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- Nicolas, Aude, et al.
(författare)
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Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
- 2018
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Ingår i: Neuron. - : Cell Press. - 0896-6273 .- 1097-4199. ; 97:6, s. 1268-1283.e6
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Tidskriftsartikel (refereegranskat)abstract
- To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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| 2. |
- Getman, Yaroslav, et al.
(författare)
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Developing an AI-Assisted Low-Resource Spoken Language Learning App for Children
- 2023
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Ingår i: IEEE Access. - : Institute of Electrical and Electronics Engineers (IEEE). - 2169-3536. ; 11, s. 86025-86037
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Tidskriftsartikel (refereegranskat)abstract
- Computer-assisted Language Learning (CALL) is a rapidly developing area accelerated by advancements in the field of AI. A well-designed and reliable CALL system allows students to practice language skills, like pronunciation, any time outside of the classroom. Furthermore, gamification via mobile applications has shown encouraging results on learning outcomes and motivates young users to practice more and perceive language learning as a positive experience. In this work, we adapt the latest speech recognition technology to be a part of an online pronunciation training system for small children. As part of our gamified mobile application, our models will assess the pronunciation quality of young Swedish children diagnosed with Speech Sound Disorder, and participating in speech therapy. Additionally, the models provide feedback to young non-native children learning to pronounce Swedish and Finnish words. Our experiments revealed that these new models fit into an online game as they function as speech recognizers and pronunciation evaluators simultaneously. To make our systems more trustworthy and explainable, we investigated whether the combination of modern input attribution algorithms and time-aligned transcripts can explain the decisions made by the models, give us insights into how the models work and provide a tool to develop more reliable solutions.
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| 4. |
- Schmiegelow, Kjeld, et al.
(författare)
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Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study.
- 2009
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 113:24, s. 6077-84
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Tidskriftsartikel (refereegranskat)abstract
- Among 1614 children with acute lymphoblastic leukemia (ALL) treated with the Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL-92 protocol, 20 patients developed a second malignant neoplasm (SMN) with a cumulative risk of 1.6% at 12 years from the diagnosis of ALL. Nine of the 16 acute myeloid leukemias or myelodysplastic syndromes had monosomy 7 (n = 7) or 7q deletions (n = 2). In Cox multivariate analysis, longer duration of oral 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy (P = .02; longest for standard-risk patients) and presence of high hyperdiploidy (P = .07) were related to increased risk of SMN. Thiopurine methyltransferase (TPMT) methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. Of 524 patients who had erythrocyte TPMT activity measured, the median TPMT activity in 9 patients developing an SMN was significantly lower than in the 515 that did not develop an SMN (median, 12.1 vs 18.1 IU/mL; P = .02). Among 427 TPMT wild-type patients for whom the 6MP dose was registered, those who developed SMN received higher average 6MP doses than the remaining patients (69.7 vs 60.4 mg/m2; P = .03). This study indicates that the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMNs in childhood ALL.
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