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- Medical English LInking keywords finder for the PubMed Zipped Archive (ELIZA) -

return kwic search for risk out of >500 occurrences
421954 occurrences (No.40 in the rank) during 5 years in the PubMed. [cache]
5) Functional and genetic studies demonstrated that SorLA deficiency results in increased production of Aβ peptides, and thus a higher risk of AD.
--- ABSTRACT ---
PMID:34922638 DOI:10.1186/s40478-021-01294-4
2021 Acta neuropathologica communications
* Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease.
- The SorLA protein, encoded by the SORL1 gene, is a major player in Alzheimer's disease (AD) pathophysiology. Functional and genetic studies demonstrated that SorLA deficiency results in increased production of Aβ peptides, and thus a higher risk of AD. A large number of SORL1 missense variants have been identified in AD patients, but their functional consequences remain largely undefined. Here, we identified a new pathophysiological mechanism, by which rare SORL1 missense variants identified in AD patients result in altered maturation and trafficking of the SorLA protein. An initial screening, based on the overexpression of 70 SorLA variants in HEK293 cells, revealed that 15 of them (S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S) induced a maturation and trafficking-deficient phenotype. Three of these variants (R332W, S577P, and R654W) and two maturation-competent variants (S124R and N371T) were further studied in details in CRISPR/Cas9-modified hiPSCs. When expressed at endogenous levels, the R332W, S577P, and R654W SorLA variants also showed a maturation defective profile. We further demonstrated that these variants were largely retained in the endoplasmic reticulum, resulting in a reduction in the delivery of SorLA mature protein to the plasma membrane and to the endosomal system. Importantly, expression of the R332W and R654W variants in hiPSCs was associated with a clear increase of Aβ secretion, demonstrating a loss-of-function effect of these SorLA variants regarding this ultimate readout, and a direct link with AD pathophysiology. Furthermore, structural analysis of the impact of missense variants on SorLA protein suggested that impaired cellular trafficking of SorLA protein could be due to subtle variations of the protein 3D structure resulting from changes in the interatomic interactions.
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[frequency of next (right) word to risk]
(1)139 of (11)7 prediction (21)3 decision (31)2 markers
(2)49 factors (12)6 stratification (22)3 or (32)2 mitigation
(3)46 for (13)5 individuals (23)3 patients (33)2 population
(4)21 *null* (14)4 genes (24)2 (OR (34)2 ratio
(5)19 factor (15)4 populations (25)2 among (35)2 reduction
(6)16 and (16)4 score (26)2 communication (36)2 screening
(7)13 assessment (17)4 to (27)2 communication, (37)2 strategies
(8)12 in (18)4 variants (28)2 designations
(9)8 perception (19)3 alleles (29)2 group
(10)7 factors, (20)3 assessment, (30)2 is

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--- WordNet output for risk --- =>1.損害の恐れ, 危険, 冒険, リスク, 2.危険にさらす, 3.敢えてする, 被保険者, 被保険物, 危険にさらす, 賭けてみる Overview of noun risk The noun risk has 4 senses (first 2 from tagged texts) 1. (4) hazard, jeopardy, peril, risk, endangerment -- (a source of danger; a possibility of incurring loss or misfortune; "drinking alcohol is a health hazard") 2. (2) risk, peril, danger -- (a venture undertaken without regard to possible loss or injury; "he saw the rewards but not the risks of crime"; "there was a danger he would do the wrong thing") 3. risk, risk of infection -- (the probability of becoming infected given that exposure to an infectious agent has occurred) 4. risk, risk of exposure -- (the probability of being exposed to an infectious agent) Overview of verb risk The verb risk has 2 senses (first 2 from tagged texts) 1. (8) risk, put on the line, lay on the line -- (expose to a chance of loss or damage; "We risked losing a lot of money in this venture"; "Why risk your life?"; "She laid her job on the line when she told the boss that he was wrong") 2. (2) gamble, chance, risk, hazard, take chances, adventure, run a risk, take a chance -- (take a risk in the hope of a favorable outcome; "When you buy these stocks you are gambling") --- WordNet end ---