| 1. |
- Orr, Russell J.S., et al.
(författare)
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Paleozoic origins of cheilostome bryozoans and their parental care inferred by a new genome-skimmed phylogeny
- 2022
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 8:13
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Tidskriftsartikel (refereegranskat)abstract
- Phylogenetic relationships and the timing of evolutionary events are essential for understanding evolution on longer time scales. Cheilostome bryozoans are a group of ubiquitous, species-rich, marine colonial organisms with an excellent fossil record but lack phylogenetic relationships inferred from molecular data. We present genome-skimmed data for 395 cheilostomes and combine these with 315 published sequences to infer relationships and the timing of key events among c. 500 cheilostome species. We find that named cheilostome genera and species are phylogenetically coherent, rendering fossil or contemporary specimens readily delimited using only skeletal morphology. Our phylogeny shows that parental care in the form of brooding evolved several times independently but was never lost in cheilostomes. Our fossil calibration, robust to varied assumptions, indicates that the cheilostome lineage and parental care therein could have Paleozoic origins, much older than the first known fossil record of cheilostomes in the Late Jurassic.
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| 2. |
- Waszak, S. M., et al.
(författare)
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Germline Elongator mutations in Sonic Hedgehog medulloblastoma
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 580:7803
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Tidskriftsartikel (refereegranskat)abstract
- Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children(1,2), and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma(3). Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHH alpha subtype(4) and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U-34) position(5,6). Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems(7-9). Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.
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| 3. |
- Hilmi, N., et al.
(författare)
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Exposure of Mediterranean Countries to Ocean Acidification
- 2014
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Ingår i: Water. - : MDPI AG. - 2073-4441. ; 6:6, s. 1719-1744
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Tidskriftsartikel (refereegranskat)abstract
- This study examines the potential effects of ocean acidification on countries and fisheries of the Mediterranean Sea. The implications for seafood security and supply are evaluated by examining the sensitivity of the Mediterranean to ocean acidification at chemical, biological, and macro-economic levels. The limited information available on impacts of ocean acidification on harvested (industrial, recreational, and artisanal fishing) and cultured species (aquaculture) prevents any biological impact assessment. However, it appears that non-developed nations around the Mediterranean, particularly those for which fisheries are increasing, yet rely heavily on artisanal fleets, are most greatly exposed to socioeconomic consequences from ocean acidification.
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| 4. |
- Mok, T. H., et al.
(författare)
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Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease
- 2023
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 146:6
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Tidskriftsartikel (refereegranskat)abstract
- Human prion diseases are remarkable for long incubation times followed typically by rapid clinical decline. Seed amplification assays and neurodegeneration biofluid biomarkers are remarkably useful in the clinical phase, but their potential to predict clinical onset in healthy people remains unclear. This is relevant not only to the design of preventive strategies in those at-risk of prion diseases, but more broadly, because prion-like mechanisms are thought to underpin many neurodegenerative disorders. Here, we report the accrual of a longitudinal biofluid resource in patients, controls and healthy people at risk of prion diseases, to which ultrasensitive techniques such as real-time quaking-induced conversion (RT-QuIC) and single molecule array (Simoa) digital immunoassays were applied for preclinical biomarker discovery. We studied 648 CSF and plasma samples, including 16 people who had samples taken when healthy but later developed inherited prion disease (IPD) ('converters'; range from 9.9 prior to, and 7.4 years after onset). Symptomatic IPD CSF samples were screened by RT-QuIC assay variations, before testing the entire collection of at-risk samples using the most sensitive assay. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), tau and UCH-L1 levels were measured in plasma and CSF. Second generation (IQ-CSF) RT-QuIC proved 100% sensitive and specific for sporadic Creutzfeldt-Jakob disease (CJD), iatrogenic and familial CJD phenotypes, and subsequently detected seeding activity in four presymptomatic CSF samples from three E200K carriers; one converted in under 2 months while two remain asymptomatic after at least 3 years' follow-up. A bespoke HuPrP P102L RT-QuIC showed partial sensitivity for P102L disease. No compatible RT-QuIC assay was discovered for classical 6-OPRI, A117V and D178N, and these at-risk samples tested negative with bank vole RT-QuIC. Plasma GFAP and NfL, and CSF NfL levels emerged as proximity markers of neurodegeneration in the typically slow IPDs (e.g. P102L), with significant differences in mean values segregating healthy control from IPD carriers (within 2 years to onset) and symptomatic IPD cohorts; plasma GFAP appears to change before NfL, and before clinical conversion. In conclusion, we show distinct biomarker trajectories in fast and slow IPDs. Specifically, we identify several years of presymptomatic seeding positivity in E200K, a new proximity marker (plasma GFAP) and sequential neurodegenerative marker evolution (plasma GFAP followed by NfL) in slow IPDs. We suggest a new preclinical staging system featuring clinical, seeding and neurodegeneration aspects, for validation with larger prion at-risk cohorts, and with potential application to other neurodegenerative proteopathies.
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