| 1. |
- Laforet, P., et al.
(författare)
-
Deep morphological analysis of muscle biopsies from type III glycogenesis (GSDIII), debranching enzyme deficiency, revealed stereotyped vacuolar myopathy and autophagy impairment
- 2019
-
Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 7:1
-
Tidskriftsartikel (refereegranskat)abstract
- Glycogen storage disorder type III (GSDIII), or debranching enzyme (GDE) deficiency, is a rare metabolic disorder characterized by variable liver, cardiac, and skeletal muscle involvement. GSDIII manifests with liver symptoms in infancy and muscle involvement during early adulthood. Muscle biopsy is mainly performed in patients diagnosed in adulthood, as routine diagnosis relies on blood or liver GDE analysis, followed by AGL gene sequencing. The GSDIII mouse model recapitulate the clinical phenotype in humans, and a nearly full rescue of muscle function was observed in mice treated with the dual AAV vector expressing the GDE transgene. In order to characterize GSDIII muscle morphological spectrum and identify novel disease markers and pathways, we performed a large international multicentric morphological study on 30 muscle biopsies from GSDIII patients. Autophagy flux studies were performed in human muscle biopsies and muscles from GSDIII mice. The human muscle biopsies revealed a typical and constant vacuolar myopathy, characterized by multiple and variably sized vacuoles filled with PAS-positive material. Using electron microscopy, we confirmed the presence of large nonmembrane bound sarcoplasmic deposits of normally structured glycogen as well as smaller rounded sac structures lined by a continuous double membrane containing only glycogen, corresponding to autophagosomes. A consistent SQSTM1/p62 decrease and beclin-1 increase in human muscle biopsies suggested an enhanced autophagy. Consistent with this, an increase in the lipidated form of LC3, LC3II was found in patients compared to controls. A decrease in SQSTM1/p62 was also found in the GSDIII mouse model. In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples. These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.
|
|
| 2. |
- Mingozzi, M., et al.
(författare)
-
CO excitation in the Seyfert galaxy NGC 34 : stars, shock or AGN driven?
- 2018
-
Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966. ; 474:3, s. 3640-3648
-
Tidskriftsartikel (refereegranskat)abstract
- We present a detailed analysis of the X-ray and molecular gas emission in the nearby galaxy NGC 34, to constrain the properties of molecular gas, and assess whether, and to what extent, the radiation produced by the accretion on to the central black hole affects the CO line emission. We analyse the CO spectral line energy distribution (SLED) as resulting mainly from Herschel and ALMA data, along with X-ray data from NuSTAR and XMM-Newton. The X-ray data analysis suggests the presence of a heavily obscured active galactic nucleus (AGN) with an intrinsic luminosity of L1-100 (keV) similar or equal to 4.0 x 10(42) erg s(-1). ALMA high-resolution data (theta similar or equal to 0.2 arcsec) allow us to scan the nuclear region down to a spatial scale of approximate to 100 pc for the CO(6-5) transition. We model the observed SLED using photodissociation region (PDR), X-ray-dominated region (XDR), and shock models, finding that a combination of a PDR and an XDR provides the best fit to the observations. The PDR component, characterized by gas density log(n/cm(-3)) = 2.5 and temperature T = 30 K, reproduces the low-J CO line luminosities. The XDR is instead characterized by a denser and warmer gas (log(n/cm(-3)) = 4.5, T = 65 K), and is necessary to fit the high-J transitions. The addition of a third component to account for the presence of shocks has been also tested but does not improve the fit of the CO SLED. We conclude that the AGN contribution is significant in heating the molecular gas in NGC 34.
|
|
| 3. |
- Pozzi, F., et al.
(författare)
-
CO excitation in the Seyfert galaxy NGC 7130
- 2017
-
Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966 .- 1745-3925 .- 1745-3933. ; 470:1, s. L64-L68
-
Tidskriftsartikel (refereegranskat)abstract
- We present a coherent multiband modelling of the carbon monoxide (CO) spectral energy distribution of the local Seyfert galaxy NGC 7130 to assess the impact of the active galactic nucleus (AGN) activity on the molecular gas. We take advantage of all the available data from X-ray to the submillimetre, including ALMA data. The high-resolution (~0.2 arcsec) ALMA CO(6-5) data constrain the spatial extension of the CO emission down to an ~70 pc scale. From the analysis of the archival Chandra and NuSTAR data, we infer the presence of a buried, Compton-thick AGN of moderate luminosity, L2-10 keV ~1.6 × 1043 erg s-1. We explore photodissociation and X-ray-dominated-region (PDR and XDR) models to reproduce the CO emission. We find that PDRs can reproduce the CO lines up to J ~ 6; however, the higher rotational ladder requires the presence of a separate source of excitation. We consider X-ray heating by the AGNs as a source of excitation, and find that it can reproduce the observed CO spectral energy distribution. By adopting a composite PDR+XDR model, we derivemolecular cloud properties. Our study clearly indicates the capabilities offered by the current generation of instruments to shed light on the properties of nearby galaxies by adopting state-of-the-art physical modelling.
|
|
