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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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- Van Der Woude, Auke M., et al.
(författare)
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Near-real-time CO2 fluxes from CarbonTracker Europe for high-resolution atmospheric modeling
- 2023
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Ingår i: Earth System Science Data. - : Copernicus GmbH. - 1866-3508 .- 1866-3516. ; 15:2, s. 579-605
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Tidskriftsartikel (refereegranskat)abstract
- We present the CarbonTracker Europe High-Resolution (CTE-HR) system that estimates carbon dioxide (CO2) exchange over Europe at high resolution (0.1 × 0.2° ) and in near real time (about 2 months' latency). It includes a dynamic anthropogenic emission model, which uses easily available statistics on economic activity, energy use, and weather to generate anthropogenic emissions with dynamic time profiles at high spatial and temporal resolution (0.1×0.2° hourly). Hourly net ecosystem productivity (NEP) calculated by the Simple Biosphere model Version 4 (SiB4) is driven by meteorology from the European Centre for Medium-Range Weather Forecasts (ECMWF) Reanalysis 5th Generation (ERA5) dataset. This NEP is downscaled to 0.1×0.2° using the high-resolution Coordination of Information on the Environment (CORINE) land-cover map and combined with the Global Fire Assimilation System (GFAS) fire emissions to create terrestrial carbon fluxes. Ocean CO2 fluxes are included in our product, based on Jena CarboScope ocean CO2 fluxes, which are downscaled using wind speed and temperature. Jointly, these flux estimates enable modeling of atmospheric CO2 mole fractions over Europe. We assess the skill of the CTE-HR CO2 fluxes (a) to reproduce observed anomalies in biospheric fluxes and atmospheric CO2 mole fractions during the 2018 European drought, (b) to capture the reduction of anthropogenic emissions due to COVID-19 lockdowns, (c) to match mole fraction observations at Integrated Carbon Observation System (ICOS) sites across Europe after atmospheric transport with the Transport Model, version 5 (TM5) and the Stochastic Time-Inverted Lagrangian Transport (STILT), driven by ECMWF-IFS, and (d) to capture the magnitude and variability of measured CO2 fluxes in the city center of Amsterdam (the Netherlands). We show that CTE-HR fluxes reproduce large-scale flux anomalies reported in previous studies for both biospheric fluxes (drought of 2018) and anthropogenic emissions (COVID-19 pandemic in 2020). After applying transport of emitted CO2, the CTE-HR fluxes have lower median root mean square errors (RMSEs) relative to mole fraction observations than fluxes from a non-informed flux estimate, in which biosphere fluxes are scaled to match the global growth rate of CO2 (poor person's inversion). RMSEs are close to those of the reanalysis with the CTE data assimilation system. This is encouraging given that CTE-HR fluxes did not profit from the weekly assimilation of CO2 observations as in CTE. We furthermore compare CO2 concentration observations at the Dutch Lutjewad coastal tower with high-resolution STILT transport to show that the high-resolution fluxes manifest variability due to different emission sectors in summer and winter. Interestingly, in periods where synoptic-scale transport variability dominates CO2 concentration variations, the CTE-HR fluxes perform similarly to low-resolution fluxes (5-10× coarsened). The remaining 10 % of the simulated CO2 mole fraction differs by >2 ppm between the low-resolution and high-resolution flux representation and is clearly associated with coherent structures ("plumes") originating from emission hotspots such as power plants. We therefore note that the added resolution of our product will matter most for very specific locations and times when used for atmospheric CO2 modeling. Finally, in a densely populated region like the Amsterdam city center, our modeled fluxes underestimate the magnitude of measured eddy covariance fluxes but capture their substantial diurnal variations in summertime and wintertime well. We conclude that our product is a promising tool for modeling the European carbon budget at a high resolution in near real time. The fluxes are freely available from the ICOS Carbon Portal (CC-BY-4.0) to be used for near-real-time monitoring and modeling, for example, as an a priori flux product in a CO2 data assimilation system. The data are available at 10.18160/20Z1-AYJ2 .
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