Müller glia activation in response to inherited retinal degeneration is highly varied and disease-specific

Despite different aetiologies, most inherited retinal disorders culminate in photoreceptor loss, which induces concomitant changes in the neural retina, one of the most striking being reactive gliosis by Müller cells. It is typically assumed that photoreceptor loss leads to an upregulation of glial fibrilliary acidic protein (Gfap) and other intermediate filament proteins, together with other gliosis-related changes, including loss of integrity of the outer limiting membrane (OLM) and deposition of proteoglycans. However, this is based on a mix of both injury-induced and genetic causes of photoreceptor loss. There are very few longitudinal studies of gliosis in the retina and none comparing these changes across models over time. Here, we present a comprehensive spatiotemporal assessment of features of gliosis in the degenerating murine retina that involves Müller glia. Specifically, we assessed Gfap, vimentin and chondroitin sulphate proteoglycan (CSPG) levels and outer limiting membrane (OLM) integrity over time in four murine models of inherited photoreceptor degeneration that encompass a range of disease severities (Crb1rd8/rd8, Prph2+/Δ307, Rho-/-, Pde6brd1/rd1). These features underwent very different changes, depending upon the disease-causing mutation, and that these changes are not correlated with disease severity. Intermediate filament expression did indeed increase with disease progression in Crb1rd8/rd8 and Prph2+/Δ307, but decreased in the Prph2+/Δ307 and Pde6brd1/rd1 models. CSPG deposition usually, but not always, followed the trends in intermediate filament expression. The OLM adherens junctions underwent significant remodelling in all models, but with differences in the composition of the resulting junctions; in Rho-/- mice, the adherens junctions maintained the typical rod-Müller glia interactions, while in the Pde6brd1/rd1 model they formed predominantly between Müller cells in late stage of degeneration. Together, these results show that gliosis and its associated processes are variable and disease-dependent

Physical Activity, Sedentary Time, and Fatness in a Biethnic Sample of Young Children.

PURPOSE: To investigate associations of objectively-measured physical activity (PA) and sedentary time (ST) with adiposity in a predominantly bi-ethnic (South Asian and White British) sample of young children. METHODS: The sample included 333 children aged 11 months to 5 years who provided 526 cross-sectional observations for PA and body composition. Total PA volume (vector magnitude counts per minute (cpm)), daily time at multiple intensity levels (the cumulative time in activity >500 cpm, >1000 cpm, >1500 cpm and so on up to >6000 cpm), and time spent sedentary (6000 cpm: -1.57 (-3.01 to -0.12) mm per 20 min/d). Substitution of 20 min/d of ST with MVPA was associated with a lower sum of skinfolds (-0.77 (-1.46 to -0.084) mm). CONCLUSIONS: High light-intensity PA appears to be beneficial for body composition in young South Asian and White British children, but higher-intensity PA is more advantageous.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal

Statistical relational learning with soft quantifiers

Quantification in statistical relational learning (SRL) is either existential or universal, however humans might be more inclined to express knowledge using soft quantifiers, such as ``most'' and ``a few''. In this paper, we define the syntax and semantics of PSL^Q, a new SRL framework that supports reasoning with soft quantifiers, and present its most probable explanation (MPE) inference algorithm. To the best of our knowledge, PSL^Q is the first SRL framework that combines soft quantifiers with first-order logic rules for modelling uncertain relational data. Our experimental results for link prediction in social trust networks demonstrate that the use of soft quantifiers not only allows for a natural and intuitive formulation of domain knowledge, but also improves the accuracy of inferred results

Transplantation of Photoreceptor Precursors Isolated via a Cell Surface Biomarker Panel From Embryonic Stem Cell-Derived Self-Forming Retina.

Loss of photoreceptors due to retinal degeneration is a major cause of untreatable blindness. Cell replacement therapy, using pluripotent stem cell-derived photoreceptor cells, may be a feasible future treatment. Achieving safe and effective cell replacement is critically dependent on the stringent selection and purification of optimal cells for transplantation. Previously, we demonstrated effective transplantation of post-mitotic photoreceptor precursor cells labelled by fluorescent reporter genes. As genetically labelled cells are not desirable for therapy, here we developed a surface biomarker cell selection strategy for application to complex pluripotent stem cell differentiation cultures. We show that a five cell surface biomarker panel CD73(+)CD24(+)CD133(+)CD47(+)CD15(-) facilitates the isolation of photoreceptor precursors from three-dimensional self-forming retina differentiated from mouse embryonic stem cells. Importantly, stem cell-derived cells isolated using the biomarker panel successfully integrate and mature into new rod photoreceptors in the adult mouse retinae after subretinal transplantation. Conversely, unsorted or negatively selected cells do not give rise to newly integrated rods after transplantation. The biomarker panel also removes detrimental proliferating cells prior to transplantation. Notably, we demonstrate how expression of the biomarker panel is conserved in the human retina and propose that a similar selection strategy will facilitate isolation of human transplantation-competent cells for therapeutic application. Stem Cells 2015;33:2469-2482

Evidence for a fractional quantum Hall state with anisotropic longitudinal transport

At high magnetic fields, where the Fermi level lies in the N=0 lowest Landau level (LL), a clean two-dimensional electron system (2DES) exhibits numerous incompressible liquid phases which display the fractional quantized Hall effect (FQHE) (Das Sarma and Pinczuk, 1997). These liquid phases do not break rotational symmetry, exhibiting resistivities which are isotropic in the plane. In contrast, at lower fields, when the Fermi level lies in the $N\ge2$ third and several higher LLs, the 2DES displays a distinctly different class of collective states. In particular, near half filling of these high LLs the 2DES exhibits a strongly anisotropic longitudinal resistance at low temperatures (Lilly et al., 1999; Du et al., 1999). These "stripe" phases, which do not exhibit the quantized Hall effect, resemble nematic liquid crystals, possessing broken rotational symmetry and orientational order (Koulakov et al., 1996; Fogler et al., 1996; Moessner and Chalker, 1996; Fradkin and Kivelson, 1999; Fradkin et al, 2010). Here we report a surprising new observation: An electronic configuration in the N=1 second LL whose resistivity tensor simultaneously displays a robust fractionally quantized Hall plateau and a strongly anisotropic longitudinal resistance resembling that of the stripe phases.Comment: Nature Physics, (2011

Differential geometry with a projection: Application to double field theory

In recent development of double field theory, as for the description of the massless sector of closed strings, the spacetime dimension is formally doubled, i.e. from D to D+D, and the T-duality is realized manifestly as a global O(D,D) rotation. In this paper, we conceive a differential geometry characterized by a O(D,D) symmetric projection, as the underlying mathematical structure of double field theory. We introduce a differential operator compatible with the projection, which, contracted with the projection, can be covariantized and may replace the ordinary derivatives in the generalized Lie derivative that generates the gauge symmetry of double field theory. We construct various gauge covariant tensors which include a scalar and a tensor carrying two O(D,D) vector indices.Comment: 1+22 pages, No figure; a previous result on 4-index tensor removed, presentation improve

Integrated Borehole, Radar, and Seismic Velocity Analysis Reveals Dynamic Spatial Variations Within a Firn Aquifer in Southeast Greenland

Perennial water storage in firn aquifers has been observed within the lower percolation zone of the southeast Greenland ice sheet. Spatially distributed seismic and radar observations, made ~50 km upstream of the Helheim Glacier terminus, reveal spatial variations of seismic velocity within a firn aquifer. From 1.65 to 1.8 km elevation, shear‐wave velocity (Vs) is 1,290 ± 180 m/s in the unsaturated firn, decreasing below the water table (~15 m depth) to 1,130 ± 250 m/s. Below 1.65 km elevation, Vs in the saturated firn is 1,270 ± 220 m/s. The compressional‐to‐shear velocity ratio decreases in the downstream saturated zone, from 2.30 ± 0.54 to 2.01 ± 0.46, closer to its value for pure ice (2.00). Consistent with colocated firn cores, these results imply an increasing concentration of ice in the downstream sites, reducing the porosity and storage potential of the firn likely caused by episodic melt and freeze during the evolution of the aquifer. Plain Language Summary An integrated geophysical analysis of seismic, radar, and borehole measurements has been completed over a firn aquifer in southeast Greenland. We show the stiffness of the aquifer increases at lower elevations, closer to sea level, which leads to a decrease in pore space for the meltwater to be stored. This corresponds to an increase in ice content within the firn at lower elevations, as observed in borehole measurements, and likely caused by the meltwater refreezing within and below the aquifer

Fission yeast Pcp1 links polo kinase-mediated mitotic entry to γ-tubulin-dependent spindle formation

The centrosomal pericentrin-related proteins play pivotal roles in various aspects of cell division; however their underlying mechanisms remain largely elusive. Here we show that fission-yeast pericentrin-like Pcp1 regulates multiple functions of the spindle pole body (SPB) through recruiting two critical factors, the γ-tubulin complex (γ-TuC) and polo kinase (Plo1). We isolated two pcp1 mutants (pcp1-15 and pcp1-18) that display similar abnormal spindles, but with remarkably different molecular defects. Both mutants exhibit defective monopolar spindle microtubules that emanate from the mother SPB. However, while pcp1-15 fails to localise the γ-TuC to the mitotic SPB, pcp1-18 is specifically defective in recruiting Plo1. Consistently Pcp1 forms a complex with both γ-TuC and Plo1 in the cell. pcp1-18 is further defective in the mitotic-specific reorganisation of the nuclear envelope (NE), leading to impairment of SPB insertion into the NE. Moreover pcp1-18, but not pcp1-15, is rescued by overproducing nuclear pore components or advancing mitotic onset. The central role for Pcp1 in orchestrating these processes provides mechanistic insight into how the centrosome regulates multiple cellular pathways

Parental transfer of the antimicrobial protein LBP/BPI protects Biomphalaria glabrata eggs against oomycete infections

Copyright: © 2013 Baron et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was funded by ANR (ANR-07-BLAN-0214 and ANR-12-EMMA-00O7-01), CNRS and INRA. PvW was financially supported by the BBSRC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

How large should whales be?

The evolution and distribution of species body sizes for terrestrial mammals is well-explained by a macroevolutionary tradeoff between short-term selective advantages and long-term extinction risks from increased species body size, unfolding above the 2g minimum size induced by thermoregulation in air. Here, we consider whether this same tradeoff, formalized as a constrained convection-reaction-diffusion system, can also explain the sizes of fully aquatic mammals, which have not previously been considered. By replacing the terrestrial minimum with a pelagic one, at roughly 7000g, the terrestrial mammal tradeoff model accurately predicts, with no tunable parameters, the observed body masses of all extant cetacean species, including the 175,000,000g Blue Whale. This strong agreement between theory and data suggests that a universal macroevolutionary tradeoff governs body size evolution for all mammals, regardless of their habitat. The dramatic sizes of cetaceans can thus be attributed mainly to the increased convective heat loss is water, which shifts the species size distribution upward and pushes its right tail into ranges inaccessible to terrestrial mammals. Under this macroevolutionary tradeoff, the largest expected species occurs where the rate at which smaller-bodied species move up into large-bodied niches approximately equals the rate at which extinction removes them.Comment: 7 pages, 3 figures, 2 data table