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286534 occurrences (No.87 in the rank) during 5 years in the PubMed. [no cache] 500 found

385) Exposed to mutant substrate, the winning PrP(Sc) conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to the lowest stability.

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PMID:24401672 DOI:10.1097/COC.0000000000000004

2015 Prion

* Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases.

- There is a growing body of evidence indicating that number of human neurodegenerative diseases, including Alzheimer disease, Parkinson disease, fronto-temporal dementias, and amyotrophic lateral sclerosis, propagate in the brain via prion-like intercellular induction of protein misfolding. Prions cause lethal neurodegenerative diseases in humans, the most prevalent being sporadic Creutzfeldt-Jakob disease (sCJD); they self-replicate and spread by converting the cellular form of prion protein (PrP(C)) to a misfolded pathogenic conformer (PrP(Sc)). The extensive phenotypic heterogeneity of human prion diseases is determined by polymorphisms in the prion protein gene, and by prion strain-specific conformation of PrP(Sc). Remarkably, even though informative nucleic acid is absent, prions may undergo rapid adaptation and evolution in cloned cells and upon crossing the species barrier. In the course of our investigation of this process, we isolated distinct populations of PrP(Sc) particles that frequently co-exist in sCJD. The human prion particles replicate independently and undergo competitive selection of those with lower initial conformational stability. Exposed to mutant substrate, the winning PrP(Sc) conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to the lowest stability. Thus, the evolution and adaptation of human prions is enabled by a dynamic collection of distinct populations of particles, whose evolution is governed by the selection of progressively less stable, faster replicating PrP(Sc) conformers. This fundamental biological mechanism may explain the drug resistance that some prions gained after exposure to compounds targeting PrP(Sc). Whether the phenotypic heterogeneity of other neurodegenerative diseases caused by protein misfolding is determined by the spectrum of misfolded conformers (strains) remains to be established. However, the prospect that these conformers may evolve and adapt by a prion-like mechanism calls for the reevaluation of therapeutic strategies that target aggregates of misfolded proteins, and argues for new therapeutic approaches that will focus on prior pathogenetic steps.

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(1)163 of	(9)7 to	(17)3 were	(25)2 may
(2)56 was	(10)6 at	(18)3 without	(26)2 or
(3)44 and	(11)4 as	(19)2 (HR)	(27)2 per
(4)34 null	(12)4 from	(20)2 =	(28)2 product
(5)14 in	(13)4 variability	(21)2 by	(29)2 step
(6)9 is	(14)3 after	(22)2 compared	(30)2 that
(7)8 for	(15)3 coding	(23)2 due	(31)2 under
(8)7 than	(16)3 ranged	(24)2 enzyme	(32)2 which

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--- WordNet output for rate --- =>価格を評定する, 割合, 率, 歩合, 料金, 値段, 相場, 速度, 度合, 人を〜を思う, みなす, 価値がある, 人を〜とみなす, 科金, 評価する Overview of noun rate The noun rate has 4 senses (first 3 from tagged texts) 1. (68) rate -- (a magnitude or frequency relative to a time unit; "they traveled at a rate of 55 miles per hour"; "the rate of change was faster than expected") 2. (39) rate, charge per unit -- (amount of a charge or payment relative to some basis; "a 10-minute phone call at that rate would cost $5") 3. (1) pace, rate -- (the relative speed of progress or change; "he lived at a fast pace"; "he works at a great rate"; "the pace of events accelerated") 4. rate -- (a quantity or amount or measure considered as a proportion of another quantity or amount or measure; "the literacy rate"; "the retention rate"; "the dropout rate") Overview of verb rate The verb rate has 3 senses (first 3 from tagged texts) 1. (9) rate, rank, range, order, grade, place -- (assign a rank or rating to; "how would you rank these students?"; "The restaurant is rated highly in the food guide") 2. (2) rate -- (be worthy of or have a certain rating; "This bond rates highly") 3. (1) rate, value -- (estimate the value of; "How would you rate his chances to become President?"; "Gold was rated highly among the Romans") --- WordNet end ---