| 1. |
- Hansson Petersen, Camilla A., et al.
(författare)
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The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae
- 2008
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 105:35, s. 13145-13150
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Tidskriftsartikel (refereegranskat)abstract
- The amyloid beta-peptide (Abeta) has been suggested to exert its toxicity intracellularly. Mitochondrial functions can be negatively affected by Abeta and accumulation of Abeta has been detected in mitochondria. Because Abeta is not likely to be produced locally in mitochondria, we decided to investigate the mechanisms for mitochondrial Abeta uptake. Our results from rat mitochondria show that Abeta is transported into mitochondria via the translocase of the outer membrane (TOM) machinery. The import was insensitive to valinomycin, indicating that it is independent of the mitochondrial membrane potential. Subfractionation studies following the import experiments revealed Abeta association with the inner membrane fraction, and immunoelectron microscopy after import showed localization of Abeta to mitochondrial cristae. A similar distribution pattern of Abeta in mitochondria was shown by immunoelectron microscopy in human cortical brain biopsies obtained from living subjects with normal pressure hydrocephalus. Thus, we present a unique import mechanism for Abeta in mitochondria and demonstrate both in vitro and in vivo that Abeta is located to the mitochondrial cristae. Importantly, we also show that extracellulary applied Abeta can be internalized by human neuroblastoma cells and can colocalize with mitochondrial markers. Together, these results provide further insight into the mitochondrial uptake of Abeta, a peptide considered to be of major significance in Alzheimer's disease.
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| 2. |
- Ishigaki, Kazuyoshi, et al.
(författare)
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Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:11, s. 1640-1651
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10−8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.
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| 3. |
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| 4. |
- Ito, Komei, et al.
(författare)
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The usefulness of casein-specific IgE and IgG4 antibodies in cow's milk allergic children
- 2012
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Ingår i: Clinical and Molecular Allergy. - : Springer Science and Business Media LLC. - 1476-7961. ; 10:1, s. 1-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundCow's milk allergy is one of the most common food allergies among younger children. We investigated IgE antibodies to milk, and IgE and IgG4 antibodies to casein, α-lactalbumin and β-lactoglobulin in cow's milk allergic (CMA) and non-allergic (non-CMA) children in order to study their clinical usefulness.MethodsEighty-three children with suspected milk allergy (median age: 3.5 years, range: 0.8-15.8 years) were diagnosed as CMA (n = 61) or non-CMA (n = 22) based on an open milk challenge or convincing clinical history. Their serum concentrations of allergen-specific (s) IgE and IgG4 antibodies were measured using ImmunoCAP®. For the sIgG4 analysis, 28 atopic and 31 non-atopic control children were additionally included (all non-milk sensitized).ResultsThe CMA group had significantly higher levels of milk-, casein- and β-lactoglobulin-sIgE antibodies as compared to the non-CMA group. The casein test showed the best discriminating performance with a clinical decision point of 6.6 kUA/L corresponding to 100% specificity. All but one of the CMA children aged > 5 years had casein-sIgE levels > 6.6 kUA/L. The non-CMA group had significantly higher sIgG4 levels against all three milk allergens compared to the CMA group. This was most pronounced for casein-sIgG4 in non-CMA children without history of previous milk allergy. These children had significantly higher casein-sIgG4 levels compared to any other group, including the non-milk sensitized control children.ConclusionsHigh levels of casein-sIgE antibodies are strongly associated with milk allergy in children and might be associated with prolonged allergy. Elevated casein-sIgG4 levels in milk-sensitized individuals on normal diet indicate a modified Th2 response. However, the protective role of IgG4 antibodies in milk allergy is unclear.
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| 5. |
- Ito, Yasuhiro, et al.
(författare)
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Delta Np73 expression in thyroid neoplasms originating from follicular cells.
- 2006
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Ingår i: Pathology. - : Elsevier BV. - 0031-3025. ; 38:3, s. 205-9
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: p73, a homologue of p53, is known as a negative regulator of tumour progression. However, delta Np73, an isoform of p73 lacking the NH2-terminal transactivation domain plays an oncogenic role by interfering with the activity of p53 and TA (full-length transactivating isoforms) p73. In this study, we investigated the expression of delta Np73 in human thyroid neoplasms originating from follicular cells. METHODS: We immunohistochemically investigated delta Np73 expression in 223 thyroid neoplasms. Delta Np73 expression level was evaluated as the sum of positivity score and intensity score. RESULTS: Normal follicular cells did not express delta Np73, but 27.3% of follicular adenoma, 85.4% of follicular carcinoma, 99.2% of papillary carcinoma, and 95.7% of anaplastic carcinoma were positive for the transcript. Delta Np73 expression level did not differ between widely invasive and minimally invasive follicular carcinomas. In papillary carcinoma, the level was inversely linked to tumour size, extrathyroid extension, and clinically apparent metastasis. Furthermore, in anaplastic carcinoma, delta Np73 expression level was significantly lower than that in papillary carcinoma. CONCLUSIONS: Our findings indicate that delta Np73 plays a role predominantly in the early phase of papillary carcinoma progression.
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| 6. |
- Komori, Shiori, et al.
(författare)
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Steeper Macular Curvature in Eyes With Non-Highly Myopic Retinitis Pigmentosa
- 2019
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Ingår i: Investigative Ophthalmology & Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 1552-5783. ; 60:8, s. 3135-3141
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: A posterior staphyloma has been reported to be present in some eyes with retinitis pigmentosa (RP), and the purpose of this study was to determine the macular curvature of non-highly myopic RP eyes. Methods: This was a retrospective, observational study. The medical charts of the right eyes of 143 patients with RP and 60 controls whose axial length ranged from 21.5 mm to 26.0 mm were reviewed. The mean curvature of Bruch's membrane within 6 mm of the central macula obtained from the horizontal optical coherence tomographic images were evaluated as the mean macular curvature index (MMCI). The relationships between the MMCI and other clinical factors were assessed. Results: The mean MMCI of RP patients (-13.73 ± 9.63 × 10-5 μm-1) was significantly lower than that of the controls (-6.63 ± 5.63 × 10-5 μm-1). This indicated a deeper concave shape of the macula in RP eyes (P < 0.001). The MMCI was significantly correlated with the age (r = 0.20; P = 0.016) and the axial length (r = -0.24; P = 0.004). Further analysis suggested a nonlinear effect of the ellipsoid zone width on the macular curvature in the RP eyes. Conclusions: There is a high incidence of steeper macular curvatures even in non-highly myopic RP eyes, and the steepness was also affected by the degree of photoreceptor degeneration.
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| 8. |
- Meinert, Monika, et al.
(författare)
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Longitudinal changes of macular curvature in patients with retinitis pigmentosa
- 2020
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Ingår i: Translational Vision Science and Technology. - : Association for Research in Vision and Ophthalmology (ARVO). - 2164-2591. ; 9:10
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To investigate the longitudinal changes of the macular curvature in eyes with retinitis pigmentosa (RP) and to determine the factors associated with the changes. Methods: We reviewed the medical charts of 107 RP patients, for whom the axial length of their right eyes ranged from 21.5 to 26.0 mm and who had had been followed by spectral-domain optical coherence tomography (OCT). The OCT images at the initial and the most recent examinations were compared. The mean curvature of Bruch’s membrane within 6 mm of the central macula obtained from the OCT images was evalu-ated as the mean macular curvature index (MMCI). Changes in the MMCI and their relationships with other clinical factors, including the ellipsoid zone (EZ) width, were assessed. Results: The MMCI decreased significantly in the vertical OCT images, from –15.47 × 10−5 μm−1 to –16.36 × 10−5 μm−1 (P = 0.008) during the mean observation period of 3.4 ± 1.4 years (mean ± SD). This indicated that the macular shape became more concave. The change to a steeper shape was more prominent in eyes with less photoreceptor degeneration and for which the EZ width was preserved at >2000 μm. In three eyes, the MMCI increased markedly by >5 × 10−5 μm−1, and this was accompanied by absorption of the macular edema. Conclusions: The macular curvature in RP eyes becomes more concave in eyes with preserved EZ width. Translational Relevance: Longitudinal changes of the macular curvature in RP should be considered in future therapies, such as the implantation of the retinal prosthesis.
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| 9. |
- Nakajima, Yoko, et al.
(författare)
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Clinical, biochemical and molecular analysis of 13 Japanese patients with beta-ureidopropionase deficiency demonstrates high prevalence of the c.977G > A (p.R326Q) mutation
- 2014
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Ingår i: Journal of Inherited Metabolic Disease. - : Wiley. - 0141-8955 .- 1573-2665. ; 37:5, s. 801-812
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Tidskriftsartikel (refereegranskat)abstract
- beta-ureidopropionase (beta UP) deficiency is an autosomal recessive disease characterized by N-carbamyl-beta-amino aciduria. To date, only 16 genetically confirmed patients with beta UP deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 13 Japanese beta UP deficient patients. In this group of patients, three novel missense mutations (p.G31S, p.E271K, and p.I286T) and a recently described mutation (p.R326Q) were identified. The p.R326Q mutation was detected in all 13 patients with eight patients being homozygous for this mutation. Screening for the p.R326Q mutation in 110 Japanese individuals showed an allele frequency of 0.9 %. Transient expression of mutant beta UP enzymes in HEK293 cells showed that the p.E271K and p.R326Q mutations cause profound decreases in activity (a parts per thousand currency sign 1.3 %). Conversely, beta UP enzymes containing the p.G31S and p.I286T mutations possess residual activities of 50 and 70 %, respectively, suggesting we cannot exclude the presence of additional mutations in the non-coding region of the UPB1 gene. Analysis of a human beta UP homology model revealed that the effects of the mutations (p.G31S, p.E271K, and p.R326Q) on enzyme activity are most likely linked to improper oligomer assembly. Highly variable phenotypes ranging from neurological involvement (including convulsions and autism) to asymptomatic, were observed in diagnosed patients. High prevalence of p.R326Q in the normal Japanese population indicates that beta UP deficiency is not as rare as generally considered and screening for beta UP deficiency should be included in diagnosis of patients with unexplained neurological abnormalities.
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