Function of mammalian M-cones depends on the level of CRALBP in Müller cells

Cone photoreceptors mediate daytime vision in vertebrates. The rapid and efficient regeneration of their visual pigments following photoactivation is critical for the cones to remain photoresponsive in bright and rapidly changing light conditions. Cone pigment regeneration depends on the recycling of visual chromophore, which takes place via the canonical visual cycle in the retinal pigment epithelium (RPE) and the Müller cell-driven intraretinal visual cycle. The molecular mechanisms that enable the neural retina to regenerate visual chromophore for cones have not been fully elucidated. However, one known component of the two visual cycles is the cellular retinaldehyde-binding protein (CRALBP), which is expressed both in the RPE and in Müller cells. To understand the significance of CRALBP in cone pigment regeneration, we examined the function of cones in mice heterozygous for Rlbp1, the gene encoding CRALBP. We found that CRALBP expression was reduced by ∼50% in both the RPE and retina of Rlbp1+/- mice. Electroretinography (ERG) showed that the dark adaptation of rods and cones is unaltered in Rlbp1+/- mice, indicating a normal RPE visual cycle. However, pharmacologic blockade of the RPE visual cycle revealed suppressed cone dark adaptation in Rlbp1+/- mice in comparison with controls. We conclude that the expression level of CRALPB specifically in the Müller cells modulates the efficiency of the retina visual cycle. Finally, blocking the RPE visual cycle also suppressed further cone dark adaptation in Rlbp1-/- mice, revealing a shunt in the classical RPE visual cycle that bypasses CRALBP and allows partial but unexpectedly rapid cone dark adaptation

Structure, properties and phase composition of composite materials based on the system NiTi-TiB2

This article considers issues pertinent to the research of the phase composition, structure and mechanical properties of materials obtained from powders of composite (Ni-Ti)-TiB2, which have prospective applications in aerospace and automotive industry and engine construction. The starting powder materials (Ni-Ti)-TiB2 were obtained by self-propagating high-temperature synthesis (SHS). Research samples were produced using high-temperature vacuum sintering. It was shown that the use of such materials increases the wettability of the particles and allows the production of composites, the density of which is 95% of the theoretical one. Average particle size was 1.54 µm, average microhardness was 8 GPa, which is an order of magnitude higher than the average microhardness of pure nickel-based and titanium-based alloys, and the ultimate strength values were comparable to those of tungsten-based heavy alloys

Anatomy of the Ediacaran rangeomorph Charnia masoni.

The Ediacaran macrofossil Charnia masoni Ford is perhaps the most iconic member of the Rangeomorpha: a group of seemingly sessile, frondose organisms that dominates late Ediacaran benthic, deep-marine fossil assemblages. Despite C. masoni exhibiting broad palaeogeographical and stratigraphical ranges, there have been few morphological studies that consider the variation observed among populations of specimens derived from multiple global localities. We present an analysis of C. masoni that evaluates specimens from the UK, Canada and Russia, representing the largest morphological study of this taxon to date. We describe substantial morphological variation within C. masoni and present a new morphological model for this species that has significant implications both for interpretation of rangeomorph architecture, and potentially for existing taxonomic schemes. Previous reconstructions of Charnia include assumptions regarding the presence of structures seen in other rangeomorphs (e.g. an internal stalk) and of homogeneity in higher order branch morphology; observations that are not borne out by our investigations. We describe variation in the morphology of third and fourth order branches, as well as variation in gross structure near the base of the frond. The diagnosis of Charnia masoni is emended to take account of these new features. These findings highlight the need for large-scale analyses of rangeomorph morphology in order to better understand the biology of this long-enigmatic group.NER

Crime and Psychiatric Disorders Among Youth in the US population: An Analysis of the National Comorbidity Survey-Adolescent Supplement

Objective Current knowledge regarding psychiatric disorders and crime in youth is limited to juvenile justice and community samples. This study examined relationships between psychiatric disorders and self-reported crime involvement in a sample of youth representative of the US population. Method The National Comorbidity Survey–Adolescent Supplement (N = 10,123; ages 13–17 years; 2001–2004) was used to examine the relationship between lifetime DSM-IV–based diagnoses, reported crime (property, violent, other), and arrest history. Logistic regression compared the odds of reported crime involvement with specific psychiatric disorders to those without any diagnoses, and examined the odds of crime by psychiatric comorbidity. Results Prevalence of crime was 18.4%. Youth with lifetime psychiatric disorders, compared to no disorders, had significantly greater odds of crime, including violent crime. For violent crime resulting in arrest, conduct disorder (CD) (odds ratio OR = 57.5; 95% CI = 30.4, 108.8), alcohol use disorders (OR = 19.5; 95% CI = 8.8, 43.2), and drug use disorders (OR = 16.1; 95% CI = 9.3, 27.7) had the greatest odds with similar findings for violent crime with no arrest. Psychiatric comorbidity increased the odds of crime. Youth with 3 or more diagnoses (16.0% of population) accounted for 54.1% of those reporting arrest for violent crime. Youth with at least 1 diagnosis committed 85.8% of crime, which was reduced to 67.9% by removing individuals with CD. Importantly, 88.2% of youth with mental illness reported never having committed any crime. Conclusion Our findings highlight the importance of improving access to mental health services for youthful offenders in community settings, given the substantial associations found between mental illness and crime in this nationally representative epidemiological sample

The developmental biology of <i>Charnia</i> and the eumetazoan affinity of the Ediacaran rangeomorphs.

Molecular timescales estimate that early animal lineages diverged tens of millions of years before their earliest unequivocal fossil evidence. The Ediacaran macrobiota (~574 to 538 million years ago) are largely eschewed from this debate, primarily due to their extreme phylogenetic uncertainty, but remain germane. We characterize the development of Charnia masoni and establish the affinity of rangeomorphs, among the oldest and most enigmatic components of the Ediacaran macrobiota. We provide the first direct evidence for the internal interconnected nature of rangeomorphs and show that Charnia was constructed of repeated branches that derived successively from pre-existing branches. We find homology and rationalize morphogenesis between disparate rangeomorph taxa, before producing a phylogenetic analysis, resolving Charnia as a stem-eumetazoan and expanding the anatomical disparity of that group to include a long-extinct bodyplan. These data bring competing records of early animal evolution into closer agreement, reformulating our understanding of the evolutionary emergence of animal bodyplans

Self-gravitating fragmentation of eccentric accretion disks

We consider the effects of eccentricity on the fragmentation of gravitationally unstable accretion disks, using numerical hydrodynamics. We find that eccentricity does not affect the overall stability of the disk against fragmentation, but significantly alters the manner in which such fragments accrete gas. Variable tidal forces around an eccentric orbit slow the accretion process, and suppress the formation of weakly-bound clumps. The "stellar" mass function resulting from the fragmentation of an eccentric disk is found to have a significantly higher characteristic mass than that from a corresponding circular disk. We discuss our results in terms of the disk(s) of massive stars at ~0.1pc from the Galactic Center, and find that the fragmentation of an eccentric accretion disk, due to gravitational instability, is a viable mechanism for the formation of these systems.Comment: 9 pages, 7 figures. Accepted for publication in Ap

Structure of the cytosine-cytosine mismatch in the thymidylate synthase mRNA binding site and analysis of its interaction with the aminoglycoside paromomycin

ABSTRACT The structure of a cytosine-cytosine (CC) mismatch-containing RNA molecule derived from a hairpin structure in the thymidylate synthase mRNA that binds the aminoglycoside paromomycin with high affinity was determined using nuclear magnetic resonance (NMR) spectroscopy. The cytosines in the mismatch form a noncanonical base pair where both cytosines are uncharged and stack within the stem of the RNA structure. Binding to paromomycin was analyzed using isothermal titration calorimetry (ITC) to demonstrate the necessity of the CC mismatch and to determine the affinity dissociation constant of this RNA to paromomycin to be 0.5 6 0.3 mM. The CC mismatch, and the neighboring GC base pairs experienced the highest degree of chemical shift changes in their H6 and H5 resonances indicating that paromomycin binds in the major groove at the CC mismatch site. In comparing the structure of CC mismatch RNA with a fully Watson-Crick GC base paired stem, the CC mismatch is shown to confer a widening of the major groove. This widening, combined with the dynamic nature of the CC mismatch, enables binding of paromomycin to this RNA molecule

Retinoid isomerase inhibitors impair but do not block mammalian cone photoreceptor function

Visual function in vertebrates critically depends on the continuous regeneration of visual pigments in rod and cone photoreceptors. RPE65 is a well-established retinoid isomerase in the pigment epithelium that regenerates rhodopsin during the rod visual cycle; however, its contribution to the regeneration of cone pigments remains obscure. In this study, we use potent and selective RPE65 inhibitors in rod- and cone-dominant animal models to discern the role of this enzyme in cone-mediated vision. We confirm that retinylamine and emixustat-family compounds selectively inhibit RPE65 over DES1, the putative retinoid isomerase of the intraretinal visual cycle. In vivo and ex vivo electroretinography experiments in Gnat1-/- mice demonstrate that acute administration of RPE65 inhibitors after a bleach suppresses the late, slow phase of cone dark adaptation without affecting the initial rapid portion, which reflects intraretinal visual cycle function. Acute administration of these compounds does not affect the light sensitivity of cone photoreceptors in mice during extended exposure to background light, but does slow all phases of subsequent dark recovery. We also show that cone function is only partially suppressed in cone-dominant ground squirrels and wild-type mice by multiday administration of an RPE65 inhibitor despite profound blockade of RPE65 activity. Complementary experiments in these animal models using the DES1 inhibitor fenretinide show more modest effects on cone recovery. Collectively, these studies demonstrate a role for continuous RPE65 activity in mammalian cone pigment regeneration and provide further evidence for RPE65-independent regeneration mechanisms

Anatomy of the Ediacaran rangeomorph Charnia masoni

The Ediacaran macrofossil Charnia masoni Ford is perhaps the most iconic member of the Rangeomorpha: a group of seemingly sessile, frondose organisms that dominates late Ediacaran benthic, deep‐marine fossil assemblages. Despite C. masoni exhibiting broad palaeogeographical and stratigraphical ranges, there have been few morphological studies that consider the variation observed among populations of specimens derived from multiple global localities. We present an analysis of C. masoni that evaluates specimens from the UK, Canada and Russia, representing the largest morphological study of this taxon to date. We describe substantial morphological variation within C. masoni and present a new morphological model for this species that has significant implications both for interpretation of rangeomorph architecture, and potentially for existing taxonomic schemes. Previous reconstructions of Charnia include assumptions regarding the presence of structures seen in other rangeomorphs (e.g. an internal stalk) and of homogeneity in higher order branch morphology; observations that are not borne out by our investigations. We describe variation in the morphology of third and fourth order branches, as well as variation in gross structure near the base of the frond. The diagnosis of Charnia masoni is emended to take account of these new features. These findings highlight the need for large‐scale analyses of rangeomorph morphology in order to better understand the biology of this long‐enigmatic group