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- Meisgen, S, et al.
(författare)
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Auxilin is a novel susceptibility gene for congenital heart block which directly impacts fetal heart function
- 2022
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 81:8, s. 1151-1161
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Tidskriftsartikel (refereegranskat)abstract
- Neonatal lupus erythematosus (NLE) may develop after transplacental transfer of maternal autoantibodies with cardiac manifestations (congenital heart block, CHB) including atrioventricular block, atrial and ventricular arrhythmias, and cardiomyopathies. The association with anti-Ro/SSA antibodies is well established, but a recurrence rate of only 12%–16% despite persisting maternal autoantibodies suggests that additional factors are required for CHB development. Here, we identify fetal genetic variants conferring risk of CHB and elucidate their effects on cardiac function.MethodsA genome-wide association study was performed in families with at least one case of CHB. Gene expression was analysed by microarrays, RNA sequencing and PCR and protein expression by western blot, immunohistochemistry, immunofluorescence and flow cytometry. Calcium regulation and connectivity were analysed in primary cardiomyocytes and cells induced from pleuripotent stem cells. Fetal heart performance was analysed by Doppler/echocardiography.ResultsWe identified DNAJC6 as a novel fetal susceptibility gene, with decreased cardiac expression of DNAJC6 associated with the disease risk genotype. We further demonstrate that fetal cardiomyocytes deficient in auxilin, the protein encoded by DNAJC6, have abnormal connectivity and Ca2+ homoeostasis in culture, as well as decreased cell surface expression of the Cav1.3 calcium channel. Doppler echocardiography of auxilin-deficient fetal mice revealed cardiac NLE abnormalities in utero, including abnormal heart rhythm with atrial and ventricular ectopias, as well as a prolonged atrioventricular time intervals.ConclusionsOur study identifies auxilin as the first genetic susceptibility factor in NLE modulating cardiac function, opening new avenues for the development of screening and therapeutic strategies in CHB.
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- Chase, A., et al.
(författare)
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Profound parental bias associated with chromosome 14 acquired uniparental disomy indicates targeting of an imprinted locus
- 2015
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 29:10, s. 2069-2074
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Tidskriftsartikel (refereegranskat)abstract
- Acquired uniparental disomy (aUPD) is a common finding in myeloid malignancies and typically acts to convert a somatically acquired heterozygous mutation to homozygosity. We sought to identify the target of chromosome 14 aUPD (aUPD14), a recurrent abnormality in myeloid neoplasms and population cohorts of elderly individuals. We identified 29 cases with aUPD14q that defined a minimal affected region (MAR) of 11.2 Mb running from 14q32.12 to the telomere. Exome sequencing (n = 7) did not identify recurrently mutated genes, but methylation-specific PCR at the imprinted MEG3-DLK1 locus located within the MAR demonstrated loss of maternal chromosome 14 and gain of paternal chromosome 14 (P < 0.0001), with the degree of methylation imbalance correlating with the level of aUPD (r = 0.76; P = 0.0001). The absence of driver gene mutations in the exomes of three individuals with aUPD14q but no known haematological disorder suggests that aUPD14q may be sufficient to drive clonal haemopoiesis. Analysis of cases with both aUPD14q and JAK2 V617F (n = 11) indicated that aUPD14q may be an early event in some cases but a late event in others. We conclude that aUPD14q is a recurrent abnormality that targets an imprinted locus and may promote clonal haemopoiesis either as an initiating event or as a secondary change.
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- Cox, D. M., et al.
(författare)
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Spectroscopy along flerovium decay chains. II. Fine structure in odd-A 289Fl
- 2023
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Ingår i: Physical Review C. - 2469-9985. ; 107:2
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Tidskriftsartikel (refereegranskat)abstract
- Fifteen correlated α-decay chains starting from the odd-A superheavy nucleus 289Fl were observed following the fusion-evaporation reaction 48Ca+244Pu. The results call for at least two parallel α-decay sequences starting from at least two different states of 289Fl. This implies that close-lying levels in nuclei along these chains have quite different spin-parity assignments. Further, observed α-electron and α-photon coincidences, as well as the α-decay fine structure along the decay chains, suggest a change in the ground-state spin assignment between 285Cn and 281Ds. Our experimental results, on the excited level structure of the heaviest odd-N nuclei to date, provide a direct testing ground for theory. This is illustrated by comparison with new nuclear structure calculations based on the symmetry-conserving configuration mixing theory.
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- Lorenz, Ch, et al.
(författare)
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Quantum-state-selective decay spectroscopy of 213Ra
- 2017
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Ingår i: Physical Review C. - 2469-9985. ; 96:3
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Tidskriftsartikel (refereegranskat)abstract
- An experimental scheme combining the mass resolving power of a Penning trap with contemporary decay spectroscopy has been established at GSI Darmstadt. The Universal Linear Accelerator (UNILAC) at GSI Darmstadt provided a 48Ca beam impinging on a thin 170Er target foil. Subsequent to velocity filtering of reaction products in the Separator for Heavy Ion reaction Products (SHIP), the nuclear ground state of the 5n evaporation channel 213Ra was mass-selected in SHIPTRAP, and the 213Ra ions were finally transferred into an array of silicon strip detectors surrounded by large composite germanium detectors. Based on comprehensive Geant4 simulations and supported by theoretical calculations, the spectroscopic results call for a revision of the decay path of 213Ra, thereby exemplifying the potential of a combination of a mass-selective Penning trap device with a dedicated nuclear decay station and contemporary Geant4 simulations.
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- Lundgren, Fredrik, et al.
(författare)
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PTFE bypass to below-knee arteries : distal vein collar or not? A prospective randomised multicentre study
- 2010
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Ingår i: European Journal of Vascular and Endovascular Surgery. - : Elsevier BV. - 1078-5884 .- 1532-2165. ; 39:6, s. 747-754
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPatency and limb salvage after synthetic bypass to the arteries below-knee are inferior to that which can be achieved with autologous vein. Use of a vein collar at the distal anastomosis has been suggested to improve patency and limb salvage, a problem that is analysed in this randomised clinical study.MethodsPatients with critical limb ischaemia undergoing polytetrafluoroethylene (PTFE) bypass to below-knee arteries were randomly either assigned a vein collar or not in two groups – bypass to the popliteal artery below-knee (femoro-popliteal below-knee (FemPopBK)) and more distal bypass (femoro-distal bypass (FemDist)). Follow-up was scheduled until amputation, death or at most 5 years, whichever event occurred first.ResultsIn the FemPopBK and in the FemDist groups, 115/202 and 72/150 were randomised to have a vein collar, respectively. Information was available for 345 of 352 randomised patients (98%).At 3 years, primary patency was 26% (95% confidence interval (CI) 18–38) with a vein collar and 43 (33–58) without a vein collar for femoro-popliteal bypass and 20 (11–38), and 17 (9–33) for femoro-distal bypass, respectively. The corresponding figures for limb salvage were 64 (54–75) and 61 (50–74) for femoro-popliteal bypass, and 59 (46–76) and 44 (32–61) for femoro-distal bypass with and without a vein collar, respectively. Log-rank-test for the whole Kaplan–Meier life table curve showed no statistically significant differences with or without vein collar primary patency: p = 0.0853, p = 0.228; secondary patency: p = 0.317, p = 0.280; limb salvage: p = 0.757, p = 0.187 for FemPopBK and FemDist, respectively. The use of a vein collar did not influence patency or limb salvage.ConclusionThis study failed to show any benefit for vein collar with PTFE bypass to a below-knee artery.
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