Pharmacological LRRK2 kinase inhibition induces LRRK2 protein destabilization and proteasomal degradation

Leucine-rich repeat kinase 2 (LRRK2) kinase activity is increased in several pathogenic mutations, including the most common mutation, G2019S, and is known to play a role in Parkinson’s disease (PD) pathobiology. This has stimulated the development of potent, selective LRRK2 kinase inhibitors as one of the most prevailing disease-modifying therapeutic PD strategies. Although several lines of evidence support beneficial effects of LRRK2 kinase inhibitors, many questions need to be answered before clinical applications can be envisaged. Using six different LRRK2 kinase inhibitors, we show that LRRK2 kinase inhibition induces LRRK2 dephosphorylation and can reduce LRRK2 protein levels of overexpressed wild type and G2019S, but not A2016T or K1906M, LRRK2 as well as endogenous LRRK2 in mouse brain, lung and kidney. The inhibitor-induced reduction in LRRK2 levels could be reversed by proteasomal inhibition, but not by lysosomal inhibition, while mRNA levels remained unaffected. In addition, using LRRK2 S910A and S935A phosphorylation mutants, we show that dephosphorylation of these sites is not required for LRRK2 degradation. Increasing our insight in the molecular and cellular consequences of LRRK2 kinase inhibition will be crucial in the further development of LRRK2-based PD therapies

Early star formation traced by the highest redshift quasars

The iron abundance relative to alpha-elements in the circumnuclear region of quasars is regarded as a clock of the star formation history and, more specifically, of the enrichment by SNIa. We investigate the iron abundance in a sample of 22 quasars in the redshift range 3.0<z<6.4 by measuring their rest frame UV FeII bump, which is shifted into the near-IR, and by comparing it with the MgII 2798 flux. The observations were performed with a device that can obtain near-IR spectra in the range 0.8-2.4 um in one shot, thereby enabling an optimal removal of the continuum underlying the FeII bump. We detect iron in all quasars including the highest redshift (z=6.4) quasar currently known. The uniform observational technique and the wide redshift range allows a reliable study of the trend of the FeII/MgII ratio with redshift. We find the FeII/MgII ratio is nearly constant at all redshifts, although there is marginal evidence for a higher FeII/MgII ratio in the quasars at z~6. If the FeII/MgII ratio reflects the Fe/alpha abundance, this result suggests that the z~6 quasars have already undergone a major episode of iron enrichment. We discuss the possible implications of this finding for the star formation history at z>6. We also detect a population of weak iron emitters at z~4.5, which are possibly hosted in systems that evolved more slowly. Alternatively, the trend of the FeII/MgII ratio at high redshift may reflect significantly different physical conditions of the circumnuclear gas in such high redshift quasars.Comment: Replaced to match the accepted version (ApJL in press), 5 page

Globular Clusters in the Magellanic Clouds.I:BV CCD-Photometry for 11 Clusters

We present BV CCD-data for 11 intermediate-age LMC clusters; the main conclusions are: 1. in the (V_to, V_cl,m) and (V-to, (V_to-V_cl,m)) planes the models yield a good overall description of the data; 2. with the current sample, it is impossible to firmly choose between "classical" and "overshooting" models; 3. the separation in colour between the MS band and the Red He-burning Clump is smaller than predicted by theoretical tracks; 4. the existence of the so-called "RGB phase-transition (Renzini and Buzzoni 1986) seems to be confirmed.Comment: 62 pages, 37 figures and tables 6 to 16 available on request, uuencoded compressed postscript file with tables 1-5 and 17-18 included, BAP 08-1994-020-OA

The NIR structure of the barred galaxy NGC253 from VISTA

[abridged] We used J and Ks band images acquired with the VISTA telescope as part of the science verification to quantify the structures in the stellar disk of the barred Sc galaxy NGC253. Moving outward from the galaxy center, we find a nuclear ring within the bright 1 kpc diameter nucleus, then a bar, a ring with 2.9 kpc radius. From the Ks image we obtain a new measure of the deprojected length of the bar of 2.5 kpc. The bar's strength, as derived from the curvature of the dust lanes in the J-Ks image, is typical of weak bars. From the deprojected length of the bar, we establish the corotation radius (R_CR=3 kpc) and bar pattern speed (Omega_b = 61.3 km /s kpc), which provides the connection between the high-frequency structures in the disk and the orbital resonances induced by the bar. The nuclear ring is located at the inner Lindblad resonance. The second ring does not have a resonant origin, but it could be a merger remnant or a transient structure formed during an intermediate stage of the bar formation. The inferred bar pattern speed places the outer Lindblad resonance within the optical disk at 4.9 kpc, in the same radial range as the peak in the HI surface density. The disk of NGC253 has a down-bending profile with a break at R~9.3 kpc, which corresponds to about 3 times the scale length of the inner disk. We discuss the evidence for a threshold in star formation efficiency as a possible explanation of the steep gradient in the surface brightness profile at large radii. The NIR photometry unveils the dynamical response of the NGC253 stellar disk to its central bar. The formation of the bar may be related to the merger event that determined the truncation of stars and gas at large radii and the perturbation of the disk's outer edge.Comment: Accepted for publication in Astronomy & Astrphysics. High resolution pdf file is available at the following link: https://www.dropbox.com/s/4o4cofs1lyjrtpv/NGC253.pd

Geochemical Characterization of Groundwater in the Confined and Unconfined Aquifers of the Northern Italy

Having an accurate and easily accessible geochemical database is crucial for a correct groundwater management. Here, for the first time in Italy, chemico-physical data of groundwater collected by different Environmental Protection Agencies during the 2018 were integrated into a single database to assess the geochemical status of a wide and complex aquifer system. Data were assembled, reformatted, corrected, homogenized, and then grouped according to the aquifer type (phreatic, semi-confined, and confined) and the sampling seasons. A total of 3671 validated samples were classified into hydrochemical facies; inorganic N compounds and trace elements were also evaluated. The water were classified mainly as Ca-HCO3 and Ca-Mg-HCO3 (90%); locally, Na-HCO3, Mg-HCO3, Ca-SO4, Na-Cl, and Ca-Cl types were detected. In the phreatic aquifers, NO3 contamination and high concentrations of Na+, K+, and NH4+ were found and linked to anthropogenic sources, such as agricultural and livestock activities. Along the Adriatic coast, Na-Cl water confirmed saltwater intrusion phenomena. Landward, evaporitic rocks dissolution, and the upconing of relict marine water explained high EC, Na+, K+, Cl-, and SO42- concentrations. The dissolution of Fe-Mn oxide-hydroxides coupled with organic carbon oxidation under reducing environment justified high NH4+, Fe, Mn, and As recorded in the semi-confined and confined aquifers

The Star Formation History of NGC 1705: a Post-Starburst Galaxy on the Verge of Activity

We infer the star formation history in different regions of the blue compact dwarf NGC 1705 by comparing synthetic color-magnitude diagrams with HST optical and near-infrared photometry. We find that NGC 1705 is not a young galaxy because its star formation commenced at least 5 Gyr ago. On the other hand, we confirm the existence of a recent burst of star formation between 15 and 10 Myr ago. We also find evidence for new strong activity, which started 3 Myr ago and is still continuing. The old population is spread across the entire galaxy, while the young and intermediate stars are more concentrated in the central regions. We derive an almost continuous star formation with variable rate, and exclude the presence of long quiescent phases between the episodes during the last ~1 Gyr. The central regions experienced an episode of star formation of \~0.07 Msun/yr (for a Salpeter initial mass function [IMF]) 15 to 10 Myr ago. This coincides with the strong activity in the central super star cluster. We find a rate of ~0.3 Msun/yr for the youngest ongoing burst which started ~3 Myr ago. This is higher than in other dwarfs and comparable to the rate of NGC 1569. The star formation rate of earlier episodes is not especially high and falls in the range 10^{-3}-10^{-1} Msun/yr. The IMF is close to the Salpeter value or slightly steeper.Comment: 34 pages, including 6 tables and 14 .ps figures (9 in colour), AJ in pres

The Expected Rate of Gamma-Ray Burst Afterglows In Supernova Searches

We predict the rate at which Gamma-Ray Burst (GRB) afterglows should be detected in supernova searches as a function of limiting flux. Although GRB afterglows are rarer than supernovae, they are detectable at greater distances because of their higher intrinsic luminosity. Assuming that GRBs trace the cosmic star formation history and that every GRB gives rise to a bright afterglow, we find that the average detection rate of supernovae and afterglows should be comparable at limiting magnitudes brighter than K=18. The actual rate of afterglows is expected to be somewhat lower since only a fraction of all gamma-ray selected GRBs were observed to have associated afterglows. However, the rate could also be higher if the initial gamma-ray emission from GRB sources is more beamed than their late afterglow emission. Hence, current and future supernova searches can place strong constraints on the afterglow appearance fraction and the initial beaming angle of GRB sources.Comment: 13 pages, submitted to ApJ