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- Chelban, V., et al.
(författare)
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PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation
- 2019
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 86:2, s. 225-240
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. Results: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5′-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. Interpretation: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225–240. © 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
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- Rehman, S., et al.
(författare)
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Maximum Acceptable Concentrations of DBDS, Sulphur Mercaptan and Optimal Concentration of Passivators for Safe and Prolonged Operation of Power Transformers
- 2016
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Ingår i: IEEE transactions on dielectrics and electrical insulation. - 1070-9878 .- 1558-4135. ; 23:4, s. 2438-2442
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Tidskriftsartikel (refereegranskat)abstract
- The study presents the results of experimental investigation of finding out the maximum acceptable concentrations of DBDS, sulfur mercaptan, and optimal concentration of passivator for safe and prolonged operation of power transformers in the local environmental conditions of Saudi Arabia. For experimental investigation of optimal concentrations of DBDS and sulfur mercaptan, new oil free of sulfur compounds was acquired. Four specimens of this were spiked with different concentrations of DBDS and another four with free sulfur mercaptan RSH concentrations. The covered conductor deposition (CCD) tests were performed in accordance with IEC 62535 method on all the specimens. Next, to study the effect of passivator concentrations and temperatures on corrosive sulfur formation, 10 specimens from new oil were spiked with different concentrations of BTA and Irgamet 39. Copper strips were immersed in these specimens and the vials containing the oil and the copper strips were subjected to different temperature from 50 to 150 degrees C for 24 hours in the oven. The experimental results indicated that the concentration of DBDS should always be <4 ppm and sulfur mercaptan < 1 ppm in the new oils before putting in to the service. Based on the effectiveness of the passivators, BTA was found to be effective with 50 ppm concentration at 150 degrees C compared to Irgamet 39 which was effective only with 150 ppm concentration.
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- Palecanda, A, et al.
(författare)
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Role of the scavenger receptor MARCO in alveolar macrophage binding of unopsonized environmental particles
- 1999
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 189:9, s. 1497-1506
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Tidskriftsartikel (refereegranskat)abstract
- Alveolar macrophages (AMs) avidly bind and ingest unopsonized environmental particles and bacteria through scavenger-type receptors (SRs). AMs from mice with a genetic deletion of the major macrophage SR (types AI and AII; SR−/−) showed no decrease in particle binding compared with SR+/+ mice, suggesting that other SRs are involved. To identify these receptors, we generated a monoclonal antibody (mAb), PAL-1, that inhibits hamster AM binding of unopsonized particles (TiO2, Fe2O3, and latex beads; 66 ± 5, 77 ± 2, and 85 ± 2% inhibition, respectively, measured by flow cytometry). This antibody identifies a protein of ∼70 kD on the AM surface (immunoprecipitation) that is expressed by AMs and other macrophages in situ. A cDNA clone encoding the mAb PAL-1–reactive protein isolated by means of COS cell expression was found to be 84 and 77% homologous to mouse and human scavenger receptor MARCO mRNA, respectively. Transfection of COS cells with MARCO cDNA conferred mAb-inhibitable TiO2 binding. Hamster MARCO also mediates AM binding of unopsonized bacteria (67 ± 5 and 47 ± 4% inhibition of Escherichia coli and Staphylococcus aureus binding by mAb PAL-1). A polyclonal antibody to human MARCO identified the expected ∼70-kD band on Western blots of lysates of normal bronchoalveolar lavage (BAL) cells (>90% AMs) and showed strong immunolabeling of human AMs in BAL cytocentrifuge preparations and within lung tissue specimens. In normal mouse AMs, the anti-MARCO mAb ED31 also showed immunoreactivity and inhibited binding of unopsonized particles (e.g., TiO2 ∼40%) and bacteria. The novel function of binding unopsonized environmental dusts and pathogens suggests an important role for MARCO in the lungs' response to inhaled particles.
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