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- Nango, E., et al.
(författare)
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A three-dimensional movie of structural changes in bacteriorhodopsin
- 2016
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 354:6319, s. 1552-1557
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Tidskriftsartikel (refereegranskat)abstract
- Bacteriorhodopsin (bR) is a light-driven proton pump and a model membrane transport protein. We used time-resolved serial femtosecond crystallography at an x-ray free electron laser to visualize conformational changes in bR from nanoseconds to milliseconds following photoactivation. An initially twisted retinal chromophore displaces a conserved tryptophan residue of transmembrane helix F on the cytoplasmic side of the protein while dislodging a key water molecule on the extracellular side. The resulting cascade of structural changes throughout the protein shows how motions are choreographed as bR transports protons uphill against a transmembrane concentration gradient.
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| 7. |
- Hakkarainen, M, et al.
(författare)
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The clinical picture of ERCC6L2 disease: from bone marrow failure to acute leukemia
- 2023
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 141:23, s. 2853-2866
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Tidskriftsartikel (refereegranskat)abstract
- Biallelic germline ERCC6L2 variants strongly predispose to bone marrow failure (BMF) and myeloid malignancies characterized by somatic TP53-mutated clones and erythroid predominance. We present a series of 52 subjects (35 families) with ERCC6L2 biallelic germline variants collected retrospectively in 11 centers globally, including follow-up of 1165 person-years. At initial investigations, 32 individuals were diagnosed with BMF and 15 with a hematological malignancy (HM). Subjects presented with 19 different variants across ERCC6L2, and we identified a founder mutation c.1424delT in the Finnish patients. The median age of subjects at baseline was 18 years (range 2-65). Changes in complete blood count (CBC) were mild despite severe bone marrow hypoplasia and somatic TP53 mutations, with no significant difference between subjects with or without (HM). Signs of a progressive disease were increasing TP53 variant allele frequency, dysplasia in megakaryocytes and/or erythroid lineage, and erythroid predominance in bone marrow morphology. The median age at onset of HM was 37.0 years (95% CI: 31.5-42.5; range 12-65). Overall survival (OS) at 3 years was 95% (95% CI: 85-100) and 19% (95% CI: 0-39) for patients with BMF and HM, respectively. Patients with myelodysplastic syndrome or acute myeloid leukemia with mutated TP53 undergoing hematopoietic stem cell transplantation had a poor outcome: 3-year OS is 28% (95% CI: 0-61). Our results demonstrate the importance of early recognition and active surveillance of patients with biallelic germline ERCC6L2 variants.
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- Sekiguchi, M, et al.
(författare)
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Integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets
- 2020
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Ingår i: NPJ precision oncology. - : Springer Science and Business Media LLC. - 2397-768X. ; 4:1, s. 20-
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Tidskriftsartikel (refereegranskat)abstract
- Although hepatoblastoma is the most common pediatric liver cancer, its genetic heterogeneity and therapeutic targets are not well elucidated. Therefore, we conducted a multiomics analysis, including mutatome, DNA methylome, and transcriptome analyses, of 59 hepatoblastoma samples. Based on DNA methylation patterns, hepatoblastoma was classified into three clusters exhibiting remarkable correlation with clinical, histological, and genetic features. Cluster F was largely composed of cases with fetal histology and good outcomes, whereas clusters E1 and E2 corresponded primarily to embryonal/combined histology and poor outcomes. E1 and E2, albeit distinguishable by different patient age distributions, were genetically characterized by hypermethylation of the HNF4A/CEBPA-binding regions, fetal liver-like expression patterns, upregulation of the cell cycle pathway, and overexpression of NQO1 and ODC1. Inhibition of NQO1 and ODC1 in hepatoblastoma cells induced chemosensitization and growth suppression, respectively. Our results provide a comprehensive description of the molecular basis of hepatoblastoma and rational therapeutic strategies for high-risk cases.
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