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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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- Cook, D. O., et al.
(författare)
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Star cluster catalogues for the LEGUS dwarf galaxies
- 2019
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 484:4, s. 4897-4919
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Tidskriftsartikel (refereegranskat)abstract
- We present the star cluster catalogues for 17 dwarf and irregular galaxies in the HST Treasury Program 'Legacy ExtraGalactic UV Survey' (LEGUS). Cluster identification and photometry in this sub-sample are similar to that of the entire LEGUS sample, but special methods were developed to provide robust catalogues with accurate fluxes due to low cluster statistics. The colours and ages are largely consistent for two widely used aperture corrections, but a significant fraction of the clusters are more compact than the average training cluster. However, the ensemble luminosity, mass, and age distributions are consistent suggesting that the systematics between the two methods are less than the random errors. When compared with the clusters from previous dwarf galaxy samples, we find that the LEGUS catalogues are more complete and provide more accurate total fluxes. Combining all clusters into a composite dwarf galaxy, we find that the luminosity and mass functions can be described by a power law with the canonical index of -2 independent of age and global SFR binning. The age distribution declines as a power law, with an index of approximate to -0.80 +/- 0.15, independent of cluster mass and global SFR binning. This decline of clusters is dominated by cluster disruption since the combined star formation histories and integrated-light SFRs are both approximately constant over the last few hundred Myr. Finally, we find little evidence for an upper-mass cut-off (< 2 sigma) in the composite cluster mass function, and can rule out a truncation mass below approximate to 10(4.5)M(circle dot) but cannot rule out the existence of a truncation at higher masses.
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- Bryant, J. M., et al.
(författare)
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Emergence and spread of a human-transmissible multidrug-resistant nontuberculous mycobacterium
- 2016
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 354:6313, s. 751-757
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Tidskriftsartikel (refereegranskat)abstract
- Lung infections with Mycobacterium abscessus, a species of multidrug-resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF), in whom M. abscessus accelerates inflammatory lung damage, leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole-genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge.
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- Sabbi, E., et al.
(författare)
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The Resolved Stellar Populations in the LEGUS Galaxies
- 2018
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Ingår i: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 235:1
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Tidskriftsartikel (refereegranskat)abstract
- The Legacy ExtraGalactic UV Survey (LEGUS) is a multiwavelength Cycle 21 Treasury program on the Hubble Space Telescope. It studied 50 nearby star-forming galaxies in 5 bands from the near-UV to the I-band, combining new Wide Field Camera 3 observations with archival Advanced Camera for Surveys data. LEGUS was designed to investigate how star formation occurs and develops on both small and large scales, and how it relates to the galactic environments. In this paper we present the photometric catalogs for all the apparently single stars identified in the 50 LEGUS galaxies. Photometric catalogs and mosaicked images for all filters are available for download. We present optical and near-UV color-magnitude diagrams for all the galaxies. For each galaxy we derived the distance from the tip of the red giant branch. We then used the NUV color-magnitude diagrams to identify stars more massive than 14 Me, and compared their number with the number of massive stars expected from the GALEX FUV luminosity. Our analysis shows that the fraction of massive stars forming in star clusters and stellar associations is about constant with the star formation rate. This lack of a relation suggests that the timescale for evaporation of unbound structures is comparable or longer than 10 Myr. At low star formation rates this translates to an excess of mass in clustered environments as compared to model predictions of cluster evolution, suggesting that a significant fraction of stars form in unbound systems.
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- Adamo, Angela, et al.
(författare)
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Legacy ExtraGalactic UV Survey with The Hubble Space Telescope : Stellar Cluster Catalogs and First Insights Into Cluster Formation and Evolution in NGC 628
- 2017
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Ingår i: Astrophysical Journal. - : IOP PUBLISHING LTD. - 0004-637X .- 1538-4357. ; 841:2
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Tidskriftsartikel (refereegranskat)abstract
- We report the large effort that is producing comprehensive high-level young star cluster (YSC) catalogs for a significant fraction of galaxies observed with the Legacy ExtraGalactic UV Survey (LEGUS) Hubble treasury program. We present the methodology developed to extract cluster positions, verify their genuine nature, produce multiband photometry (from NUV to NIR), and derive their physical properties via spectral energy distribution fitting analyses. We use the nearby spiral galaxy NGC 628 as a test case for demonstrating the impact that LEGUS will have on our understanding of the formation and evolution of YSCs and compact stellar associations within their host galaxy. Our analysis of the cluster luminosity function from the UV to the NIR finds a steepening at the bright end and at all wavelengths suggesting a dearth of luminous clusters. The cluster mass function of NGC 628 is consistent with a power-law distribution of slopes similar to-2 and a truncation of a few times 10(5) M-circle dot. After their formation, YSCs and compact associations follow different evolutionary paths. YSCs survive for a longer time frame, confirming their being potentially bound systems. Associations disappear on timescales comparable to hierarchically organized star-forming regions, suggesting that they are expanding systems. We find massindependent cluster disruption in the inner region of NGC 628, while in the outer part of the galaxy there is little or no disruption. We observe faster disruption rates for low mass (<= 10(4) M-circle dot) clusters, suggesting that a massdependent component is necessary to fully describe the YSC disruption process in NGC 628.
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