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| 2. |
- Hammarsjö, A., et al.
(författare)
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High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses
- 2021
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Ingår i: Journal of Human Genetics. - : Springer Nature. - 1434-5161 .- 1435-232X. ; 66:10, s. 995-1008
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Tidskriftsartikel (refereegranskat)abstract
- Skeletal ciliopathies are a heterogenous group of disorders with overlapping clinical and radiographic features including bone dysplasia and internal abnormalities. To date, pathogenic variants in at least 30 genes, coding for different structural cilia proteins, are reported to cause skeletal ciliopathies. Here, we summarize genetic and phenotypic features of 34 affected individuals from 29 families with skeletal ciliopathies. Molecular diagnostic testing was performed using massively parallel sequencing (MPS) in combination with copy number variant (CNV) analyses and in silico filtering for variants in known skeletal ciliopathy genes. We identified biallelic disease-causing variants in seven genes: DYNC2H1, KIAA0753, WDR19, C2CD3, TTC21B, EVC, and EVC2. Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA. Furthermore, CNV analyses showed an intragenic deletion of DYNC2H1 in one individual and a 6.7 Mb de novo deletion on chromosome 1q24q25 in another. In five unsolved cases, MPS was performed in family setting. In one proband we identified a de novo variant in PRKACA and in another we found a homozygous intragenic deletion of IFT74, removing the first coding exon and leading to expression of a shorter message predicted to result in loss of 40 amino acids at the N-terminus. These findings establish IFT74 as a new skeletal ciliopathy gene. In conclusion, combined single nucleotide variant, CNV and cDNA analyses lead to a high yield of genetic diagnoses (90%) in a cohort of patients with skeletal ciliopathies.
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| 3. |
- Lundström, Ulla, et al.
(författare)
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Advances in understanding the podzolization process resulting from a multidisciplinary study of three coniferous forest soils in the Nordic Countries
- 2000
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Ingår i: Geoderma. - 0016-7061 .- 1872-6259. ; 94:04-feb, s. 335-353
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Tidskriftsartikel (refereegranskat)abstract
- Geochemical, mineralogical, micromorphological, microbiological, hydrochemical and hpdrological joint investigations were performed at two coniferous podzolic sites in the north of Sweden and at one in the south of Finland. Mycorrhizal fungi were found to create numerous pens (3-10-mu m diameter) in many weatherable mineral grains in the eluvial (E) horizon. During the growing season, identified low molecular weight (LMW) organic acids such as citric, shikimic, oxalic and fumaric acids comprised 0.5-5% of the DOC and 0.5-15% of the total acidity in soil solutions. Between 20% and 40% of the dissolved Al was bound to the identified LMW organic acids. Mineral dissolution via complexing LMW acids, probably exuded in part by the mycorrhiza hyphae, is likely to be a major weathering process in podzols. We found no evidence for a decreasing C/metal ratio of the migrating organo-metal complexes that could explain the precipitation of secondary Fe and AL in the illuvial (B) horizon. Instead, microbial degradation of organic ligands resulting in the release of ionic,Al and Fe to the soil solution may he an important process facilitating the formation of solid Al-SI-OH and Fe-OH phases in the podzol B horizon. However, within the B horizon transport as proto-imogilite (PI) sols might be possible. In the B horizon, the extractable,Al and Fe was predominantly inorganic. The large specific surface area (SSA) removable by oxalate extraction, the high point of zero charge salt effect (PZSE), the low cation exchange capacity (CEC) and the high sulphate exchange capacity (SEC), painted to the presence of short-range ordered variable charge phases. Imogolite type material (ITM) was indeed identified in all B horizons by IR spectroscopy and crystalline imogolite was found in the deep B horizon of one profile. Mossbauer spectroscopy indicated that Fe in the form of ferrihydrite was formed by intergrowth with an Al-Si-OH phase. The high amounts of Fe and Al transported from the O to the E horizon indicate that there could be an upward transport of these elements before they are leached to the B horizon. We hypothesize that the LMW Al complexes an transported by hyphae to the mor (O) layer, partly released and subsequently complexed by high molecular weight (HMW) acids.
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| 4. |
- López-Guajardo, A., et al.
(författare)
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Regulation of cellular contractile force, shape and migration of fibroblasts by oncogenes and Histone deacetylase 6
- 2023
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Ingår i: Frontiers in Molecular Biosciences. - : Frontiers Media SA. - 2296-889X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The capacity of cells to adhere to, exert forces upon and migrate through their surrounding environment governs tissue regeneration and cancer metastasis. The role of the physical contractile forces that cells exert in this process, and the underlying molecular mechanisms are not fully understood. We, therefore, aimed to clarify if the extracellular forces that cells exert on their environment and/or the intracellular forces that deform the cell nucleus, and the link between these forces, are defective in transformed and invasive fibroblasts, and to indicate the underlying molecular mechanism of control. Confocal, Epifluorescence and Traction force microscopy, followed by computational analysis, showed an increased maximum contractile force that cells apply on their environment and a decreased intracellular force on the cell nucleus in the invasive fibroblasts, as compared to normal control cells. Loss of HDAC6 activity by tubacin-treatment and siRNA-mediated HDAC6 knockdown also reversed the reduced size and more circular shape and defective migration of the transformed and invasive cells to normal. However, only tubacin-mediated, and not siRNA knockdown reversed the increased force of the invasive cells on their surrounding environment to normal, with no effects on nuclear forces. We observed that the forces on the environment and the nucleus were weakly positively correlated, with the exception of HDAC6 siRNA-treated cells, in which the correlation was weakly negative. The transformed and invasive fibroblasts showed an increased number and smaller cell-matrix adhesions than control, and neither tubacin-treatment, nor HDAC6 knockdown reversed this phenotype to normal, but instead increased it further. This highlights the possibility that the control of contractile force requires separate functions of HDAC6, than the control of cell adhesions, spreading and shape. These data are consistent with the possibility that defective force-transduction from the extracellular environment to the nucleus contributes to metastasis, via a mechanism that depends upon HDAC6. To our knowledge, our findings present the first correlation between the cellular forces that deforms the surrounding environment and the nucleus in fibroblasts, and it expands our understanding of how cells generate contractile forces that contribute to cell invasion and metastasis. Copyright © 2023 López-Guajardo, Zafar, Al Hennawi, Rossi, Alrwaili, Medcalf, Dunning, Nordgren, Pettersson, Estabrook, Hawkins and Gad.
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| 5. |
- Nilsson, D., et al.
(författare)
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From cytogenetics to cytogenomics : whole genome sequencing as a comprehensive genetic test in rare disease diagnostics
- 2019
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Ingår i: European Journal of Human Genetics. - : Springer Nature. - 1018-4813 .- 1476-5438. ; 27, s. 1666-1667
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Rare genetic diseases are caused by different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements. Recent data indicates that whole genome sequencing (WGS) may be used as a comprehensive test to identify multiple types of pathologic genetic aberrations in a single analysis.We present FindSV, a bioinformatic pipeline for detection of balanced (inversions and translocations) and unbalanced (deletions and duplications) structural variants (SVs). First, FindSV was tested on 106 validated deletions and duplications with a median size of 850 kb (min: 511 bp, max: 155 Mb). All variants were detected. Second, we demonstrated the clinical utility in 138 monogenic WGS panels. SV analysis yielded 11 diagnostic findings (8%). Remarkably, a complex structural rearrangement involving two clustered deletions disrupting SCN1A, SCN2A, and SCN3A was identified in a three months old girl with epileptic encephalopathy. Finally, 100 consecutive samples referred for clinical microarray were also analyzed by WGS. The WGS data was screened for large (>2 kbp) SVs genome wide, processed for visualization in our clinical routine arrayCGH workflow with the newly developed tool vcf2cytosure, and for exonic SVs and SNVs in a panel of 700 genes linked to intellectual disability. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7. The diagnostic rate (29%) was doubled compared to clinical microarray (12%).In conclusion, using WGS we have detected a wide range of structural variation with high accuracy, confirming it a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.
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| 6. |
- Nilsson, D., et al.
(författare)
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Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights the Importance of Microhomology in the Mechanism of Formation
- 2017
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Ingår i: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 38:2, s. 180-192
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Tidskriftsartikel (refereegranskat)abstract
- Most balanced translocations are thought to result mechanistically from nonhomologous end joining or, in rare cases of recurrent events, by nonallelic homologous recombination. Here, we use low-coverage mate pair whole-genome sequencing to fine map rearrangement breakpoint junctions in both phenotypically normal and affected translocation carriers. In total, 46 junctions from 22 carriers of balanced translocations were characterized. Genes were disrupted in 48% of the breakpoints; recessive genes in four normal carriers and known dominant intellectual disability genes in three affected carriers. Finally, seven candidate disease genes were disrupted in five carriers with neurocognitive disabilities (SVOPL, SUSD1, TOX, NCALD, SLC4A10) and one XX-male carrier with Tourette syndrome (LYPD6, GPC5). Breakpoint junction analyses revealed microhomology and small templated insertions in a substantive fraction of the analyzed translocations (17.4%; n = 4); an observation that was substantiated by reanalysis of 37 previously published translocation junctions. Microhomology associated with templated insertions is a characteristic seen in the breakpoint junctions of rearrangements mediated by error-prone replication-based repair mechanisms. Our data implicate that a mechanism involving template switching might contribute to the formation of at least 15% of the interchromosomal translocation events.
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| 7. |
- Rohringer, N., et al.
(författare)
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Stimulated X-Ray Raman Scattering with Free-Electron Laser Sources
- 2016
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Ingår i: X-Ray Lasers 2014. - Cham : Springer. - 0930-8989. - 9783319195216 - 9783319195209 ; , s. 201-207
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Bokkapitel (refereegranskat)abstract
- Stimulated electronic x-ray Raman scattering is the building block for several proposed x-ray pump probe techniques, that would allow the study of electron dynamics at unprecedented timescales.We present high spectral resolution data on stimulated electronic x-ray Raman scattering in a gas sample of neon using a self-amplified spontaneous emission x-ray free-electron laser. Despite the limited spectral coherence and broad bandwidth of these sources, high-resolution spectra can be obtained by statistical methods, opening the path to coherent stimulated x-ray Raman spectroscopy. An extension of these ideas to molecules and the results of a recent experiment in CO are discussed.
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| 8. |
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| 9. |
- Modin, A., et al.
(författare)
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Electronic structure of Cu3N films studied by soft x-ray spectroscopy
- 2008
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Ingår i: Journal of Physics. - : IOP Publishing. - 0953-8984 .- 1361-648X. ; 20:23
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Tidskriftsartikel (refereegranskat)abstract
- Soft x- ray emission spectroscopy was used to characterize the electronic structure of seven copper nitride films, one synthesized with atomic layer deposition ( ALD) and six grown with chemical vapor deposition ( CVD) at different preparation temperatures. Interpretation of the x- ray emission spectra was supported by calculations of the electronic structure for bulk pure Cu3N and Cu3N with: an excess of Cu atoms, oxygen or carbon impurities, and N vacancies. The calculations are shown to describe the experimental spectra quite well. Analysis of the x- ray spectra suggests that films grown in copper rich environments and above a cut- off temperature of approximately 360 degrees C have a growing fraction of copper enriched areas, while films prepared below this temperature do not have these areas with excess copper.
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| 10. |
- Persson, Clas, et al.
(författare)
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X-ray absorption and emission spectroscopy of ZnO nanoparticle and highly oriented ZnO microrod arrays
- 2006
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Ingår i: Microelectronics Journal. - : Elsevier BV. - 0026-2692. ; 37:8, s. 686-689
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Tidskriftsartikel (refereegranskat)abstract
- The electronic structures of ZnO nanoparticles and microrod arrays are studied by 0 Is X-ray absorption spectroscopy (XAS) and O K alpha X-ray emission spectroscopy (XES). We show that the present LDA +U-SIC calculation approach is suitable to correct the LDA self-interaction error of the cation d-states. The atomic eigenstates of 3d in zinc and 2p in oxygen are energetically close, which induces strong Zn-3d-O-2p hybridization. This anomalous valence band cation-d-anion-p hybridization is affected when the localization of the Zn 3d-states is taken into account. Experimentally, the XES spectra show energy dependence in the spectral shape revealing selected excitations to the Zn 3d, 4s and 4p states, hybridized with 0 2p states. Strong anisotropic effects are observed for the highly oriented ZnO rods, but not for the isotropic spherical nanoparticles. The nanostructured ZnO has primarily bulk XAS and XES properties.
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