| 1. |
- Hu, H., et al.
(författare)
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X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes
- 2016
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 21:1, s. 133-148
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Tidskriftsartikel (refereegranskat)abstract
- X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.
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| 2. |
- Okabayashi, M., et al.
(författare)
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Control of the resistive wall mode with internal coils in the DIII-D tokamak
- 2005
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 45:12, s. 1715-1731
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Tidskriftsartikel (refereegranskat)abstract
- Internal coils, 'I-Coils', were installed inside the vacuum vessel of the DIII-D device to generate non-axisymmetric magnetic fields to act directly on the plasma. These fields are predicted to stabilize the resistive wall mode (RWM) branch of the long-wavelength external kink mode with plasma beta close to the ideal wall limit. Feedback using these I-Coils was found to be more effective as compared to using external coils located outside the vacuum vessel. Locating the coils inside the vessel allows for a faster response and the coil geometry also allows for better coupling to the helical mode structure. Initial results were reported previously (Strait E.J. et al 2004 Phys. Plasmas 11 2505). This paper reports on results from extended feedback stabilization operations, achieving plasma parameters up to the regime of Cβ ≈ 1.0 and open loop growth rates of γopenτw ≳ 25 where the RWM was predicted to be unstable with only the 'rotational viscous stabilization mechanism'. Here Cβ ≈ (β - βno-wall.limit)/(βideal.wall.limit - βno-wall.limit) is a measure of the beta relative to the stability limits without a wall and with a perfectly conducting wall, and τw is the resistive flux penetration time of the wall. These feedback experimental results clarified the processes of dynamic error field correction and direct RWM stabilization, both of which took place simultaneously during RWM feedback stabilization operation. MARS-F modelling provides a critical rotation velocity in reasonable agreement with the experiment and predicts that the growth rate increases rapidly as rotation decreases below the critical. The MARS-F code also predicted that for successful RWM magnetic feedback, the characteristic time of the power supply should be limited to a fraction of the growth time of the targeted RWM. The possibility of further improvements in the presently achievable range of operation of feedback gain values is also discussed.
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| 3. |
- Chu, M.S., et al.
(författare)
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Physics of Plasmas Modeling of Feedback and Rotation Stabilization of the Resistive Wall Mode in Tokamaks
- 2004
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Ingår i: Physics of Plasmas. ; 11, s. 2497-
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Tidskriftsartikel (refereegranskat)abstract
- Steady-state operation of the advanced tokamak reactor relies on maintaining plasma stability with respect to the resistive wall mode ~RWM!. Active magnetic feedback and plasma rotation are the two methods proposed and demonstrated for this purpose. A comprehensive modeling effort including both magnetic feedback and plasma rotation is needed for understanding the physical mechanisms of the stabilization and to project to future devices. For plasma with low rotation, a complete solution for the feedback issue is obtained by assuming the plasma obeys ideal magnetohydrodynamics ~MHDs! and utilizing a normal mode approach ~NMA! @M. S. Chu et al., Nucl. Fusion 43, 441 ~2003!#. It is found that poloidal sensors are more effective than radial sensors and coils inside of the vacuum vessel more effective than outside. For plasmas with non-negligible rotation, a comprehensive linear nonideal MHD code, the MARS-F has been found to be suitable. MARS-F @Y. Q. Liu et al., Phys. Plasmas 7, 3681 ~2000!# has been benchmarked in the ideal MHD limit against the NMA. The effect of rotation stabilization of the plasma depends on the plasma dissipation model. Broad qualitative features of the experiment are reproduced. Rotation reduces the feedback gain required for RWM stabilization. Reduction is significant when rotation is near the critical rotation speed needed for stabilization. The International Thermonuclear Experimental Reactor ~ITER! @R. Aymar et al., Plasma Phys. Controlled Fusion 44, 519 ~2002!# ~scenario IV for advanced tokamak operation! may be feedback stabilized with babove the no wall limit and up to an increment of ;50% towards the ideal limit. Rotation further improves the stability.
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| 4. |
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| 5. |
- Sabbagh, S. A., et al.
(författare)
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Resistive wall stabilized operation in rotating high beta NSTX plasmas
- 2006
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 46:5, s. 635-644
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Tidskriftsartikel (refereegranskat)abstract
- The National Spherical Torus Experiment (NSTX) has demonstrated the advantages of low aspect ratio geometry in accessing high toroidal and normalized plasma beta, and βN ≡ 10 8〈βt〉 aB0/Ip. Experiments have reached βt = 39% and βN = 7.2 through boundary and profile optimization. High βN plasmas can exceed the ideal no-wall stability limit, βNno-wall, for periods much greater than the wall eddy current decay time. Resistive wall mode (RWM) physics is studied to understand mode stabilization in these plasmas. The toroidal mode spectrum of unstable RWMs has been measured with mode number n up to 3. The critical rotation frequency of Bondeson-Chu, Ωcrit = ωA/(4q2), describes well the RWM stability of NSTX plasmas when applied over the entire rotation profile and in conjunction with the ideal stability criterion. Rotation damping and global rotation collapse observed in plasmas exceeding βNno-wall differs from the damping observed during tearing mode activity and can be described qualitatively by drag due to neoclassical toroidal viscosity in the helically perturbed field of an ideal displacement. Resonant field amplification of an applied n = 1 field perturbation has been measured and increases with increasing βN. Equilibria are reconstructed including measured ion and electron pressure, toroidal rotation and flux isotherm constraint in plasmas with core rotation ω/ωA up to 0.48. Peak pressure shifts of 18% of the minor radius from the magnetic axis have been reconstructed.
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| 6. |
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| 7. |
- Johansson, J., et al.
(författare)
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Gustavson syndrome is caused by an in-frame deletion in RBMX associated with potentially disturbed SH3 domain interactions
- 2024
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Ingår i: European Journal of Human Genetics. - : SPRINGERNATURE. - 1018-4813 .- 1476-5438. ; 32:3, s. 333-341
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Tidskriftsartikel (refereegranskat)abstract
- RNA binding motif protein X-linked (RBMX) encodes the heterogeneous nuclear ribonucleoprotein G (hnRNP G) that regulates splicing, sister chromatid cohesion and genome stability. RBMX knock down experiments in various model organisms highlight the gene's importance for brain development. Deletion of the RGG/RG motif in hnRNP G has previously been associated with Shashi syndrome, however involvement of other hnRNP G domains in intellectual disability remain unknown. In the current study, we present the underlying genetic and molecular cause of Gustavson syndrome. Gustavson syndrome was first reported in 1993 in a large Swedish five-generation family presented with profound X-linked intellectual disability and an early death. Extensive genomic analyses of the family revealed hemizygosity for a novel in-frame deletion in RBMX in affected individuals (NM_002139.4; c.484_486del, p.(Pro162del)). Carrier females were asymptomatic and presented with skewed X-chromosome inactivation, indicating silencing of the pathogenic allele. Affected individuals presented minor phenotypic overlap with Shashi syndrome, indicating a different disease-causing mechanism. Investigation of the variant effect in a neuronal cell line (SH-SY5Y) revealed differentially expressed genes enriched for transcription factors involved in RNA polymerase II transcription. Prediction tools and a fluorescence polarization assay imply a novel SH3-binding motif of hnRNP G, and potentially a reduced affinity to SH3 domains caused by the deletion. In conclusion, we present a novel in-frame deletion in RBMX segregating with Gustavson syndrome, leading to disturbed RNA polymerase II transcription, and potentially reduced SH3 binding. The results indicate that disruption of different protein domains affects the severity of RBMX-associated intellectual disabilities.
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| 8. |
- La Haye, R.J., et al.
(författare)
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Scaling of the Plasma Rotation Needed for Stabilizing the n = 1 Resistive Wall Mode (Ideal Kink) in the DIII D Tokamak
- 2004
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Ingår i: Nuclear Fusion. - 1741-4326 .- 0029-5515. ; 44, s. 1197-
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Tidskriftsartikel (refereegranskat)abstract
- Experiments in the DIII-D tokamak show that the n = 1 ideal kink can be stabilized by a resistive wall if the plasma is rotating fast enough. A database of the onset of the n = 1 resistive wall mode as a function of the equilibrium toroidal magnetic field, the plasma density and the toroidal rotation has been assembled for plasmas with beta between the theoretically predicted no wall and ideal wall stability limits. The critical rotation frequency is found to scale as the inverse of the Alfvén time with ? ?A 0.02 (evaluated at the q = 2 surface at ? 0.6) or ? ?S 0.7, where ?S is the sound time. The dependence of ? ? A or ? ?S on ?N/?N,no wall from 1?2 is weak and suggests the plasmas are in the 'intermediate dissipation' regime.
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| 9. |
- Bergqvist, A, et al.
(författare)
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Loss of DNA-binding and new transcriptional trans-activation function in polyomavirus large T-antigen with mutation of zinc finger motif.
- 1990
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Ingår i: Nucleic Acids Research. - 0305-1048 .- 1362-4962. ; 18:9, s. 2715-20
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Tidskriftsartikel (refereegranskat)abstract
- A putative zinc finger in polyomavirus large T-antigen was investigated. We were unable to demonstrate unequivocally a requirement for zinc in specific DNA-binding using the chelating agent 1, 10-phenanthroline. An involvement of the putative zinc finger in specific DNA-binding was nevertheless suggested by the properties of a mutant protein with a cys----ser replacement in the finger motif. Probably as a result of the defective DNA-binding, the mutant protein had lost its activity in initiation of viral DNA-replication and in negative regulation of viral early transcription. However, the trans-activation of the viral late promoter was normal. The analysis also revealed a previously unrecognized activity of large T-antigen. The mutant protein trans-activated the viral early promoter. In the wild-type protein this activity is probably concealed by the separate, negative regulatory function.
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| 10. |
- Bondeson, K, et al.
(författare)
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Lactose repressor-operator DNA interactions : kinetic analysis by a surface plasmon resonance biosensor.
- 1993
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Ingår i: Analytical Biochemistry. - 0003-2697 .- 1096-0309. ; 214:1, s. 245-51
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Tidskriftsartikel (refereegranskat)abstract
- Lactose repressor binding to operator DNA and subsequent dissociation of the complex was monitored continuously by a biosensor, measuring surface plasmon resonance. In this analysis a synthetic, double-stranded oligonucleotide containing the operator site was immobilized on the sensor surface and repressor protein was passed over the surface. The formation of the repressor-operator complex was specific and could be inhibited by isopropyl-beta-D-thiogalactopyranoside inducer. From the association curve, the apparent kass was determined to be 1.8 x 10(6) M-1 s-1. Dissociation of the complex was, for the first time for the lac repressor, determined as an uncatalyzed reaction and the kdiss was determined to be 3.4 x 10(-4) s-1. As a reference, the repressor-operator interaction was analyzed by electrophoretic mobility shift assay under similar reaction conditions. With this method the equilibrium binding constant was calculated to be 2.4 (+/- 0.2) x 10(8) M-1. The corresponding value calculated from biosensor data was 5.1 x 10(9) M-1.
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