Periventricular Heterotopia: Shuttling of Proteins through Vesicles and Actin in Cortical Development and Disease

During cortical development, proliferating neural progenitors exhibit polarized apical and basolateral membranes that are maintained by tightly controlled and membrane-specific vesicular trafficking pathways. Disruption of polarity through impaired delivery of proteins can alter cell fate decisions and consequent expansion of the progenitor pool, as well as impact the integrity of the neuroependymal lining. Loss of neuroependymal integrity disrupts radial glial scaffolding and alters initial neuronal migration from the ventricular zone. Vesicle trafficking is also required for maintenance of lipid and protein cycling within the leading and trailing edge of migratory neurons, as well as dendrites and synapses of mature neurons. Defects in this transport machinery disrupt neuronal identity, migration, and connectivity and give rise to a malformation of cortical development termed as periventricular heterotopia (PH). PH is characterized by a reduction in brain size, ectopic clusters of neurons localized along the lateral ventricle, and epilepsy and dyslexia. These anatomical anomalies correlate with developmental impairments in neural progenitor proliferation and specification, migration from loss of neuroependymal integrity and neuronal motility, and aberrant neuronal process extension. Genes causal for PH regulate vesicle-mediated endocytosis along an actin cytoskeletal network. This paper explores the role of these dynamic processes in cortical development and disease

Filamin A mediated Big2 dependent endocytosis: From apical abscission to periventricular heterotopia

Periventricular heterotopia (PH) is one of the most common malformations of cortical development (MCD). Nodules along the lateral ventricles of the brain, disruption of the ventricular lining, and a reduced brain size are hallmarks of this disorder. PH results in a disruption of the neuroependyma, inhibition of neural proliferation and differentiation, and altered neuronal migration. Human mutations in the genes encoding the actin-binding Filamin A (FLNA) and the vesicle trafficking Brefeldin A-associated guanine exchange factor 2 (BIG2 is encoded by the ARFGEF2 gene) proteins are implicated in PH formation. Recent studies have shown that the transition from proliferating neural progenitors to post-mitotic neurons relies on apical abscission along the neuroepithelium. This mechanism involves an actin dependent contraction of the apical portion of a neural progenitor along the ventricular lining to complete abscission. Actin also maintains stability of various cell adhesion molecules along the neuroependyma. Loss of cadherin directs disassembly of the primary cilium, which transduces sonic-hedgehog (Shh) signaling. Shh signaling is required for continued proliferation. In this context, apical abscission regulates neuronal progenitor exit and migration from the ventricular zone by detachment from the neuroependyma, relies on adhesion molecules that maintain the integrity of the neuroepithelial lining, and directs neural proliferation. Each of these processes is disrupted in PH, suggesting that genes causal for this MCD, may fundamentally mediate apical abscission in cortical development. Here we discuss several recent reports that demonstrate a coordinated role for actin and vesicle trafficking in modulating neural development along the neurepithelium, and potentially the neural stem cell to neuronal transition

Filamin B Regulates Chondrocyte Proliferation and Differentiation through Cdk1 Signaling

Humans who harbor loss of function mutations in the actin-associated filamin B (FLNB) gene develop spondylocarpotarsal syndrome (SCT), a disorder characterized by dwarfism (delayed bone formation) and premature fusion of the vertebral, carpal and tarsal bones (premature differentiation). To better understand the cellular and molecular mechanisms governing these seemingly divergent processes, we generated and characterized FlnB knockdown ATDC5 cell lines. We found that FlnB knockdown led to reduced proliferation and enhanced differentiation in chondrocytes. Within the shortened growth plate of postnatal FlnB−/− mice long bone, we observed a similarly progressive decline in the number of rapidly proliferating chondrocytes and premature differentiation characterized by an enlarged prehypertrophic zone, a widened Col2a1+/Col10a1+ overlapping region, but relatively reduced hypertrophic zone length. The reduced chondrocyte proliferation and premature differentiation were, in part, attributable to enhanced G2/M phase progression, where fewer FlnB deficient ATDC5 chondrocytes resided in the G2/M phase of the cell cycle. FlnB loss reduced Cdk1 phosphorylation (an inhibitor of G2/M phase progression) and Cdk1 inhibition in chondrocytes mimicked the null FlnB, premature differentiation phenotype, through a β1-integrin receptor- Pi3k/Akt (a key regulator of chondrocyte differentiation) mediated pathway. In this context, the early prehypertrophic differentiation provides an explanation for the premature differentiation seen in this disorder, whereas the progressive decline in proliferating chondrocytes would ultimately lead to reduced chondrocyte production and shortened bone length. These findings begin to define a role for filamin proteins in directing both cell proliferation and differentiation through indirect regulation of cell cycle associated proteins

Generation of internal waves by eddies impinging on the western boundary of the North Atlantic

Despite the major role played by mesoscale eddies in redistributing the energy of the large-scale circulation, our understanding of their dissipation is still incomplete. This study investigates the generation of internal waves by decaying eddies in the North Atlantic western boundary. The eddy presence and decay are measured from the altimetric surface relative vorticity associated with an array of full-depth current meters extending ~100 km offshore at 26.5°N. In addition, internal waves are analysed over a topographic rise from 2-year high-frequency measurements of an Acoustic Doppler Current Profiler (ADCP), which is located 13 km offshore in 600 m deep water. Despite an apparent polarity independence of the eddy decay observed from altimetric data, the flow in the deepest 100 m is enhanced for anticyclones (25.2 cm s−1) compared with cyclones (-4.7 cm s−1). Accordingly, the internal wave field is sensitive to this polarity-dependent deep velocity. This is apparent from the eddy-modulated enhanced dissipation rate, which is obtained from a finescale parameterization and exceeds 10−9 W kg−1 for near-bottom flows greater than 8 cm s−1. The present study underlines the importance of oceanic western boundaries for removing the energy of low-mode westward-propagating eddies to higher-mode internal waves

Vertical flow in the Southern Ocean estimated from individual moorings

In this study, we demonstrate that oceanic vertical velocities can be estimated from individual mooring measurements, even for non-stationary flow. This result is obtained under three assumptions: i. weak diffusion (Péclet number ≫1), ii. weak friction (Reynolds number ≫1), and iii. small inertial terms (Rossby number ≪1). The theoretical framework is applied to a set of 4 moorings located in the Southern Ocean. For this site, the diagnosed vertical velocities are highly variable in time, their standard deviation being one-to-two orders of magnitude greater than their mean. We demonstrate that the time-averaged vertical velocities are largely induced by geostrophic flow, and can be estimated from the time-averaged density and horizontal velocities. This suggests that local time-mean vertical velocities are primarily forced by the time-mean ocean dynamics, rather than by e.g. transient eddies or internal waves. We also show that, in the context of these four moorings, the time-mean vertical flow is consistent with stratified Taylor column dynamics in the presence of a topographic obstacle

NGC 4102: High Resolution Infrared Observations of a Nuclear Starburst Ring

The composite galaxy NGC 4102 hosts a LINER nucleus and a starburst. We mapped NGC 4102 in the 12.8 micron line of [NeII], using the echelon spectrometer TEXES on the NASA IRTF, to obtain a data cube with 1.5" spatial and 25 km/s spectral, resolution. Combining near-infrared, radio, and the [NeII] data shows that the extinction to the starburst is substantial, more than 2 magnitudes at K band, and that the neon abundance is less than half solar. We find that the star formation in the nuclear region is confined to a rotating ring or disk of 4.3" (~300 pc) diameter, inside the Inner Lindblad Resonance. This region is an intense concentration of mass, with a dynamical mass of ~3 x 10^9 solar masses, and of star formation. The young stars in the ring produce the [NeII] flux reported by Spitzer for the entire galaxy. The mysterious blue component of line emission detected in the near-infrared is also seen in [NeII]; it is not a normal AGN outflow.Comment: submitted to Ap

GASP II. A MUSE view of extreme ram-pressure stripping along the line of sight: kinematics of the jellyfish galaxy JO201

This paper presents a spatially-resolved kinematic study of the jellyfish galaxy JO201, one of the most spectacular cases of ram-pressure stripping (RPS) in the GASP (GAs Stripping Phenomena in Galaxies with MUSE) survey. By studying the environment of JO201, we find that it is moving through the dense intra-cluster medium of Abell 85 at supersonic speeds along our line of sight, and that it is likely accompanied by a small group of galaxies. Given the density of the intra-cluster medium and the galaxy's mass, projected position and velocity within the cluster, we estimate that JO201 must so far have lost ~50% of its gas during infall via RPS. The MUSE data indeed reveal a smooth stellar disk, accompanied by large projected tails of ionised (Halpha) gas, composed of kinematically cold (velocity dispersion <40km/s) star-forming knots and very warm (>100km/s) diffuse emission which extend out to at least ~50 kpc from the galaxy centre. The ionised Halpha-emitting gas in the disk rotates with the stars out to ~6 kpc but in the disk outskirts becomes increasingly redshifted with respect to the (undisturbed) stellar disk. The observed disturbances are consistent with the presence of gas trailing behind the stellar component, resulting from intense face-on RPS happening along the line of sight. Our kinematic analysis is consistent with the estimated fraction of lost gas, and reveals that stripping of the disk happens outside-in, causing shock heating and gas compression in the stripped tails.Comment: ApJ, revised version after referee comments, 15 pages, 16 figures. The interactive version of Figure 9 can be viewed at web.oapd.inaf.it/gasp/publications.htm

Internal lee wave closures : parameter sensitivity and comparison to observations

Author Posting. © American Geophysical Union, 2015. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research: Oceans 120 (2015): 7997–8019, doi:10.1002/2015JC010892.This paper examines two internal lee wave closures that have been used together with ocean models to predict the time-averaged global energy conversion rate into lee waves and dissipation rate associated with lee waves and topographic blocking: the Garner (2005) scheme and the Bell (1975) theory. The closure predictions in two Southern Ocean regions where geostrophic flows dominate over tides are examined and compared to microstructure profiler observations of the turbulent kinetic energy dissipation rate, where the latter are assumed to reflect the dissipation associated with topographic blocking and generated lee wave energy. It is shown that when applied to these Southern Ocean regions, the two closures differ most in their treatment of topographic blocking. For several reasons, pointwise validation of the closures is not possible using existing observations, but horizontally averaged comparisons between closure predictions and observations are made. When anisotropy of the underlying topography is accounted for, the two horizontally averaged closure predictions near the seafloor are approximately equal. The dissipation associated with topographic blocking is predicted by the Garner (2005) scheme to account for the majority of the depth-integrated dissipation over the bottom 1000 m of the water column, where the horizontally averaged predictions lie well within the spatial variability of the horizontally averaged observations. Simplifications made by the Garner (2005) scheme that are inappropriate for the oceanic context, together with imperfect observational information, can partially account for the prediction-observation disagreement, particularly in the upper water column.National Science Foundation Grant Number: OCE-0960820; Office of Naval Research (ONR) Grant Number: N00014-11-1-0487; Australian Research Council Grant Number: (DE120102927 and CE110001028); National Science and Engineering Research Council of Canada Grant Number: (22R23085)2016-06-1

Investigating spillover of multidrug-resistant tuberculosis from a prison: a spatial and molecular epidemiological analysis.

BACKGROUND: Congregate settings may serve as institutional amplifiers of tuberculosis (TB) and multidrug-resistant tuberculosis (MDR-TB). We analyze spatial, epidemiological, and pathogen genetic data prospectively collected from neighborhoods surrounding a prison in Lima, Peru, where inmates experience a high risk of MDR-TB, to investigate the risk of spillover into the surrounding community. METHODS: Using hierarchical Bayesian statistical modeling, we address three questions regarding the MDR-TB risk: (i) Does the excess risk observed among prisoners also extend outside the prison? (ii) If so, what is the magnitude, shape, and spatial range of this spillover effect? (iii) Is there evidence of additional transmission across the region? RESULTS: The region of spillover risk extends for 5.47 km outside of the prison (95% credible interval: 1.38, 9.63 km). Within this spillover region, we find that nine of the 467 non-inmate patients (35 with MDR-TB) have MDR-TB strains that are genetic matches to strains collected from current inmates with MDR-TB, compared to seven out of 1080 patients (89 with MDR-TB) outside the spillover region (p values: 0.022 and 0.008). We also identify eight spatially aggregated genetic clusters of MDR-TB, four within the spillover region, consistent with local transmission among individuals living close to the prison. CONCLUSIONS: We demonstrate a clear prison spillover effect in this population, which suggests that interventions in the prison may have benefits that extend to the surrounding community

Modification of turbulent dissipation rates by a deep Southern Ocean eddy

The impact of a mesoscale eddy on the magnitude and spatial distribution of diapycnal ocean mixing is investigated using a set of hydrographic and microstructure measurements collected in the Southern Ocean. These data sampled a baroclinic, mid-depth eddy formed during the disintegration of a deep boundary current. Turbulent dissipation is suppressed within the eddy, but is elevated by up to an order of magnitude along the upper and lower eddy boundaries. A ray-tracing approximation is employed asa heuristic device to elucidate how the internal wave field evolves in the ambient velocity and stratification conditions accompanying the eddy. These calculations are consistent with the observations, suggesting reflection of internal wave energy from the eddy center and enhanced breaking through critical layer processes along the eddy boundaries. These results have important implications for understanding where and how internal wave energy is dissipated in the presence of energetic deep geostrophic flows