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| 2. |
- Helbig, K. L., et al.
(författare)
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De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias
- 2018
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 103:5, s. 666-678
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Tidskriftsartikel (refereegranskat)abstract
- Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the alpha(1)-subunit of the voltage-gated Ca(V)2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed Ca(V)2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
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| 3. |
- Brownstein, Catherine A., et al.
(författare)
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An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
- 2014
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:3, s. R53-
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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- de Andrés Prada, Roberto, et al.
(författare)
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Controlling the strength of ferromagnetic order in YBa2Cu3O7/La2/3Ca1/3MnO3 multilayers
- 2019
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Ingår i: Physical Review B. - 2469-9950 .- 2469-9969. ; 100:11
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Tidskriftsartikel (refereegranskat)abstract
- With dc magnetization and polarized neutron reflectometry we studied the ferromagnetic response of YBa2Cu3O7/La2/3Ca1/3MnO3 (YBCO/LCMO) multilayers that are grown with pulsed laser deposition. We found that whereas for certain growth conditions (denoted as A type) the ferromagnetic moment of the LCMO layer is strongly dependent on the structural details of the YBCO layer on which it is deposited, for others (B type) the ferromagnetism of LCMO is much more robust. Both kinds of multilayers are of similar structural quality, but electron energy-loss spectroscopy studies with a scanning transmission electron microscope reveal an enhanced average Mn oxidation state of +3.5 for the A-type as opposed to the B-type samples, for which it is close to the nominal value of +3.33. The related, additional hole doping of the A-type LCMO layers, which likely originates from La and/or Mn vacancies, can explain their fragile ferromagnetic order, since it places them close to the boundary of the ferromagnetic order at which even weak perturbations can induce an antiferromagnetic or glassy state. On the other hand, we show that the B-type samples allow one to obtain YBCO/LCMO heterostructures with very thick YBCO layers and, yet, strongly ferromagnetic LCMO layers.
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| 7. |
- Perret, E., et al.
(författare)
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Structural, magnetic and electronic properties of pulsed-laser-deposition grown SrFeO3-delta thin films and SrFeO3-delta/La2/3Ca1/3MnO3 multilayers
- 2017
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Ingår i: Journal of Physics. - 0953-8984 .- 1361-648X. ; 29:49
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Tidskriftsartikel (refereegranskat)abstract
- We studied the structural, magnetic and electronic properties of SrFeO3-delta (SFO) thin films and SrFeO3-delta/La2/3Ca1/3MnO3 (LCMO) superlattices that have been grown with pulsed laser deposition (PLD) on La0.3Sr0.7Al0.65Ta0.35O3 (LSAT) substrates. X-ray reflectometry and scanning transmission electron microscopy (STEM) confirm the high structural quality of the films and flat and atomically sharp interfaces of the superlattices. The STEM data also reveal a difference in the interfacial layer stacking with a SrO layer at the LCMO/SFO and a LaO layer at the SFO/LCMO interfaces along the PLD growth direction. The x-ray diffraction (XRD) data suggest that the as grown SFO films and SFO/LCMO superlattices have an oxygen-deficient SrFeO3-delta structure with I4/mmm space group symmetry (delta <= 0.2). Subsequent ozone annealed SFO films are consistent with an almost oxygen stoichiometric structure (delta approximate to 0). The electronic and magnetic properties of these SFO films are similar to the ones of corresponding single crystals. In particular, the as grown SrFeO3-delta films are insulating whereas the ozone annealed films are metallic. The magneto-resistance effects of the as grown SFO films have a similar magnitude as in the single crystals, but extend over a much wider temperature range. Last but not least, for the SFO/LCMO superlattices we observe a rather large exchange bias effect that varies as a function of the cooling field.
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| 8. |
- Sen, K., et al.
(författare)
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Superconductivity and charge-carrier localization in ultrathin La1.85Sr0.15CuO4/La2CuO4 bilayers
- 2017
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Ingår i: Physical Review B. - 2469-9950 .- 2469-9969. ; 95:21
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Tidskriftsartikel (refereegranskat)abstract
- La1.85Sr0.15CuO4/La2CuO4 (LSCO15/LCO) bilayers with a precisely controlled thickness of N unit cells (UCs) of the former and M UCs of the latter ([LSCO15_N/LCO_M]) were grown on (001)-oriented SrLaAlO4 (SLAO) substrates with pulsed laser deposition (PLD). X-ray diffraction and reciprocal space map (RSM) studies confirmed the epitaxial growth of the bilayers and showed that a [LSCO15_2/LCO_2] bilayer is fully strained, whereas a [LSCO15_2/LCO_7] bilayer is already partially relaxed. The in situ monitoring of the growth with reflection high energy electron diffraction (RHEED) revealed that the gas environment during deposition has a surprisingly strong effect on the growth mode and thus on the amount of disorder in the first UC of LSCO15 (or the first two monolayers of LSCO15 containing one CuO2 plane each). For samples grown in pure N2O gas (growth type B), the first LSCO15 UC next to the SLAO substrate is strongly disordered. This disorder is strongly reduced if the growth is performed in a mixture of N2O and O2 gas (growth type A). Electric transport measurements confirmed that the first UC of LSCO15 next to the SLAO substrate is highly resistive and shows no sign of superconductivity for growth type B, whereas it is superconducting for growth type A. Furthermore, we found, rather surprisingly, that the conductivity of the LSCO15 UC next to the LCO capping layer strongly depends on the thickness of the latter. A LCO capping layer with 7 UCs leads to a strong localization of the charge carriers in the adjacent LSCO15 UC and suppresses superconductivity. The magnetotransport data suggest a similarity with the case of weakly hole doped LSCO single crystals that are in a so-called ‘cluster-spin-glass state.’ We discussed several mechanisms that could lead to such a localization of holes that are embedded in a short-range ordered antiferromagnetic background for the case of a thick LCO capping layer with M=7 but not for a thin one with M=2.
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| 9. |
- Synofzik, M., et al.
(författare)
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Mutant superoxide dismutase-1 indistinguishable from wild-type causes ALS
- 2012
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP): Policy B - Oxford Open Option B. - 0964-6906 .- 1460-2083. ; 21:16, s. 3568-3574
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Tidskriftsartikel (refereegranskat)abstract
- A reason for screening amyotrophic lateral sclerosis (ALS) patients for mutations in the superoxide dismutase-1 (SOD1) gene is the opportunity to find novel mutations with properties that can give information on pathogenesis. A novel c.352Cgreater thanG (L117V) SOD1 mutation was found in two Syrian ALS families living in Europe. The disease showed unusually low penetrance and slow progression. In erythrocytes, the total SOD1 activity, as well as specific activity of the mutant protein, was equal in carriers of the mutation and family controls lacking SOD1 mutations. The structural stabilities of the L117V mutant and wild-type SOD1 under denaturing conditions were likewise equal, but considerably lower than that of murine SOD1. As analyzed with an ELISA specific for misfolded SOD1 species, no differences were found in the content of misfolded SOD1 protein between extracts of fibroblasts from wild-type controls and from an L117V patient. In contrast, elevated levels of misfolded SOD1 protein were found in fibroblasts from ALS patients carrying seven other mutations in the SOD1 gene. We conclude that mutations in SOD1 that result in a fully stable protein are associated with low disease penetrance for ALS and may be found in cases of apparently sporadic ALS. Wild-type human SOD1 is moderately stable, and was found here to be within the stability range of ALS-causing SOD1 variants, lending support to the hypothesis that wild-type SOD1 could be more generally involved in ALS pathogenesis.
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