate in the environment. One 2015 study by US scientists found that repeated drying and wetting may render soil bound prions less infectious, although this was dependent on the

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Similarly, pathogenic mutations have been identified in the prion-like domains of heterogeneous nuclear riboproteins hnRNPA2B1 and hnRNPA1 in familial cases of muscle, brain, bone and motor neuron degeneration. The wild-type form of all of these proteins show a tendency to self-assemble into amyloid

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research team has provided evidence for the theory that infection can occur from prions in manure. And, since manure is present in many areas surrounding water reservoirs, as well as used on many crop fields, it raises the possibility of widespread transmission. Although it was initially reported in

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Bioinformatic screens have predicted that over 250 human proteins contain prion-like domains (PrLD). These domains are hypothesized to have the same transmissible, amyloidogenic properties of PrP and known fungal proteins. As in yeast, proteins involved in gene expression and RNA binding seem to be

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The definition of a prion-like domain arises from the study of fungal prions. In yeast, prionogenic proteins have a portable prion domain that is both necessary and sufficient for self-templating and protein aggregation. This has been shown by attaching the prion domain to a reporter protein, which

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Immerse in 1N sodium hydroxide or sodium hypochlorite (20,000 parts per million available chlorine) for 1 hour; remove and rinse in water, then transfer to an open pan and heat in a gravity-displacement (121 °C) or in a porous-load (134 °C) autoclave for 1 hour; clean;

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It has been recognized that prion diseases can arise in three different ways: acquired, familial, or sporadic. It is often assumed that the diseased form directly interacts with the normal form to make it rearrange its structure. One idea, the "Protein X" hypothesis, is that an as-yet unidentified

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has argued some of the fungal prions are not associated with any disease state, but may have a useful role; however, researchers at the NIH have also provided arguments suggesting that fungal prions could be considered a diseased state. There is evidence that fungal proteins have evolved specific

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The mechanism of prion replication has implications for designing drugs. Since the incubation period of prion diseases is so long, an effective drug does not need to eliminate all prions, but simply needs to slow down the rate of exponential growth. Models predict that the most effective way to

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fibrils in patients with degenerative diseases has been well documented. These amyloid fibrils are seen as the result of pathogenic proteins that self-propagate and form highly stable, non-functional aggregates. While this does not necessarily imply a causal relationship between amyloid and

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There are no effective treatments for prion diseases. Clinical trials in humans have not met with success and have been hampered by the rarity of prion diseases. Although some potential treatments have shown promise in the laboratory, none have been effective once the disease has commenced.

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Many different mammalian species can be affected by prion diseases, as the prion protein (PrP) is very similar in all mammals. Due to small differences in PrP between different species it is unusual for a prion disease to transmit from one species to another. The human prion disease variant

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is observed during prion disease. This can be explained by taking into account fibril breakage. A mathematical solution for the exponential growth rate resulting from the combination of fibril growth and fibril breakage has been found. The exponential growth rate depends largely on the

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The primary method of infection in animals is through ingestion. It is thought that prions may be deposited in the environment through the remains of dead animals and via urine, saliva, and other body fluids. They may then linger in the soil by binding to clay and other minerals.

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and kuru had found evidence for the transfer of pathologically inert polysaccharides that only become infectious post-transfer, in the new host. Alper and Griffith wanted to account for the discovery that the mysterious infectious agent causing the diseases scrapie and

1985:, and introducing the protein could induce the gene's expression, that is, wake the dormant gene up, then the result would be a process indistinguishable from replication, as the gene's expression would produce the protein, which would then wake the gene in other 711:. The term "PrP" may refer either to protease-resistant forms of PrP, which is isolated from infectious tissue and associated with the transmissible spongiform encephalopathy agent, or to other protease-resistant forms of PrP that, for example, might be generated 1898:. With potential fatality rates of 100%, prions could be an effective bioweapon, sometimes called a "biochemical weapon", because a prion is a biochemical. An unfavorable aspect is prions' very long incubation periods. Persistent heavy exposure of prions to the 1371:

Immerse in 1N sodium hypochlorite (20,000 parts per million available chlorine) for 1 hour; transfer instruments to water; heat in a gravity-displacement autoclave at 121 °C for 1 hour; clean; and then perform routine sterilization

2049:. When the prion was discovered, Griffith's first hypothesis, that the protein was the product of a normally silent gene was favored by many. It was subsequently discovered, however, that the same protein exists in normal hosts but in different form. 854:

showed that the heterodimer model requires PrP to be an extraordinarily effective catalyst, increasing the rate of the conversion reaction by a factor of around 10. This problem does not arise if PrP exists only in aggregated forms such as

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Jendroska K, Heinzel FP, Torchia M, Stowring L, Kretzschmar HA, Kon A, et al. (September 1991). "Proteinase-resistant prion protein accumulation in Syrian hamster brain correlates with regional pathology and scrapie infectivity".

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Models of normal (PrP) and infectious (PrP) forms of prion protein on a membrane: polypeptide (turquoise); glycans (red); glycolipid anchors (blue). The core structures are based on NMR spectroscopy (PrP) and cryo-electron microscopy

1236:), after one of the diseases first linked to prions and neurodegeneration. The precise structure of the prion is not known, though they can be formed spontaneously by combining PrP, homopolymeric polyadenylic acid, and lipids in a 1854:. AA amyloidosis, like prion disease, may be transmissible. This has given rise to the 'prion paradigm', where otherwise harmless proteins can be converted to a pathogenic form by a small number of misfolded, nucleating proteins. 753:

MAVS, RIP1, and RIP3 are prion-like proteins found in other parts of the body. They also polymerise into filamentous amyloid fibers which initiate regulated cell death in the case of a viral infection to prevent the spread of

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its conversion into PrP. The two PrP molecules then come apart and can go on to convert more PrP. However, a model of prion replication must explain both how prions propagate, and why their spontaneous appearance is so rare.

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Telling GC, Parchi P, DeArmond SJ, Cortelli P, Montagna P, Gabizon R, et al. (December 1996). "Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity".

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His second hypothesis forms the basis of the modern prion theory, and proposed that an abnormal form of a cellular protein can convert normal proteins of the same type into its abnormal form, thus leading to replication.

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More recent studies suggest scrapie prions can be degraded by diverse cellular machinery. Inhibition of autophagy accelerates prion accumulation whereas encouragement of autophagy promotes prion clearance. The

2004:, as such an antibody would result in more and more antibody being produced against itself. However, Griffith acknowledged that this third hypothesis was unlikely to be true due to the lack of a detectable 1407:

Renaturation of a completely denatured prion to infectious status has not yet been achieved; however, partially denatured prions can be renatured to an infective status under certain artificial conditions.

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have provided only limited information because these animals exhibit only minor abnormalities. In research done in mice, it was found that the cleavage of PrP in peripheral nerves causes the activation of

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has given strong support to the protein-only concept, since purified protein extracted from cells with a prion state has been demonstrated to convert the normal form of the protein into a misfolded form

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degenerative diseases, the toxicity of certain amyloid forms and the overproduction of amyloid in familial cases of degenerative disorders supports the idea that amyloid formation is generally toxic.

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Nitrini R, Rosemberg S, Passos-Bueno MR, da Silva LS, Iughetti P, Papadopoulos M, et al. (August 1997). "Familial spongiform encephalopathy associated with a novel prion protein gene mutation".

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The pathogenicity of prions and proteins with prion-like domains is hypothesized to arise from their self-templating ability and the resulting exponential growth of amyloid fibrils. The presence of

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Koga Y, Tanaka S, Sakudo A, Tobiume M, Aranishi M, Hirata A, et al. (March 2014). "Proteolysis of abnormal prion protein with a thermostable protease from Thermococcus kodakarensis KOD1".

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has a similar genetic sequence to yeast prion proteins. The prion-like formation of CPEB is essential for maintaining long-term synaptic changes associated with long-term memory formation.

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Prion-like domains have been found in a variety of other mammalian proteins. Some of these proteins have been implicated in the ontogeny of age-related neurodegenerative disorders such as

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are dependent upon it to direct their continued replication. Prions, however, are infectious by their effect on normal versions of the protein. Sterilizing prions, therefore, requires the

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Langeveld JP, Wang JJ, Van de Wiel DF, Shih GC, Garssen GJ, Bossers A, et al. (December 2003). "Enzymatic degradation of prion protein in brain stem from infected cattle and sheep".

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tissues. These diseases are progressive, have no known effective treatment, and are invariably fatal. Most prion diseases were thought to be caused by PrP until 2015 when a prion form of

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that continuously changes conformation unless bound to a specific partner, such as another protein. Once a prion binds to another in the same conformation, it stabilizes and can form a

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Caughey BW, Dong A, Bhat KS, Ernst D, Hayes SF, Caughey WS (August 1991). "Secondary structure analysis of the scrapie-associated protein PrP 27-30 in water by infrared spectroscopy".

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Bamborough P, Wille H, Telling GC, Yehiely F, Prusiner SB, Cohen FE (1996). "Prion protein structure and scrapie replication: theoretical, spectroscopic, and genetic investigations".

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for prion diseases is relatively long (5 to 20 years), once symptoms appear the disease progresses rapidly, leading to brain damage and death. Neurodegenerative symptoms can include

10262: 365:, and is short for "proteinaceous infectious particle", in reference to its ability to self-propagate and transmit its conformation to other proteins. Its main pronunciation is 8419: 10949: 3878:

Kraus A, Hoyt F, Schwartz CL, Hansen B, Artikis E, Hughson AG, et al. (November 2021). "High-resolution structure and strain comparison of infectious mammalian prions".

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Kraus A, Hoyt F, Schwartz CL, Hansen B, Artikis E, Hughson AG, et al. (November 2021). "High-resolution structure and strain comparison of infectious mammalian prions".

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affecting both humans and animals. These proteins can misfold sporadically, due to genetic mutations, or by exposure to an already misfolded protein, leading to an abnormal

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Dickinson J, Murdoch H, Dennis MJ, Hall GA, Bott R, Crabb WD, et al. (May 2009). "Decontamination of prion protein (BSE301V) using a genetically engineered protease".

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Knowles TP, Waudby CA, Devlin GL, Cohen SI, Aguzzi A, Vendruscolo M, et al. (December 2009). "An analytical solution to the kinetics of breakable filament assembly".

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functions that are beneficial to the microorganism that enhance their ability to adapt to their diverse environments. Further, within yeasts, prions can act as vectors of

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Mitsuiki S, Hui Z, Matsumoto D, Sakai M, Moriyama Y, Furukawa K, et al. (May 2006). "Degradation of PrP(Sc) by keratinolytic protease from Nocardiopsis sp. TOA-1".

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recommends any of the following three procedures for the sterilization of all heat-resistant surgical instruments to ensure that they are not contaminated with prions:

8445: 6672: 6615:"New studies on the heat resistance of hamster-adapted scrapie agent: threshold survival after ashing at 600 degrees C suggests an inorganic template of replication" 1240:(PMCA) reaction even in the absence of pre-existing infectious prions. This result is further evidence that prion replication does not require genetic information. 3913:

Bessen RA, Kocisko DA, Raymond GJ, Nandan S, Lansbury PT, Caughey B (June 1995). "Non-genetic propagation of strain-specific properties of scrapie prion protein".

1294: 8361: 2859: 2757: 481:, the enzymes in the body that can normally break down proteins. The normal form of the protein is called PrP, while the infectious form is called PrP – the 7199:

Hui Z, Doi H, Kanouchi H, Matsuura Y, Mohri S, Nonomura Y, et al. (August 2004). "Alkaline serine protease produced by Streptomyces sp. degrades PrP(Sc)".

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Safar J, Wille H, Itri V, Groth D, Serban H, Torchia M, et al. (October 1998). "Eight prion strains have PrP(Sc) molecules with different conformations".

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of the protein to a state in which the molecule is no longer able to induce the abnormal folding of normal proteins. In general, prions are quite resistant to

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A 2006 article from the Whitehead Institute for Biomedical Research indicates that PrP expression on stem cells is necessary for an organism's self-renewal of

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The physiological function of the prion protein remains poorly understood. While data from in vitro experiments suggest many dissimilar roles, studies on PrP

679:. Under most circumstances, only PrP molecules with an identical amino acid sequence to the infectious PrP are incorporated into the growing fiber. However, 2689: 5733: 4241:

Kocisko DA, Come JH, Priola SA, Chesebro B, Raymond GJ, Lansbury PT, et al. (August 1994). "Cell-free formation of protease-resistant prion protein".

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The Nobel Prize in Physiology or Medicine 1997 was awarded to Stanley B. Prusiner 'for his discovery of Prions - a new biological principle of infection.'

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Researchers at Dartmouth College discovered that endogenous host cofactor molecules such as the phospholipid molecule (e.g. phosphatidylethanolamine) and

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Goedert M (August 2015). "NEURODEGENERATION. Alzheimer's and Parkinson's diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein".

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https://www.hopkinsmedicine.org/health/conditions-and-diseases/prion-diseases#:~:text=A%20prion%20is%20a%20type,the%20abnormal%20protein%20is%20unknown

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Maglio LE, Perez MF, Martins VR, Brentani RR, Ramirez OA (November 2004). "Hippocampal synaptic plasticity in mice devoid of cellular prion protein".

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sterilization is currently being studied as a potential method for prion denaturation and deactivation. Other approaches being developed include

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achieve this, using a drug with the lowest possible dose, is to find a drug that binds to fibril ends and blocks them from growing any further.

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Saborio GP, Permanne B, Soto C (June 2001). "Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding".

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Protease-resistant PrP-like protein (PrP) is the name given to any isoform of PrP which is structurally altered and converted into a misfolded

9041: 1525:. Amyloid aggregates are fibrils, growing at their ends, and replicate when breakage causes two growing ends to become four growing ends. The 863:

may act as a barrier to spontaneous conversion. What is more, despite considerable effort, infectious monomeric PrP has never been isolated.

1277:, this report was retracted in 2024. Preliminary evidence supporting the notion that prions can be transmitted through use of urine-derived 797:

express PrP on their cell membrane and that hematopoietic tissues with PrP-null stem cells exhibit increased sensitivity to cell depletion.

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comes from "proteinaceous infectious particle". Unlike other infectious agents such as viruses, bacteria, and fungi, prions do not contain

2242: 1926:. Although the cause of scrapie was not known back then, it is probably the first transmissible spongiform encephalopathy to be recorded. 329:. These amyloids accumulate in infected tissue, causing damage and cell death. The structural stability of prions makes them resistant to 10825: 2159: 5986:"Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein" 4986:"Sequential appearance and accumulation of pathognomonic markers in the central nervous system of hamsters orally infected with scrapie" 3278: 2316: 440:(prions or whalebirds) is pronounced, is also heard. In his 1982 paper introducing the term, Prusiner specified that it is "pronounced 568:. The significance of this property is not clear, but it is presumed to relate to the protein's structure or function. PrP is readily 473:(PrP), a protein that is a natural part of the bodies of humans and other animals. The PrP found in infectious prions has a different 10897: 9106: 7708:

Halfmann R, Lindquist S (October 2010). "Epigenetics in the extreme: prions and the inheritance of environmentally acquired traits".

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cellular protein (Protein X) enables the conversion of PrP to PrP by bringing a molecule of each of the two together into a complex.

221: 8415: 6700:"Rapid chemical decontamination of infectious CJD and scrapie particles parallels treatments known to disrupt microbes and biofilms" 5425: 2014:

recognized the potential significance of the Griffith protein-only hypothesis for scrapie propagation in the second edition of his "

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Hsu RL, Lee KT, Wang JH, Lee LY, Chen RP (January 2009). "Amyloid-degrading ability of nattokinase from Bacillus subtilis natto".

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found that plants can be a vector for prions. When researchers fed hamsters grass that grew on ground where a deer that died with

9326: 9253: 7818:"Non-Mendelian determinant [ISP+] in yeast is a nuclear-residing prion form of the global transcriptional regulator Sfp1" 3300:

Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R, et al. (1997). "The cellular prion protein binds copper in vivo".

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of PrP, known as PrP, or simply the prion, is able to convert normal PrP proteins into the infectious isoform by changing their

7002:"Mitigation of prion infectivity and conversion capacity by a simulated natural process--repeated cycles of drying and wetting" 2591:

Olanow CW, Brundin P (January 2013). "Parkinson's disease and alpha synuclein: is Parkinson's disease a prion-like disorder?".

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treatments, although their infectivity can be reduced by such treatments. Effective prion decontamination relies upon protein

11065: 9349: 9300: 8846: 5968: 5935: 4875: 3272: 2054: 1094: 8441: 6531:"Methods to minimize the risks of Creutzfeldt-Jakob disease transmission by surgical procedures: where to set the standard?" 1920:"lie down, bite at their feet and legs, rub their backs against posts, fail to thrive, stop feeding and finally become lame" 1899: 259:(PrP), a naturally occurring protein with an uncertain function. They are the hypothesized cause of various TSEs, including 1937:

could be transmitted to chimpanzees by what was possibly a new infectious agent, work for which he eventually won the 1976

6676: 10758: 2101: 813:, the PrP gene, is upregulated in many viral infections and PrP has antiviral properties against many viruses, including 4901:"Copurification of Sp33-37 and scrapie agent from hamster brain prior to detectable histopathology and clinical disease" 4776:

Cohen FE, Pan KM, Huang Z, Baldwin M, Fletterick RJ, Prusiner SB (April 1994). "Structural clues to prion replication".

10929: 8390: 8357: 4670:"Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal" 2015: 1211:

was found to be transmissible and was hypothesized to be caused by a new prion, the misfolded form of a protein called

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Agarwal A, Mukhopadhyay S (January 2022). "Prion Protein Biology Through the Lens of Liquid-Liquid Phase Separation".

870:, and that fibril ends bind PrP and convert it into PrP. If this were all, then the quantity of prions would increase 11037: 10815: 9396: 4854:

Vázquez-Fernández E, Young HS, Requena JR, Wille H (2017). "The Structure of Mammalian Prions and Their Aggregates".

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rate associated with prion replication, which is a balance between the linear growth and the breakage of aggregates.

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Masel J, Jansen VA (December 2000). "Designing drugs to stop the formation of prion aggregates and other amyloids".

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structure. This disruption is characterized by "holes" in the tissue with resultant spongy architecture due to the

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Málaga-Trillo E, Solis GP, Schrock Y, Geiss C, Luncz L, Thomanetz V, et al. (March 2009). Weissmann C (ed.).

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do not always cause disease in their hosts. In yeast, protein refolding to the prion configuration is assisted by

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combined with heat and detergent. A method sufficient for sterilizing prions on one material may fail on another.

918:(e.g. single stranded RNA molecules) are necessary to form PrP molecules with high levels of specific infectivity 11191: 11135: 9381: 2736: 983: 628: 5772: 3237: 11130: 10743: 10093: 9688: 9406: 8728:

Field EJ, Farmer F, Caspary EA, Joyce G (April 1969). "Susceptibility of scrapie agent to ionizing radiation".

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Alper T, Cramp WA, Haig DA, Clarke MC (May 1967). "Does the agent of scrapie replicate without nucleic acid?".

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Eraña H, Pérez-Castro MÁ, García-Martínez S, Charco JM, López-Moreno R, Díaz-Dominguez CM, et al. (2020).

5555: 3132:"Structure of the recombinant full-length hamster prion protein PrP(29-231): the N terminus is highly flexible" 2950: 1914:

In the 18th and 19th centuries, exportation of sheep from Spain was observed to coincide with a disease called

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might shorten the overall onset. Another aspect of using prions in warfare is the difficulty of detection and

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Creutzfeldt–Jakob disease, however, is thought to be caused by a prion that typically infects cattle, causing

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Van Dorsselaer A, Carapito C, Delalande F, Schaeffer-Reiss C, Thierse D, Diemer H, et al. (March 2011).

5832:"Intracellular re-routing of prion protein prevents propagation of PrP(Sc) and delays onset of prion disease" 1963: 1811: 1278: 1078: 307: 272: 7614:"Probing the role of PrP repeats in conformational conversion and amyloid assembly of chimeric yeast prions" 6298:"Detection of prion protein in urine-derived injectable fertility products by a targeted proteomic approach" 1368:

at 121 °C for 30 minutes; clean; rinse in water; and then perform routine sterilization processes.

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Newby GA, Lindquist S (June 2013). "Blessings in disguise: biological benefits of prion-like mechanisms".

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Gilch S, Winklhofer KF, Groschup MH, Nunziante M, Lucassen R, Spielhaupter C, et al. (August 2001).

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Overwhelming evidence shows that prions resist degradation and persist in the environment for years, and

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Ayers JI, Prusiner SB (April 2020). "Prion protein - mediator of toxicity in multiple proteinopathies".

3658:"Cryo-EM structure of anchorless RML prion reveals variations in shared motifs between distinct strains" 2279: 11169: 8442:"Prions as Bioweapons? - Much Ado About Nothing; or Apt Concerns Over Tiny Proteins used in Biowarfare" 7935: 5264:"Cofactor molecules maintain infectious conformation and restrict strain properties in purified prions" 2887: 1334: 680: 229: 7445:

Johnson CJ, Bennett JP, Biro SM, Duque-Velasquez JC, Rodriguez CM, Bessen RA, et al. (May 2011).

6792:"A Novel, Reliable and Highly Versatile Method to Evaluate Different Prion Decontamination Procedures" 5077:

Masel J, Jansen VA, Nowak MA (March 1999). "Quantifying the kinetic parameters of prion replication".

3564:"Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins" 10247: 10098: 7612:

Dong J, Bloom JD, Goncharov V, Chattopadhyay M, Millhauser GL, Lynn DG, et al. (November 2007).

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Haybaeck J, Heikenwalder M, Klevenz B, Schwarz P, Margalith I, Bridel C, et al. (January 2011).

4572:"PrPC controls via protein kinase A the direction of synaptic plasticity in the immature hippocampus" 1353: 589: 225: 7816:

Rogoza T, Goginashvili A, Rodionova S, Ivanov M, Viktorovskaya O, Rubel A, et al. (June 2010).

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Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB, et al. (September 2015).

11213: 11001: 10914: 10883: 10802: 10748: 9945: 9846: 9763: 9295: 9201: 7968:"The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease" 6084:

Tamgüney G, Miller MW, Wolfe LL, Sirochman TM, Glidden DV, Palmer C, et al. (September 2009).

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Wille H, Michelitsch MD, Guenebaut V, Supattapone S, Serban A, Cohen FE, et al. (March 2002).

1930: 1922:. The disease was also observed to have the long incubation period that is a key characteristic of 1886:

fibrils, while the pathogenic mutations exacerbate this behaviour and lead to excess accumulation.

1624: 1538: 1361: 1257: 770:. As well, a 2004 study found that mice lacking genes for normal cellular PrP protein show altered 640: 464: 8302:"Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS" 6245:

Haybaeck J, Heikenwalder M, Klevenz B, Schwarz P, Margalith I, Bridel C, et al. (July 2024).

5791:"Variant Creutzfeldt-Jakob disease: risk of transmission by blood transfusion and blood therapies" 5360:

Babelhadj B, Di Bari MA, Pirisinu L, Chiappini B, Gaouar SB, Riccardi G, et al. (June 2018).

2828: 922:, whereas protein-only PrP molecules appear to lack significant levels of biological infectivity. 655:

fibers in which individual PrP molecules are stacked via intermolecular beta sheets. However, 2-D

333:

by chemical or physical agents, complicating disposal and containment, and raising concerns about

11174: 10991: 10976: 10837: 9972: 9748: 9391: 9226: 8158:"A systematic survey identifies prions and illuminates sequence features of prionogenic proteins" 7364: 3189:

Hegde RS, Mastrianni JA, Scott MR, DeFea KA, Tremblay P, Torchia M, et al. (February 1998).

1827: 1298: 1208: 1203:

Until 2015 all known mammalian prion diseases were considered to be caused by the prion protein,

1021: 841:

The first hypothesis that tried to explain how prions replicate in a protein-only manner was the

794: 597: 295: 264: 8468:"How Prions Came to Be: A Brief History – Infectious Disease: Superbugs, Science, & Society" 4053:"Cryo-EM of prion strains from the same genotype of host identifies conformational determinants" 11179: 11104: 10996: 10200: 9516: 6570:

Collins SJ, Lawson VA, Masters CL (January 2004). "Transmissible spongiform encephalopathies".

5984:

Telling GC, Scott M, Mastrianni J, Gabizon R, Torchia M, Cohen FE, et al. (October 1995).

5086: 2238: 2151: 1823: 1819: 1443: 1261:

January 2011 that researchers had discovered prions spreading through airborne transmission on

1150: 774: 303: 299: 17: 9160: 9037: 7140:

Okoroma EA, Purchase D, Garelick H, Morris R, Neale MH, Windl O, et al. (July 16, 2013).

11094: 11079: 10959: 9960: 9933: 9548: 9164: 9156: 7054:

López-Pérez Ó, Badiola JJ, Bolea R, Ferrer I, Llorens F, Martín-Burriel I (August 27, 2020).

5050: 4570:

Caiati MD, Safiulina VF, Fattorini G, Sivakumaran S, Legname G, Cherubini E (February 2013).

4492:

Shorter J, Lindquist S (June 2005). "Prions as adaptive conduits of memory and inheritance".

2533:"Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers" 2458:"Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism" 2019: 1946: 766:

A review of evidence in 2005 suggested that PrP may have a normal function in maintenance of

707:. demonstrated sustained amplification of PrP and prion infectivity by a procedure involving 542: 9536: 3770:

Hallinan GI, Ozcan KA, Hoq MR, Cracco L, Vago FS, Bharath SR, et al. (September 2022).

3523:"Conformational transitions, dissociation, and unfolding of scrapie amyloid (prion) protein" 3260: 2310: 777:. A recent study that also suggests why this might be the case, found that neuronal protein 615:

PrP (stained in red) revealed in a photomicrograph of scrapie-infected mouse neuronal cells.

11282: 11201: 11099: 11017: 10847: 9904: 9899: 9775: 8943: 8926: 8883: 8788: 8737: 8602: 8551: 8313: 8112: 7898: 7829: 7772: 7717: 7566: 7458: 7376: 7247: 7153: 6854: 6626: 6309: 6097: 5131: 4785: 4681: 4366: 4311: 4250: 3974: 3922: 3832: 3772:"Cryo-EM structures of prion protein filaments from Gerstmann-Sträussler-Scheinker disease" 3726: 3669: 3575: 3309: 3205: 3143: 3088: 2704: 2544: 2469: 2405: 2347: 1953:

are caused by an infectious agent consisting solely of proteins. Earlier investigations by

1847: 1546:

in the early 1990s. For their mechanistic similarity to mammalian prions, they were termed

1397: 639:

structure. Several highly infectious, brain-derived PrP structures have been discovered by

7142:"Enzymatic formulation capable of degrading scrapie prion under mild digestion conditions" 5450:

Mastrianni JA, Nixon R, Layzer R, Telling GC, Han D, DeArmond SJ, et al. (May 1999).

4621:"Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains" 3130:

Donne DG, Viles JH, Groth D, Mehlhorn I, James TL, Cohen FE, et al. (December 1997).

8: 11027: 10422: 10140: 9982: 9938: 9894: 9632: 9190: 5410: 4051:

Hoyt F, Alam P, Artikis E, Schwartz CL, Hughson AG, Race B, et al. (November 2022).

2034: 2023: 1561: 1510: 1338: 703:. showed that PrP could cause PrP to convert to PrP under cell-free conditions and Soto 672: 470: 453: 350: 256: 71: 42: 8887: 8792: 8741: 8606: 8555: 8317: 8116: 7833: 7776: 7721: 7570: 7510:

Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences

7462: 7380: 7251: 7157: 6858: 6630: 6313: 6273: 6246: 6101: 5330: 5135: 4789: 4685: 4370: 4315: 4254: 4128: 4103: 3978: 3926: 3836: 3730: 3673: 3579: 3313: 3209: 3147: 3092: 3074:"NMR characterization of the full-length recombinant murine prion protein, mPrP(23-231)" 2708: 2640:

Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences

2548: 2473: 2409: 2351: 1536:

Fungal proteins exhibiting templated conformational change were discovered in the yeast

845:

model. This model assumed that a single PrP molecule binds to a single PrP molecule and

718: 651:

has also been determined. All of the structures described in high resolution so far are

11162: 11045: 10716: 10638: 10190: 9014: 8989: 8907: 8812: 8761: 8670: 8645: 8626: 8575: 8519: 8494: 8334: 8301: 8282: 8234: 8209: 8182: 8157: 8133: 8100: 8040: 7992: 7967: 7852: 7817: 7793: 7760: 7741: 7640: 7613: 7589: 7554: 7530: 7505: 7481: 7447:"Degradation of the disease-associated prion protein by a serine protease from lichens" 7446: 7270: 7235: 7176: 7141: 7082: 7055: 7028: 7001: 6977: 6950: 6926: 6901: 6818: 6791: 6772: 6724: 6699: 6595: 6482:"Inactivation of transmissible spongiform encephalopathy (prion) agents by environ LpH" 6462: 6450: 6414: 6389: 6332: 6297: 6212: 6204: 6169: 6142: 6118: 6085: 6061: 6034: 6015: 5764: 5668: 5641: 5596: 5528: 5386: 5361: 5290: 5263: 5239: 5212: 5155: 4966: 4753: 4728: 4704: 4669: 4645: 4620: 4596: 4571: 4517: 4469: 4444: 4425: 4335: 4284: 4177: 4152: 4102:

Manka SW, Wenborn A, Betts J, Joiner S, Saibil HR, Collinge J, et al. (May 2023).

4079: 4052: 4033: 3946: 3796: 3771: 3747: 3714: 3690: 3657: 3562:

Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, et al. (December 1993).

3422: 3395: 3376: 3333: 3229: 3112: 3054: 3000: 2973: 2942: 2805: 2780: 2728: 2660: 2635: 2616: 2565: 2532: 2492: 2457: 2371: 2181: 1967: 1843: 1552: 1530: 1322: 879: 875: 593: 9417: 8706: 6877: 6842: 6583: 6506: 6481: 6437:

Qin K, O'Donnell M, Zhao RY (August 2006). "Doppel: more rival than double to prion".

5856: 5831: 5186: 5100: 4832: 4548: 4389: 4354: 3855: 3820: 3539: 3522: 3100: 1838:

that develops in humans and animals with inflammatory and infectious diseases such as

1556:. These prions behave similarly to PrP, but, in general, are nontoxic to their hosts. 1521:

fold, in which the protein polymerises into an aggregate consisting of tightly packed

541:

forms. The normal protein is not sedimentable; meaning that it cannot be separated by

11292: 11287: 10694: 10610: 10512: 10282: 10185: 9889: 9019: 8948: 8899: 8842: 8834: 8804: 8753: 8710: 8675: 8618: 8567: 8524: 8339: 8286: 8274: 8239: 8187: 8138: 8081: 8044: 8032: 7997: 7902: 7857: 7798: 7759:

Halfmann R, Jarosz DF, Jones SK, Chang A, Lancaster AK, Lindquist S (February 2012).

7745: 7733: 7690: 7645: 7594: 7535: 7486: 7427: 7392: 7345: 7310: 7275: 7234:

Snajder M, Vilfan T, Cernilec M, Rupreht R, Popović M, Juntes P, et al. (2012).

7216: 7181: 7122: 7087: 7033: 6982: 6931: 6882: 6823: 6764: 6729: 6654: 6649: 6614: 6587: 6552: 6511: 6454: 6419: 6388:

Pritzkow S, Morales R, Moda F, Khan U, Telling GC, Hoover E, et al. (May 2015).

6337: 6278: 6193: 6174: 6123: 6066: 6007: 6002: 5985: 5964: 5941: 5931: 5896: 5861: 5812: 5807: 5790: 5756: 5714: 5673: 5588: 5551: 5520: 5473: 5391: 5295: 5244: 5190: 5147: 5104: 5038: 5003: 4958: 4922: 4881: 4871: 4836: 4801: 4758: 4709: 4650: 4601: 4552: 4509: 4474: 4394: 4327: 4276: 4223: 4182: 4133: 4084: 4025: 3990: 3938: 3895: 3860: 3801: 3752: 3713:

Manka SW, Zhang W, Wenborn A, Betts J, Joiner S, Saibil HR, et al. (July 2022).

3695: 3656:

Hoyt F, Standke HG, Artikis E, Schwartz CL, Hansen B, Li K, et al. (July 2022).

3638: 3603: 3598: 3563: 3544: 3503: 3468: 3427: 3368: 3325: 3268: 3221: 3171: 3166: 3131: 3104: 3046: 3005: 2934: 2810: 2720: 2665: 2608: 2570: 2497: 2433: 2428: 2393: 2363: 1526: 1479: 1174: 1004: 888: 624: 474: 158: 11246: 9195: 8300:

Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, et al. (March 2013).

6599: 6497: 6466: 6019: 5768: 5600: 5532: 4970: 4429: 3380: 3233: 3116: 3058: 2946: 2864: 2620: 2375: 9921: 9815: 9448: 9009: 9001: 8938: 8911: 8891: 8816: 8796: 8765: 8745: 8702: 8665: 8657: 8630: 8610: 8579: 8559: 8514: 8506: 8329: 8321: 8266: 8229: 8221: 8177: 8169: 8128: 8120: 8071: 8024: 7987: 7983: 7979: 7894: 7847: 7837: 7788: 7780: 7725: 7680: 7672: 7635: 7625: 7584: 7574: 7525: 7517: 7476: 7466: 7419: 7384: 7337: 7302: 7265: 7255: 7208: 7171: 7161: 7114: 7077: 7067: 7023: 7013: 6972: 6962: 6921: 6913: 6872: 6862: 6813: 6803: 6776: 6756: 6719: 6711: 6644: 6634: 6579: 6542: 6501: 6493: 6446: 6409: 6401: 6361: 6327: 6317: 6268: 6258: 6185: 6164: 6154: 6113: 6105: 6056: 6046: 5997: 5923: 5888: 5851: 5843: 5802: 5752: 5748: 5704: 5663: 5653: 5584: 5580: 5512: 5463: 5381: 5373: 5285: 5275: 5234: 5224: 5182: 5159: 5139: 5096: 5030: 4993: 4950: 4912: 4863: 4828: 4793: 4748: 4740: 4699: 4689: 4640: 4632: 4591: 4587: 4583: 4544: 4521: 4501: 4464: 4456: 4417: 4384: 4374: 4339: 4319: 4288: 4266: 4258: 4213: 4172: 4164: 4123: 4115: 4074: 4064: 4037: 4017: 3982: 3950: 3930: 3887: 3850: 3840: 3791: 3783: 3742: 3734: 3685: 3677: 3630: 3593: 3583: 3534: 3495: 3458: 3417: 3407: 3360: 3337: 3317: 3213: 3161: 3151: 3096: 3036: 2995: 2985: 2926: 2800: 2792: 2732: 2712: 2655: 2647: 2600: 2560: 2552: 2487: 2477: 2423: 2413: 2355: 2111: 1895: 1462: 1342: 1158: 767: 656: 546: 530: 522: 406: 368: 177: 124: 86: 9005: 8510: 7388: 6715: 6247:"Retraction: Aerosols Transmit Prions to Immunocompetent and Immunodeficient Mice" 4636: 4168: 3986: 11272: 11223: 11060: 10906: 10554: 10178: 9872: 9851: 9780: 9583: 9206: 8101:"Self-propagation of pathogenic protein aggregates in neurodegenerative diseases" 7471: 7260: 7166: 7018: 6967: 6405: 6322: 6263: 6189: 6159: 6051: 6035:"Oral transmissibility of prion disease is enhanced by binding to soil particles" 5927: 5709: 5692: 4917: 4900: 4867: 4353:

Bieschke J, Weber P, Sarafoff N, Beekes M, Giese A, Kretzschmar H (August 2004).

4069: 3891: 3634: 3412: 3217: 2116: 2074: 2027: 2005: 1903: 1557: 1449: 1365: 1274: 1212: 1149:

Prions cause neurodegenerative disease by aggregating extracellularly within the

896: 871: 806: 581: 561: 291: 252: 7236:"Enzymatic degradation of PrPSc by a protease secreted from Aeropyrum pernix K1" 5468: 5451: 5034: 4998: 4985: 3261:"Taking aim at the transmissible spongiform encephalopathie's infectious agents" 3023:

Robertson C, Booth SA, Beniac DR, Coulthart MB, Booth TF, McNicol A (May 2006).

1215:. The endogenous, properly folded form of the prion protein is denoted PrP (for 1189:(balance and coordination dysfunction), and behavioural or personality changes. 11050: 11022: 10603: 10568: 10561: 10540: 10519: 10496: 10376: 10168: 10055: 9926: 9785: 9768: 9573: 9503: 9354: 9321: 9290: 8225: 8173: 7822: