Neural Stem Cells as Model to Study Neurodegeneration and Novel Therapeutics in Lysosomal Storage Disorders

Neural Stem Cells (NSCs) are self-renewing multipotent populations responsible for the generation of neurons and glial cells of the developing brain and account for the limited regenerative plasticity of the adult brain. In view of their reliable use as cellular model to study neurodegenerative diseases, and as potential donors in cell-based therapeutic approaches, we have isolated and characterized NSCs from a mouse model of a neurodegenerative Lysosomal Storage Disorder (LSD), the Multiple Sulfatase Deficiency (MSD), caused by mutations in the sulfatase modifying factor 1 (SUMF1) gene that encodes the enzyme responsible for sulfatase activation. Isolated MSD-NSCs are phenotypically similar to wild-type precursors and are able to differentiate into neurons and astrocytes, although they show a progressive loss of their self-renewal capacity. Moreover, differentiated MSD cells recapitulate the main pathological features of the disease, such as progressive cell vacuolization, lysosomal accumulation of glycosaminoglycans (GAGs), altered autophagy with accumulation of poly-ubiquitinated proteins, and increased levels of apoptosis. Interestingly, glia-differentiated MSD cells display the tendency to form aggresomes, perinuclear aggregates of misfolded protein, which is a common feature to many neurodegenerative diseases. We also showed that the overexpression of the Transcription Factor EB (TFEB), a master-gene that modulate lysosomal function and autophagy, induces lysosomal exocytosis through activation of mucolipin 1 (MCOLN1) and reduces significantly primary and secondary pathologic storage, ameliorating the phenotype of MSD cells (Medina et al. 2011). These results validate the use of NSCs isolated from LSD mouse models to study their neurodegenerative phenotype, and envisage their use to explore new therapeutic approaches by the modulation of TFEB expression in LSDs

GalPak3D: A Bayesian parametric tool for extracting morpho-kinematics of galaxies from 3D data

We present a method to constrain galaxy parameters directly from three-dimensional data cubes. The algorithm compares directly the data with a parametric model mapped in $x,y,\lambda$ coordinates. It uses the spectral lines-spread function (LSF) and the spatial point-spread function (PSF) to generate a three-dimensional kernel whose characteristics are instrument specific or user generated. The algorithm returns the intrinsic modeled properties along with both an `intrinsic' model data cube and the modeled galaxy convolved with the 3D-kernel. The algorithm uses a Markov Chain Monte Carlo (MCMC) approach with a nontraditional proposal distribution in order to efficiently probe the parameter space. We demonstrate the robustness of the algorithm using 1728 mock galaxies and galaxies generated from hydrodynamical simulations in various seeing conditions from 0.6" to 1.2". We find that the algorithm can recover the morphological parameters (inclination, position angle) to within 10% and the kinematic parameters (maximum rotation velocity) to within 20%, irrespectively of the PSF in seeing (up to 1.2") provided that the maximum signal-to-noise ratio (SNR) is greater than $\sim3$ pixel$^{-1}$ and that the ratio of the galaxy half-light radius to seeing radius is greater than about 1.5. One can use such an algorithm to constrain simultaneously the kinematics and morphological parameters of (nonmerging) galaxies observed in nonoptimal seeing conditions. The algorithm can also be used on adaptive-optics (AO) data or on high-quality, high-SNR data to look for nonaxisymmetric structures in the residuals.Comment: 16 pages, 10 figures, accepted to publication in AJ, revised version after proofs corrections. Algorithm available at http://galpak.irap.omp.e

What Determines the Incidence and Extent of MgII Absorbing Gas Around Galaxies?

We study the connections between on-going star formation, galaxy mass, and extended halo gas, in order to distinguish between starburst-driven outflows and infalling clouds that produce the majority of observed MgII absorbers at large galactic radii (>~ 10 h^{-1} kpc) and to gain insights into halo gas contents around galaxies. We present new measurements of total stellar mass (M_star), H-alpha emission line strength (EW(H-alpha)), and specific star formation rate (sSFR) for the 94 galaxies published in H.-W. Chen et al. (2010). We find that the extent of MgII absorbing gas, R_MgII, scales with M_star and sSFR, following R_MgII \propto M_star^{0.28}\times sSFR^{0.11}. The strong dependence of R_MgII on M_star is most naturally explained, if more massive galaxies possess more extended halos of cool gas and the observed MgII absorbers arise in infalling clouds which will subsequently fuel star formation in the galaxies. The additional scaling relation of R_MgII with sSFR can be understood either as accounting for extra gas supplies due to starburst outflows or as correcting for suppressed cool gas content in high-mass halos. The latter is motivated by the well-known sSFR--M_star} inverse correlation in field galaxies. Our analysis shows that a joint study of galaxies and MgII absorbers along common sightlines provides an empirical characterization of halo gaseous radius versus halo mass. A comparison study of R_MgII around red- and blue-sequence galaxies may provide the first empirical constraint for resolving the physical origin of the observed sSFR--M_star} relation in galaxies.Comment: 6 pages, 3 figures; ApJL in pres

Targeting PKCθ promotes satellite cell self-renewal

Skeletal muscle regeneration following injury depends on the ability of satellite cells (SCs) to proliferate, self-renew, and eventually differentiate. The factors that regulate the process of self-renewal are poorly understood. In this study we examined the role of PKCθ in SC self-renewal and differentiation. We show that PKCθ is expressed in SCs, and its active form is localized to the chromosomes, centrosomes, and midbody during mitosis. Lack of PKCθ promotes SC symmetric self-renewal division by regulating Pard3 polarity protein localization, without affecting the overall proliferation rate. Genetic ablation of PKCθ or its pharmacological inhibition in vivo did not affect SC number in healthy muscle. By contrast, after induction of muscle injury, lack or inhibition of PKCθ resulted in a significant expansion of the quiescent SC pool. Finally, we show that lack of PKCθ does not alter the inflammatory milieu after acute injury in muscle, suggesting that the enhanced self-renewal ability of SCs in PKCθ-/- mice is not due to an alteration in the inflammatory milieu. Together, these results suggest that PKCθ plays an important role in SC self-renewal by stimulating their expansion through symmetric division, and it may represent a promising target to manipulate satellite cell self-renewal in pathological conditions

Submillimetre Cosmology at High Angular Resolution

Over the last decade observations at submillimetre (submm) and millimetre (mm) wavelengths, with their unique ability to trace molecular gas and dust, have attained a central role in our exploration of galaxies at all redshifts. Due to the limited sensitivities and angular resolutions of current submm/mm telescopes, however, only the most luminous objects have been uncovered at high redshifts, with interferometric follow-up observations succeeding in resolving the dust and gas reservoirs in only a handful of cases. The coming years will witness a drastic improvement in the current situation, thanks to the arrival of a new suite of powerful submm observatories (single-dish and interferometers) with an order of magnitude improvement in sensitivity and resolution. In this overview I outline a few of what I expect to be the major advances in the field of galaxy formation and evolution that these new ground-breaking facilities will facilitate.Comment: (10 pages, 3 figures. Invited talk, proceedings for the 3rd ARENA Conference "An astronomical observatory at CONCORDIA (Antarctica) for the next decade", 11-15 May 2009, Frascati, Ital

Skeletal muscle: a significant novel neurohypophyseal hormone-secreting organ

Vasopressin (arg8-vasopressin) and oxytocin are closely relalated hormones, synthesized as pre-hormones in the magnocellular neurons of the paraventricular Q6 and supraoptic nuclei of the hypothalamus. Vasopressin and oxytocin are secreted in response to a variety of physiological stimuli, serving such different functions as controlling water balance, milk ejection, uterine contraction, mood, and parental behavior (Lechan and Toni, 2000; Costa et al., 2014a)

The Star Formation Rate-Density Relationship at Redshift 3

We study the star formation rate (SFR) as a function of environment for UV-selected Lyman break galaxies (LBGs) at redshift 3. From deep [μ (sky) ≃ 27.6] UBVI MOSAIC images, covering a total of 0.90 deg , we select 334 LBGs in slices 100 h Mpc (comoving) deep spanning the redshift range 2.9 \u3c z \u3c 3.4 based on Bayesian photometric redshifts that include the I magnitude as a prior. The slice width (100 h Mpc) corresponds to the photometric redshift accuracy (Δ ∼ 0.15). We used mock catalogs from the GIF2 cosmological simulations to show that this redshift resolution is sufficient to statistically differentiate the high-density regions from the low-density regions using ∑ , the projected density to the fifth nearest neighbor. These mock catalogs have a redshift depth of 110 h Mpc, similar to our slice width. The large area of the MOSAIC images, ∼40 × 40 Mpc (comoving) per field, allows us to measure the SFR from the dust-corrected UV continuum as a function of ∑ . In contrast to low-redshift galaxies, we find that the SFR (or UV luminosity) of LBGs at z = 3 shows no detectable dependence on environment over 2 orders of magnitude in densities. To test the significance of our result, we use Monte Carlo simulations (from the mock catalogs) and the same projected density estimators that we applied to our data. We find that we can reject the steep z = 0 SFR-density relation at the 5 σ level. We conclude that the SFR-density relation at z = 3 must be at least 3.6 times flatter than it is locally; i.e., the SFR of LBGs is significantly less dependent on environment than the SFR of local star-forming galaxies. We find that the rest-frame UV colors are also independent of environment