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- Rice, Gillian I, et al.
(författare)
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Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease.
- 2017
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Ingår i: Neuropediatrics. - : Georg Thieme Verlag KG. - 1439-1899 .- 0174-304X. ; 48:3, s. 166-184
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.
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| 3. |
- Peña-Pérez, L., et al.
(författare)
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Linked-read whole-genome sequencing resolves common and private structural variants in multiple myeloma
- 2022
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 6:17, s. 5009-5023
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is an incurable and aggressive plasma cell malignancy characterized by a complex karyotype with multiple structural variants (SVs) and copy-number variations (CNVs). Linked-read whole-genome sequencing (lrWGS) allows for refined detection and reconstruction of SVs by providing long-range genetic information from standard short-read sequencing. This makes lrWGS an attractive solution for capturing the full genomic complexity of MM. Here we show that high-quality lrWGS data can be generated from low numbers of cells subjected to fluorescence-activated cell sorting (FACS) without DNA purification. Using this protocol, we analyzed MM cells after FACS from 37 patients with MM using lrWGS. We found high concordance between lrWGS and fluorescence in situ hybridization (FISH) for the detection of recurrent translocations and CNVs. Outside of the regions investigated by FISH, we identified .150 additional SVs and CNVs across the cohort. Analysis of the lrWGS data allowed for resolution of the structure of diverse SVs affecting the MYC and t(11;14) loci, causing the duplication of genes and gene regulatory elements. In addition, we identified private SVs causing the dysregulation of genes recurrently involved in translocations with the IGH locus and show that these can alter the molecular classification of MM. Overall, we conclude that lrWGS allows for the detection of aberrations critical for MM prognostics and provides a feasible route for providing comprehensive genetics. Implementing lrWGS could provide more accurate clinical prognostics, facilitate genomic medicine initiatives, and greatly improve the stratification of patients included in clinical trials.
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| 4. |
- Arber, Charles, et al.
(författare)
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Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis.
- 2021
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Ingår i: Cell reports. - : Elsevier BV. - 2211-1247. ; 34:2
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in presenilin 1 (PSEN1) or presenilin 2 (PSEN2), the catalytic subunit of γ-secretase, cause familial Alzheimer's disease (fAD). We hypothesized that mutations in PSEN1 reduce Notch signaling and alter neurogenesis. Expression data from developmental and adult neurogenesis show relative enrichment of Notch and γ-secretase expression in stem cells, whereas expression of APP and β-secretase is enriched in neurons. We observe premature neurogenesis in fAD iPSCs harboring PSEN1 mutations using two orthogonal systems: cortical differentiation in 2D and cerebral organoid generation in 3D. This is partly driven by reduced Notch signaling. We extend these studies to adult hippocampal neurogenesis in mutation-confirmed postmortem tissue. fAD cases show mutation-specific effects and a trend toward reduced abundance of newborn neurons, supporting a premature aging phenotype. Altogether, these results support altered neurogenesis as a result of fAD mutations and suggest that neural stem cell biology is affected in aging and disease.
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| 6. |
- Brijs, J., et al.
(författare)
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Humane slaughter of African sharptooth catfish (Clarias gariepinus): Effects of various stunning methods on brain function
- 2021
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Ingår i: Aquaculture. - : Elsevier BV. - 0044-8486 .- 1873-5622. ; 531
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Tidskriftsartikel (refereegranskat)abstract
- © 2020 The Authors Common slaughter procedures for African sharptooth catfish (Clarias gariepinus) include asphyxiation, ice chilling and exsanguination, which may all cause substantial suffering over prolonged periods of time before death. Therefore, comprehensive evaluations of potentially more humane slaughter procedures for this species are urgently needed. Here, we use a non-invasive electroencephalographic (EEG) method to assess the state of sensibility in African sharptooth catfish in response to various stunning methods (e.g. ice chilling, electrical stunning, electrical stunning followed by exsanguination, percussive stunning, and immersion in isoeugenol). Based on the abolition of visually evoked responses (VERs) on the EEG, ice slurry immersion induced insensibility between 2.6 and 7.6 min, during which catfish exhibited aversive behaviours. Once VERs were lost, they remained absent so long as catfish remained immersed in the ice slurry. Electrical stunning (i.e. exposure to ~1.7 A dm−2 at a water conductivity of ~997 μS cm−1) induced insensibility immediately but not irreversibly. Depending on the duration of the stun (i.e. from 1 to 10 s), catfish either regained VERs immediately or within 4.9 min after the completion of the electrical insult. However, when a 10 s electrical stun was immediately followed by exsanguination and immersion in an ice slurry, the duration of insensibility was sufficient to humanely kill catfish. When administered correctly, manual percussive stunning with a fish priest induced insensibility immediately and irreversibly. However, 36% of catfish regained VERs, which is likely explained by the difficulty associated with administering an accurate manual percussive stun of sufficient force on a live and struggling catfish. Catfish appeared to be sedated following immersion in isoeugenol (i.e. catfish were calm and easy to handle), yet VERs remained present at doses exceeding that recommended for euthanasia in salmonids, which indicates that this substance may not be suitable for stunning catfish. However, the potential for using isoeugenol as a pre-stunning sedative for improving handleability and reducing handling stress of this species warrants further investigation. In conclusion, this study clearly demonstrates that when singularly administered, none of the abovementioned stunning methods could reliably induce insensibility immediately and/or irreversibly without welfare implications. Yet, our findings indicate that these shortcomings can be resolved by using a combination of methods. This could include an electrical or percussive stun to immediately induce insensibility that should be immediately followed by exsanguination and immersion in an ice slurry to maintain insensibility until death.
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