The L444P Gba1 mutation enhances alpha-synuclein induced loss of nigral dopaminergic neurons in mice

Mutations in glucocerebrosidase 1 (GBA1) represent the most prevalent risk factor for Parkinson's disease. The molecular mechanisms underlying the link between GBA1 mutations and Parkinson's disease are incompletely understood. We analysed two aged (24-month-old) Gba1 mouse models, one carrying a knock-out mutation and the other a L444P knock-in mutation. A significant reduction of glucocerebrosidase activity was associated with increased total alpha-synuclein accumulation in both these models. Gba1 mutations alone did not alter the number of nigral dopaminergic neurons nor striatal dopamine levels. We then investigated the effect of overexpression of human alpha-synuclein in the substantia nigra of aged (18 to 21-month-old) L444P Gba1 mice. Following intraparenchymal injections of human alpha-synuclein carrying viral vectors, pathological accumulation of phosphorylated alpha-synuclein occurred within the transduced neurons. Stereological counts of nigral dopaminergic neurons revealed a significantly greater cell loss in Gba1-mutant than wild-type mice. These results indicate that Gba1 deficiency enhances neuronal vulnerability to neurodegenerative processes triggered by increased alpha-synuclein expression

The Bostrichidae of the Maltese Islands (Coleoptera)

The Bostrichidae of the Maltese Islands are reviewed. Ten species are recorded with certainty from this Archipelago, of which 6 namely, Trogoxylon impressum (Comolli, 1837), Amphicerus bimaculatus (A.G. Olivier, 1790), Heterobostrychus aequalis (Waterhouse, 1884), Sinoxylon unidentatum (Fabricius, 1801), Xyloperthella picea (A.G. Olivier, 1790) and Apate monachus Fabricius, 1775 are recorded for the first time. Two of the mentioned species (H. aequalis and S. unidentatum) are alien and recorded only on the basis of single captures and the possible establishment of these species is discussed. Earlier records of Scobicia pustulata (Fabricius, 1801) from Malta are incorrect and should be attributed to S. chevrieri (A. Villa & J.B. Villa, 1835). A zoogeographical analysis and an updated checklist of the 12 species of Bostrichidae recorded from the Maltese Islands and neighbouring Sicilian islands (Pantelleria, Linosa and Lampedusa) are also provided. Rhizopertha dominica (Fabricius, 1792) form granulipennis Lesne in Beeson & Bhatia, 1937 from Uttarakhand (northern India) was overlooked by almost all subsequent authors. Its history is summarized and the following new synonymy is established: Rhizopertha dominica (Fabricius, 1792) form granulipennis Lesne in Beeson & Bhatia, 1937 = Rhyzopertha dominica (Fabricius, 1792), syn. n. Finally, records of Amphicerus bimaculatus from Azerbaijan, of Bostrichus capucinus (Linnaeus, 1758) from Jordan and Syria, of Scobicia chevrieri from Jordan and Italy, of Xyloperthella picea from Italy, and of Apate monachus from Corsica (France) and Italy, are also provided.peer-reviewe

Multiwavelength observations of 3C 454.3. III. Eighteen months of AGILE monitoring of the "Crazy Diamond"

We report on 18 months of multiwavelength observations of the blazar 3C 454.3 (Crazy Diamond) carried out in July 2007-January 2009. We show the results of the AGILE campaigns which took place on May-June 2008, July-August 2008, and October 2008-January 2009. During the May 2008-January 2009 period, the source average flux was highly variable, from an average gamma-ray flux F(E>100MeV) > 200E-8 ph/cm2/s in May-June 2008, to F(E>100MeV)~80E-8 ph/cm2/s in October 2008-January 2009. The average gamma-ray spectrum between 100 MeV and 1 GeV can be fit by a simple power law (Gamma_GRID ~ 2.0 to 2.2). Only 3-sigma upper limits can be derived in the 20-60 keV energy band with Super-AGILE. During July-August 2007 and May-June 2008, RXTE measured a flux of F(3-20 keV)= 8.4E-11 erg/cm2/s, and F(3-20 keV)=4.5E-11 erg/cm2/s, respectively and a constant photon index Gamma_PCA=1.65. Swift/XRT observations were carried out during all AGILE campaigns, obtaining a F(2-10 keV)=(0.9-7.5)E-11 erg/cm2/s and a photon index Gamma_XRT=1.33-2.04. BAT measured an average flux of ~5 mCrab. GASP-WEBT monitored 3C 454.3 during the whole 2007-2008 period from the radio to the optical. A correlation analysis between the optical and the gamma-ray fluxes shows a time lag of tau=-0.4 days. An analysis of 15 GHz and 43 GHz VLBI core radio flux observations shows an increasing trend of the core radio flux, anti- correlated with the higher frequency data. The modeling SEDs, and the behavior of the long-term light curves in different energy bands, allow us to compare the jet properties during different emission states, and to study the geometrical properties of the jet on a time-span longer than one year.Comment: Accepted for publication in ApJ. Adapted Abstract. 17 pages, 19 Figures, 5 Table

A change in the optical polarization associated with a gamma-ray flare in the blazar 3C 279

It is widely accepted that strong and variable radiation detected over all accessible energy bands in a number of active galaxies arises from a relativistic, Doppler-boosted jet pointing close to our line of sight. The size of the emitting zone and the location of this region relative to the central supermassive black hole are, however, poorly known, with estimates ranging from light-hours to a light-year or more. Here we report the coincidence of a gamma-ray flare with a dramatic change of optical polarization angle. This provides evidence for co-spatiality of optical and gamma-ray emission regions and indicates a highly ordered jet magnetic field. The results also require a non-axisymmetric structure of the emission zone, implying a curved trajectory for the emitting material within the jet, with the dissipation region located at a considerable distance from the black hole, at about 10^5 gravitational radii.Comment: Published in Nature issued on 18 February 2010. Corresponding authors: Masaaki Hayashida and Greg Madejsk

Suppression of Lung Adenocarcinoma Progression by Nkx2-1

Despite the high prevalence and poor outcome of patients with metastatic lung cancer the mechanisms of tumour progression and metastasis remain largely uncharacterized. Here we modelled human lung adenocarcinoma, which frequently harbours activating point mutations in KRAS and inactivation of the p53 pathway, using conditional alleles in mice. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of Kras[superscript LSL-G12D/+];p53[superscript flox/flox] mice initiates lung adenocarcinoma development4. Although tumours are initiated synchronously by defined genetic alterations, only a subset becomes malignant, indicating that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed us to distinguish metastatic from non-metastatic tumours and determine the gene expression alterations that distinguish these tumour types. Cross-species analysis identified the NK2-related homeobox transcription factor Nkx2-1 (also called Ttf-1 or Titf1) as a candidate suppressor of malignant progression. In this mouse model, Nkx2-1 negativity is pathognomonic of high-grade poorly differentiated tumours. Gain- and loss-of-function experiments in cells derived from metastatic and non-metastatic tumours demonstrated that Nkx2-1 controls tumour differentiation and limitsmetastatic potential in vivo. Interrogation of Nkx2-1-regulated genes, analysis of tumours at defined developmental stages, and functional complementation experiments indicate that Nkx2-1 constrains tumours in part by repressing the embryonically restricted chromatin regulator Hmga2. Whereas focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas has focused attention on its oncogenic function, our data specifically link Nkx2-1 downregulation to loss of differentiation, enhanced tumour seeding ability and increased metastatic proclivity. Thus, the oncogenic and suppressive functions ofNkx2-1 in the sametumourNational Institutes of Health (U.S.) (grant U01-CA84306 )National Institutes of Health (U.S.) (grant K99-CA151968)Howard Hughes Medical InstituteLudwig Center for Molecular OncologyNational Cancer Institute (U.S.) (Cancer Center Support (core) grant P30-CA14051

A polarimetrically oriented X-ray stare at the accreting pulsar EXO 2030+375

Accreting X-ray pulsars (XRPs) are presumed to be ideal targets for polarization measurements, as their high magnetic field strength is expected to polarize the emission up to a polarization degree of 80%. However, such expectations are being challenged by recent observations of XRPs with the Imaging X-ray Polarimeter Explorer (IXPE). Here, we report on the results of yet another XRP, namely, EXO 2030+375, observed with IXPE and contemporarily monitored with Insight-HXMT and SRG/ART-XC. In line with recent results obtained with IXPE for similar sources, an analysis of the EXO 2030+375 data returns a low polarization degree of 0%- 3% in the phase-averaged study and a variation in the range of 2%- 7% in the phase-resolved study. Using the rotating vector model, we constrained the geometry of the system and obtained a value of 60 for the magnetic obliquity. When considering the estimated pulsar inclination of 130, this also indicates that the magnetic axis swings close to the observera's line of sight. Our joint polarimetric, spectral, and timing analyses hint toward a complex accreting geometry, whereby magnetic multipoles with an asymmetric topology and gravitational light bending significantly affect the behavior of the observed source

Complex variations in X-ray polarization in the X-ray pulsar LS V +44 17/RX J0440.9+4431

We report on Imaging X-ray polarimetry explorer (IXPE) observations of the Be-transient X-ray pulsar LS V +44 17/RX J0440.9+4431 made at two luminosity levels during the giant outburst in January- February 2023. Considering the observed spectral variability and changes in the pulse profiles, the source was likely caught in supercritical and subcritical states with significantly different emission-region geometry, associated with the presence of accretion columns and hot spots, respectively. We focus here on the pulse-phase-resolved polarimetric analysis and find that the observed dependencies of the polarization degree and polarization angle (PA) on the pulse phase are indeed drastically different for the two observations. The observed differences, if interpreted within the framework of the rotating vector model (RVM), imply dramatic variations in the spin axis inclination, the position angle, and the magnetic colatitude by tens of degrees within the space of just a few days. We suggest that the apparent changes in the observed PA phase dependence are predominantly related to the presence of an unpulsed polarized component in addition to the polarized radiation associated with the pulsar itself. We then show that the observed PA phase dependence in both observations can be explained with a single set of RVM parameters defining the pulsar s geometry. We also suggest that the additional polarized component is likely produced by scattering of the pulsar radiation in the equatorial disk wind

Discovery of strongly variable X-ray polarization in the neutron star low-mass X-ray binary transient XTE J1701-462

CONTEXT: After about 16 years since its first outburst, the transient neutron star low-mass X-ray binary XTE J1701−462 turned on again in September 2022, allowing for the first study of its X-ray polarimetric characteristics by a dedicated observing program with the Imaging X-ray Polarimeter Explorer (IXPE). AIMS: Polarimetric studies of XTE J1701−462 have been expected to improve our understanding of accreting weakly magnetized neutron stars, in particular, the physics and the geometry of the hot inner regions close to the compact object. METHOD: The IXPE data of two triggered observations were analyzed using time-resolved spectroscopic and polarimetric techniques, following the source along its Z-track of the color–color diagram. RESULTS: During the first pointing on 2022 September 29, an average 2–8 keV polarization degree of (4.6 ± 0.4)% was measured, the highest value found up to now for this class of sources. Conversely, only a ∼0.6% average degree was obtained during the second pointing ten days later. CONCLUSIONS: The polarimetric signal appears to be strictly related to the higher energy blackbody component associated with the boundary layer (BL) emission and its reflection from the inner accretion disk, and it is as strong as 6.1% and 1.2% (> 95% significant) above 3–4 keV for the two measurements, respectively. The variable polarimetric signal is apparently related to the spectral characteristics of XTE J1701−462, which is the strongest when the source was in the horizontal branch of its Z-track and the weakest in the normal branch. These IXPE results provide new important observational constraints on the physical models and geometry of the Z-sources. Here, we discuss the possible reasons for the presence of strong and variable polarization among these sources

The X-ray polarization of the Seyfert 1 galaxy IC 4329A

We present an X-ray spectro-polarimetric analysis of the bright Seyfert galaxy IC 4329A. The Imaging X-ray Polarimetry Explorer (IXPE) observed the source for ∼500 ks, supported by XMM–Newton (∼60 ks) and NuSTAR (∼80 ks) exposures. We detect polarization in the 2–8 keV band with 2.97σ confidence. We report a polarization degree of 3.3 ± 1.1 per cent and a polarization angle of 78° ± 10° (errors are 1σ confidence). The X-ray polarization is consistent with being aligned with the radio jet, albeit partially due to large uncertainties on the radio position angle. We jointly fit the spectra from the three observatories to constrain the presence of a relativistic reflection component. From this, we obtain constraints on the inclination angle to the inner disc (<39° at 99 per cent confidence) and the disc inner radius (<11 gravitational radii at 99 per cent confidence), although we note that modelling systematics in practice add to the quoted statistical error. Our spectropolarimetric modelling indicates that the 2–8 keV polarization is consistent with being dominated by emission directly observed from the X-ray corona, but the polarization of the reflection component is completely unconstrained. Our constraints on viewer inclination and polarization degree tentatively favour more asymmetric, possibly out-flowing, coronal geometries that produce more highly polarized emission, but the coronal geometry is unconstrained at the 3σ level