| 1. |
- Guergueltcheva, V., et al.
(författare)
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Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations
- 2012
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Ingår i: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 259:5, s. 838-850
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Tidskriftsartikel (refereegranskat)abstract
- Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of inherited disorders of the neuromuscular junction. A difficult to diagnose subgroup of CMS is characterised by proximal muscle weakness and fatigue while ocular and facial involvement is only minimal. DOK7 mutations have been identified as causing the disorder in about half of the cases. More recently, using classical positional cloning, we have identified mutations in a previously unrecognised CMS gene, GFPT1, in a series of DOK7-negative cases. However, detailed description of clinical features of GFPT1 patients has not been reported yet. Here we describe the clinical picture of 24 limb-girdle CMS (LG-CMS) patients and pathological findings of 18 of them, all carrying GFPT1 mutations. Additional patients with CMS, but without tubular aggregates, and patients with non-fatigable weakness with tubular aggregates were also screened. In most patients with GFPT1 mutations, onset of the disease occurs in the first decade of life with characteristic limb-girdle weakness and fatigue. A common feature was beneficial and sustained response to acetylcholinesterase inhibitor treatment. Most of the patients who had a muscle biopsy showed tubular aggregates in myofibers. Analysis of endplate morphology in one of the patients revealed unspecific abnormalities. Our study delineates the phenotype of CMS associated with GFPT1 mutations and expands the understanding of neuromuscular junction disorders. As tubular aggregates in context of a neuromuscular transmission defect appear to be highly indicative, we suggest calling this condition congenital myasthenic syndrome with tubular aggregates (CMS-TA).
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| 2. |
- Senderek, J, et al.
(författare)
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Hexosamine Biosynthetic Pathway Mutations Cause Neuromuscular Transmission Defect
- 2011
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Ingår i: American journal of human genetics. - 0002-9297. ; 88:2, s. 162-172
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Tidskriftsartikel (refereegranskat)abstract
- Neuromuscular junctions (NMJs) are synapses that transmit impulses from motor neurons to skeletal muscle fibers leading to muscle contraction. Study of hereditary disorders of neuromusculartransmission, termed congenital myasthenic syndromes (CMS), has helped elucidate fundamental processes influencing development and function of the nerve-muscle synapse. Using genetic linkage, we find 18 different biallelic mutations in the gene encoding glutamine-fructose-6-phosphate transaminase 1 (GFPT1) in 13 unrelated families with an autosomal recessive CMS. Consistent with these data, downregulation of the GFPT1 ortholog gfpt1 in zebrafish embryos altered muscle fiber morphology and impaired neuromuscular junction development. GFPT1 is the key enzyme of the hexosaminepathway yielding the amino sugar UDP-N-acetylglucosamine, an essential substrate for protein glycosylation. Our findings provide further impetus to study the glycobiology of NMJ and synapses in general.
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| 3. |
- Hajkova, V., et al.
(författare)
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X-ray laser-induced ablation of lead compounds
- 2011
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Ingår i: DAMAGE TO VUV, EUV, AND X-RAY OPTICS III. - : SPIE.
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Konferensbidrag (refereegranskat)abstract
- The recent commissioning of a X-ray free-electron laser triggered an extensive research in the area of X-ray ablation of high-Z, high-density materials. Such compounds should be used to shorten an effective attenuation length for obtaining clean ablation imprints required for the focused beam analysis. Compounds of lead (Z=82) represent the materials of first choice. In this contribution, single-shot ablation thresholds are reported for PbWO(4) and PbI(2) exposed to ultra-short pulses of extreme ultraviolet radiation and X-rays at FLASH and LCLS facilities, respectively. Interestingly, the threshold reaches only 0.11 J/cm(2) at 1.55 nm in lead tungstate although a value of 0.4 J/cm(2) is expected according to the wavelength dependence of an attenuation length and the threshold value determined in the XUV spectral region, i.e., 79 mJ/cm(2) at a FEL wavelength of 13.5 nm. Mechanisms of ablation processes are discussed to explain this discrepancy. Lead iodide shows at 1.55 nm significantly lower ablation threshold than tungstate although an attenuation length of the radiation is in both materials quite the same. Lower thermal and radiation stability of PbI(2) is responsible for this finding.
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| 4. |
- Auer-Grumbach, Michaela, et al.
(författare)
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Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies
- 2016
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 99:3, s. 607-623
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Tidskriftsartikel (refereegranskat)abstract
- Axonal polyneuropathies are a frequent cause of progressive disability in the elderly. Common etiologies comprise diabetes mellitus, paraproteinaemia, and inflammatory disorders, but often the underlying causes remain elusive. Late-onset axonal Charcot-Marie-Tooth neuropathy (CMT2) is an autosomal-dominantly inherited condition that manifests in the second half of life and is genetically largely unexplained. We assumed age-dependent penetrance of mutations in a so far unknown gene causing late-onset CMT2. We screened 51 index case subjects with late-onset CMT2 for mutations by whole-exome (WES) and Sanger sequencing and subsequently queried WES repositories for further case subjects carrying mutations in the identified candidate gene. We studied nerve pathology and tissue levels and function of the abnormal protein in order to explore consequences of the mutations. Altogether, we observed heterozygous rare loss-of-function and missense mutations in MME encoding the metalloprotease neprilysin in 19 index case subjects diagnosed with axonal polyneuropathies or neurodegenerative conditions involving the peripheral nervous system. MME mutations segregated in an autosomal-dominant fashion with age-related incomplete penetrance and some affected individuals were isolated case subjects. We also found that MME mutations resulted in strongly decreased tissue availability of neprilysin and impaired enzymatic activity. Although neprilysin is known to degrade beta-amyloid, we observed no increased amyloid deposition or increased incidence of dementia in individuals with MME mutations. Detection of MME mutations is expected to increase the diagnostic yield in late-onset polyneuropathies, and it will be tempting to explore whether substances that can elevate neprilysin activity could be a rational option for treatment.
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| 5. |
- Kunnus, K., et al.
(författare)
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Identification of the dominant photochemical pathways and mechanistic insights to the ultrafast ligand exchange of Fe(CO)(5) to Fe(CO)(4)EtOH
- 2016
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Ingår i: Structural Dynamics. - : AIP Publishing. - 2329-7778. ; 3:4
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Tidskriftsartikel (refereegranskat)abstract
- We utilized femtosecond time-resolved resonant inelastic X-ray scattering and ab initio theory to study the transient electronic structure and the photoinduced molecular dynamics of a model metal carbonyl photocatalyst Fe(CO)(5) in ethanol solution. We propose mechanistic explanation for the parallel ultrafast intra-molecular spin crossover and ligation of the Fe(CO)(4) which are observed following a charge transfer photoexcitation of Fe(CO)(5) as reported in our previous study [ Wernet et al., Nature 520, 78 (2015)]. We find that branching of the reaction pathway likely happens in the (1)A(1) state of Fe(CO)(4). A sub-picosecond time constant of the spin crossover from B-1(2) to B-3(2) is rationalized by the proposed B-1(2) -> (1)A(1) -> B-3(2) mechanism. Ultrafast ligation of the B-1(2) Fe(CO)(4) state is significantly faster than the spin-forbidden and diffusion limited ligation process occurring from the B-3(2) Fe(CO)(4) ground state that has been observed in the previous studies. We propose that the ultrafast ligation occurs via B-1(2) -> (1)A(1) -> (1)A'Fe(CO)(4)EtOH pathway and the time scale of the (1)A(1) Fe(CO)(4) state ligation is governed by the solute-solvent collision frequency. Our study emphasizes the importance of understanding the interaction of molecular excited states with the surrounding environment to explain the relaxation pathways of photoexcited metal carbonyls in solution.
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| 6. |
- Zusin, Dmitriy, et al.
(författare)
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Ultrafast perturbation of magnetic domains by optical pumping in a ferromagnetic multilayer
- 2022
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Ingår i: Physical Review B. - : American Physical Society. - 2469-9950 .- 2469-9969. ; 106:14
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Tidskriftsartikel (refereegranskat)abstract
- Ultrafast optical pumping of spatially nonuniform magnetic textures is known to induce far-from-equilibrium spin transport effects. Here, we use ultrafast x-ray diffraction with unprecedented dynamic range to study the laser-induced dynamics of labyrinth domain networks in ferromagnetic CoFe/Ni multilayers. We detected azimuthally isotropic, odd order, magnetic diffraction rings up to fifth order. The amplitudes of all three diffraction rings quench to different degrees within 1.6 ps. In addition, all three of the detected diffraction rings both broaden by 15% and radially contract by 6% during the quench process. We are able to rigorously quantify a 31% ultrafast broadening of the domain walls via Fourier analysis of the order-dependent quenching of the three detected diffraction rings. The broadening of the diffraction rings is interpreted as a reduction in the domain coherence length, but the shift in the ring radius, while unambiguous in its occurrence, remains unexplained. In particular, we demonstrate that a radial shift explained by domain-wall broadening can be ruled out. With the unprecedented dynamic range of our data, our results provide convincing evidence that labyrinth domain structures are spatially perturbed at ultrafast speeds under far-from-equilibrium conditions, albeit the mechanism inducing the perturbations remains yet to be clarified.
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