| 1. |
- 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. |
- Astrof, Sophie, et al.
(författare)
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Heart development in fibronectin-null mice is governed by a genetic modifier on chromosome four
- 2007
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Ingår i: Mechanisms of Development. - : Elsevier BV. - 0925-4773 .- 1872-6356. ; 124:7-8, s. 551-558
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Tidskriftsartikel (refereegranskat)abstract
- Absence of the fibronectin (FN) gene leads to early embryonic lethality in both 129S4 and C57BL/6J strains due to severe cardiovascular defects. However, heart development is arrested at different stages in these embryos depending on the genetic background. In the majority of 129S4 FN-null embryos, heart progenitors remain at their anterior bilateral positions and fail to fuse at the midline to form a heart tube. However, on the C57BL/6J genetic background, cardiac development progresses further and results in a centrally positioned and looped heart. To find factor(s) involved in embryonic heart formation and governing the extent of heart development in FN-null embryos in 129S4 and C57BL/6J strains, we performed genetic mapping and haplotype analyses. These analyses lead to identification of a significant linkage to a 1-Mbp interval on chromosome four. Microarray analysis and sequencing identified 21 genes in this region, including five that are differentially expressed between the strains, as potential modifiers. Since none of these genes was previously known to play a role in heart development, one or more of them is likely to be a novel modifier affecting cardiac development. Identification of the modifier would significantly enhance our understanding of the molecular underpinning of heart development and disease.
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| 3. |
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| 4. |
- Dhanraj, Santhosh, et al.
(författare)
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Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN)
- 2015
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 52:11, s. 738-748
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Tidskriftsartikel (refereegranskat)abstract
- Background Deadenylation regulates RNA function and fate. Poly(A)-specific ribonuclease (PARN) is a deadenylase that processes mRNAs and non-coding RNA. Little is known about the biological significance of germline mutations in PARN. Methods We identified mutations in PARN in patients with haematological and neurological manifestations. Genomic, biochemical and knockdown experiments in human marrow cells and in zebrafish have been performed to clarify the role of PARN in the human disease. Results We identified large monoallelic deletions in PARN in four patients with developmental delay or mental illness. One patient in particular had a severe neurological phenotype, central hypomyelination and bone marrow failure. This patient had an additional missense mutation on the non-deleted allele and severely reduced PARN protein and deadenylation activity. Cells from this patient had impaired oligoadenylation of specific H/ACA box small nucleolar RNAs. Importantly, PARN-deficient patient cells manifested short telomeres and an aberrant ribosome profile similar to those described in some variants of dyskeratosis congenita. Knocking down PARN in human marrow cells and zebrafish impaired haematopoiesis, providing further evidence for a causal link with the human disease. Conclusions Large monoallelic mutations of PARN can cause developmental/mental illness. Biallelic PARN mutations cause severe bone marrow failure and central hypomyelination.
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| 5. |
- Di Giunta, Laura, et al.
(författare)
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Longitudinal associations between mothers' and fathers' anger/irritability expressiveness, harsh parenting, and adolescents' socioemotional functioning in nine countries.
- 2020
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Ingår i: Developmental Psychology. - : American Psychological Association (APA). - 0012-1649 .- 1939-0599. ; 56:3, s. 458-474
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Tidskriftsartikel (refereegranskat)abstract
- The present study examines parents' self-efficacy about anger regulation and irritability as predictors of harsh parenting and adolescent children's irritability (i.e., mediators), which in turn were examined as predictors of adolescents' externalizing and internalizing problems. Mothers, fathers, and adolescents (N = 1,298 families) from 12 cultural groups in 9 countries (China, Colombia, Italy, Jordan, Kenya, Philippines, Sweden, Thailand, and United States) were interviewed when children were about 13 years old and again 1 and 2 years later. Models were examined separately for mothers and fathers. Overall, cross-cultural similarities emerged in the associations of both mothers' and fathers' irritability, as well as of mothers' self-efficacy about anger regulation, with subsequent maternal harsh parenting and adolescent irritability, and in the associations of the latter variables with adolescents' internalizing and externalizing problems. The findings suggest that processes linking mothers' and fathers' emotion socialization and emotionality in diverse cultures to adolescent problem behaviors are somewhat similar.
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| 6. |
- Gallagher, Michael D., et al.
(författare)
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TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions
- 2014
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 127:3, s. 407-418
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Tidskriftsartikel (refereegranskat)abstract
- Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.
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| 7. |
- Galvin, Tom, et al.
(författare)
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Characterisation of SiC Varistor Quench Protection Operating at 4 Kelvin for Use With Superconducting Magnets
- 2023
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Ingår i: IEEE transactions on applied superconductivity (Print). - : IEEE. - 1051-8223 .- 1558-2515. ; 33:5
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Tidskriftsartikel (refereegranskat)abstract
- Silicon carbide (SiC) composite high-energy varistors have been demonstrated as a viable alternative to linear resistors as energy extraction devices during an abrupt loss of superconductivity in a magnet, called a quench. These have typically been installed external to the cryostat at ambient temperatures, but for some superconducting magnets it may be beneficial to mount the varistors within the cryostat in vacuum, a gaseous environment, or submerged in liquid cryogens. Varistors are semiconductors and therefore exhibit a temperature-dependent voltage-current relationship, so characterising their behaviour at low temperatures is important to predict their energy extraction behaviour. In this paper we present characterisation data of SiC varistor devices from 4-300 K: voltage-current characteristics, thermal conductivity, specific heat capacity, thermal expansion, and flexural strength. These varistors are a candidate for protection at 1.9 K of the MCBY magnets, currently being built at Uppsala University for CERN.
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| 8. |
- Gorla, Laura, et al.
(författare)
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Adolescents' relationships with parents and romantic partners in eight countries.
- 2024
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Ingår i: Journal of Adolescence. - : Wiley-Blackwell Publishing Inc.. - 0140-1971 .- 1095-9254.
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Creating romantic relationships characterized by high-quality, satisfaction, few conflicts, and reasoning strategies to handle conflicts is an important developmental task for adolescents connected to the relational models they receive from their parents. This study examines how parent-adolescent conflicts, attachment, positive parenting, and communication are related to adolescents' romantic relationship quality, satisfaction, conflicts, and management.METHOD: We interviewed 311 adolescents at two time points (females = 52%, ages 15 and 17) in eight countries (China, Colombia, Italy, Kenya, the Philippines, Sweden, Thailand, and the United States). Generalized and linear mixed models were run considering the participants' nesting within countries.RESULTS: Adolescents with negative conflicts with their parents reported low romantic relationship quality and satisfaction and high conflicts with their romantic partners. Adolescents experiencing an anxious attachment to their parents reported low romantic relationship quality, while adolescents with positive parenting showed high romantic relationship satisfaction. However, no association between parent-adolescent relationships and conflict management skills involving reasoning with the partner was found. No associations of parent-adolescent communication with romantic relationship dimensions emerged, nor was there any effect of the country on romantic relationship quality or satisfaction.CONCLUSION: These results stress the relevance of parent-adolescent conflicts and attachment as factors connected to how adolescents experience romantic relationships.
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| 9. |
- Haniffa, Muzlifah, et al.
(författare)
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A roadmap for the Human Developmental Cell Atlas
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 597:7875, s. 196-205
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Tidskriftsartikel (refereegranskat)abstract
- This Perspective outlines the Human Developmental Cell Atlas initiative, which uses state-of-the-art technologies to map and model human development across gestation, and discusses the early milestones that have been achieved. The Human Developmental Cell Atlas (HDCA) initiative, which is part of the Human Cell Atlas, aims to create a comprehensive reference map of cells during development. This will be critical to understanding normal organogenesis, the effect of mutations, environmental factors and infectious agents on human development, congenital and childhood disorders, and the cellular basis of ageing, cancer and regenerative medicine. Here we outline the HDCA initiative and the challenges of mapping and modelling human development using state-of-the-art technologies to create a reference atlas across gestation. Similar to the Human Genome Project, the HDCA will integrate the output from a growing community of scientists who are mapping human development into a unified atlas. We describe the early milestones that have been achieved and the use of human stem-cell-derived cultures, organoids and animal models to inform the HDCA, especially for prenatal tissues that are hard to acquire. Finally, we provide a roadmap towards a complete atlas of human development.
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| 10. |
- Hudson, Lawrence N, et al.
(författare)
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The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project
- 2017
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Ingår i: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 7:1, s. 145-188
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Tidskriftsartikel (refereegranskat)abstract
- The PREDICTS project-Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)-has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.
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