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288686 occurrences (No.85 in the rank) during 5 years in the PubMed. [no cache] 500 found

219) The human prion particles replicate independently and undergo competitive selection of those with lower initial conformational stability.

--- ABSTRACT ---

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.

--- ABSTRACT END ---

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(1)38 than	(19)4 incidence	(37)3 socioeconomic	(55)2 expression
(2)35 in	(20)4 leg	(38)3 stresses	(56)2 eyelid
(3)19 levels	(21)4 spine	(39)3 values	(57)2 eyelids
(4)12 extremity	(22)4 total	(40)2 Condom	(58)2 frequencies
(5)11 risk	(23)3 (P	(41)2 EI	(59)2 frequency
(6)7 compared	(24)3 null	(42)2 IQ	(60)2 likelihood
(7)7 level	(25)3 ASM/wt	(43)2 abdominal	(61)2 limit
(8)7 limb	(26)3 education	(44)2 among	(62)2 microleakage
(9)5 at	(27)3 educational	(45)2 back	(63)2 perceived
(10)5 for	(28)3 extremities,	(46)2 birthweight	(64)2 percentage
(11)5 limbs	(29)3 heart	(47)2 bounds	(65)2 quality
(12)5 the	(30)3 initial	(48)2 by	(66)2 rate
(13)4 and	(31)3 legs	(49)2 complication	(67)2 resilience
(14)4 body	(32)3 mean	(50)2 concentration	(68)2 serum
(15)4 cervical	(33)3 odds	(51)2 concentrations	(69)2 shear
(16)4 dose	(34)3 prevalence	(52)2 demineralization
(17)4 doses	(35)3 probability	(53)2 esophageal
(18)4 extremities	(36)3 sexual	(54)2 estimated

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--- WordNet output for lower --- =>1.低くする/なる, 下げる/下がる, 卑しめる, 2.しかめっ面, 3.lowの比較級 Overview of noun lower The noun lower has 1 sense (no senses from tagged texts) 1. lower berth, lower -- (the lower of two berths) Overview of verb lower The verb lower has 5 senses (first 3 from tagged texts) 1. (15) lower, take down, let down, get down, bring down -- (move something or somebody to a lower position; "take down the vase from the shelf") 2. (6) lower, lour -- (set lower; "lower a rating"; "lower expectations") 3. (1) turn down, lower, lour -- (make lower or quieter; "turn down the volume of a radio") 4. lower, depress -- (cause to drop or sink; "The lack of rain had depressed the water level in the reservoir") 5. frown, glower, lour, lower -- (look angry or sullen, wrinkle one's forehead, as if to signal disapproval) Overview of adj low The adj low has 10 senses (first 6 from tagged texts) 1. (55) low -- (less than normal in degree or intensity or amount; "low prices"; "the reservoir is low") 2. (23) low -- (literal meanings; being at or having a relatively small elevation or upward extension; "low ceilings"; "low clouds"; "low hills"; "the sun is low"; "low furniture"; "a low bow") 3. (11) low, low-toned -- (very low in volume; "a low murmur"; "the low-toned murmur of the surf") 4. (6) low -- (unrefined in character; "low comedy") 5. (4) low, low-pitched -- (used of sounds and voices; low in pitch or frequency) 6. (3) abject, low, low-down, miserable, scummy, scurvy -- (of the most contemptible kind; "abject cowardice"; "a low stunt to pull"; "a low-down sneak"; "his miserable treatment of his family"; "You miserable skunk!"; "a scummy rabble"; "a scurvy trick") 7. humble, low, lowly, modest, small -- (low or inferior in station or quality; "a humble cottage"; "a lowly parish priest"; "a modest man of the people"; "small beginnings") 8. depleted, low -- (no longer sufficient; "supplies are low"; "our funds are depleted") 9. broken, crushed, humbled, humiliated, low -- (subdued or brought low in condition or status; "brought low"; "a broken man"; "his broken spirit") 10. gloomy, grim, blue, depressed, dispirited, down, downcast, downhearted, down in the mouth, low, low-spirited -- (filled with melancholy and despondency ; "gloomy at the thought of what he had to face"; "gloomy predictions"; "a gloomy silence"; "took a grim view of the economy"; "the darkening mood"; "lonely and blue in a strange city"; "depressed by the loss of his job"; "a dispirited and resigned expression on her face"; "downcast after his defeat"; "feeling discouraged and downhearted") --- WordNet end ---