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Abnormal microglia and enhanced inflammation-related gene transcription in mice with conditional deletion of Ctcf in Camk2a-Cre-expressing neurons

CCCTC-binding factor (CTCF) is an 11 zinc finger DNA-binding domain protein that regulates gene expression by modifying 3D chromatin structure. Human mutations inCTCFcause intellectual disability and autistic features. Knocking outCtcfin mouse embryonic neurons is lethal by neonatal age, but the effects of CTCF deficiency in postnatal neurons are less well studied. We knocked outCtcfpostnatally in glutamatergic forebrain neurons under the control ofCamk2a-Cre. CtcfloxP/loxP;Camk2a-Cre+(CtcfCKO) mice of both sexes were viable and exhibited profound deficits in spatial learning/memory, impaired motor coordination, and decreased sociability by 4 months of age.CtcfCKO mice also had reduced dendritic spine density in the hippocampus and cerebral cortex. Microarray analysis of mRNA fromCtcfCKO mouse hippocampus identified increased transcription of inflammation-related genes linked to microglia. Separate microarray analysis of mRNA isolated specifically fromCtcfCKO mouse hippocampal neurons by ribosomal affinity purification identified upregulation of chemokine signaling genes, suggesting crosstalk between neurons and microglia inCtcfCKO hippocampus. Finally, we found that microglia inCtcfCKO mouse hippocampus had abnormal morphology by Sholl analysis and increased immunostaining for CD68, a marker of microglial activation. Our findings confirm thatCtcfKO in postnatal neurons causes a neurobehavioral phenotype in mice and provide novel evidence that CTCF depletion leads to overexpression of inflammation-related genes and microglial dysfunction.SIGNIFICANCE STATEMENTCCCTC-binding factor (CTCF) is a DNA-binding protein that organizes nuclear chromatin topology. Mutations inCTCFcause intellectual disability and autistic features in humans. CTCF deficiency in embryonic neurons is lethal in mice, but mice with postnatal CTCF depletion are less well studied. We find that mice lackingCtcfinCamk2a-expressing neurons (CtcfCKO mice) have spatial learning/memory deficits, impaired fine motor skills, subtly altered social interactions, and decreased dendritic spine density. We demonstrate thatCtcfCKO mice overexpress inflammation-related genes in the brain and have microglia with abnormal morphology that label positive for CD68, a marker of microglial activation. Our findings suggest that inflammation and dysfunctional neuron–microglia interactions are factors in the pathology of CTCF deficiency.</jats:p

Radial Redshift Space Distortions

The radial component of the peculiar velocities of galaxies cause displacements in their positions in redshift space. We study the effect of the peculiar velocities on the linear redshift space two point correlation function. Our analysis takes into account the radial nature of the redshift space distortions and it highlights the limitations of the plane parallel approximation. We consider the problem of determining the value of \beta and the real space two point correlation function from the linear redshift space two point correlation function. The inversion method proposed here takes into account the radial nature of the redshift space distortions and can be applied to magnitude limited redshift surveys that have only partial sky coverage.Comment: 26 pages including 11 figures, to appear in Ap

Current transport mechanisms in GaAs/AlAs tunnel structures grown by metal–organic chemical vapor deposition

Elastic and inelastic tunneling processes are investigated in GaAs–AlAs–GaAs double heterojunctions grown in the [100] direction by metal–organic chemical vapor deposition (MOCVD). The AlAs quantum barriers in the heterostructures studied are doped p-type with Mg. Theoretical calculations of tunneling currents are performed and compared with experimental I–V data. It is found that for structures with thin AlAs barriers, the dominant current transport mechanism at low temperatures is tunneling through the AlAs band gap at both the Gamma and X points. This is consistent with inelastic processes observable in first (dI/dV) and second (d2I/dV2) derivative spectra obtained with modulation techniques. A simple model, developed for calculating impurity-assisted tunneling currents, shows that the role of barrier impurities becomes more important as the barrier is grown thicker. Implications of some of these results for resonant tunneling heterostructures consisting of two AlAs quantum barriers separated by a GaAs quantum well are discussed. Experimental second derivative spectra showing reproducible features are also presented for these double barrier structures

The Thermal Structure of the Circumstellar Disk Surrounding the Classical Be Star gamma Cassiopeia

We have computed radiative equilibrium models for the gas in the circumstellar envelope surrounding the hot, classical Be star $\gamma$Cassiopeia. This calculation is performed using a code that incorporates a number of improvements over previous treatments of the disk's thermal structure by \citet{mil98} and \citet{jon04}; most importantly, heating and cooling rates are computed with atomic models for H, He, CNO, Mg, Si, Ca, & Fe and their relevant ions. Thus, for the first time, the thermal structure of a Be disk is computed for a gas with a solar chemical composition as opposed to assuming a pure hydrogen envelope. We compare the predicted average disk temperature, the total energy loss in H$\alpha$, and the near-IR excess with observations and find that all can be accounted for by a disk that is in vertical hydrostatic equilibrium with a density in the equatorial plane of $\rho(R)\approx 3$ to $5\cdot 10^{-11} (R/R_*)^{-2.5} \rm g cm^{-3}$. We also discuss the changes in the disk's thermal structure that result from the additional heating and cooling processes available to a gas with a solar chemical composition over those available to a pure hydrogen plasma.Comment: 11 pages, 8 figures high resolution figures available at http://inverse.astro.uwo.ca/sig_jon07.htm

The Correlation Function in Redshift Space: General Formula with Wide-angle Effects and Cosmological Distortions

A general formula for the correlation function in redshift space is derived in linear theory. The formula simultaneously includes wide-angle effects and cosmological distortions. The formula is applicable to any pair with arbitrary angle $\theta$ between lines of sight, and arbitrary redshifts, $z_1$, $z_2$, which are not necessarily small. The effects of the spatial curvature both on geometry and on fluctuation spectrum are properly taken into account, and thus our formula holds in a Friedman-Lema\^{\i}tre universe with arbitrary cosmological parameters $\Omega_0$ and $\lambda_0$. We illustrate the pattern of the resulting correlation function with several models, and also show that validity region of the conventional distant observer approximation is $\theta \le 10^\circ$.Comment: 45 pages including 9 figures, To Appear in Astrophys. J. 535 (2000

Stable isotopes demonstrate intraspecific variation in habitat use and trophic level of non‐breeding albatrosses

The non‐breeding period is critical for restoration of body condition and self‐maintenance in albatrosses, yet detailed information on diet and distribution during this stage of the annual cycle is lacking for many species. Here, we use stable isotope values of body feathers (δ13C, δ15N) to infer habitat use and trophic level of non‐breeding adult Grey‐headed Albatrosses Thalassarche chrysostoma (n = 194) from South Georgia. Specifically, we: (1) investigate intrinsic drivers (sex, age, previous breeding outcome) of variation in habitat use and trophic level; (2) quantify variation among feathers of the same birds; and (3) examine potential carry‐over effects of habitat use and trophic level during the non‐breeding period on subsequent breeding outcome. In agreement with previous tracking studies, δ13C values of individual feathers indicate that non‐breeding Grey‐headed Albatrosses from South Georgia foraged across a range of oceanic habitats, but mostly in subantarctic waters, between the Antarctic Polar Front and Subtropical Front. Sex differences were subtle but statistically significant, and overlap in the core isotopic niche areas was high (62%); however, males exhibited slightly lower δ13C and higher δ15N values than females, indicating that males forage at higher latitudes and at a higher trophic level. Neither age nor previous breeding outcome influenced stable isotope values, and we found no evidence of carry‐over effects of non‐breeding habitat use or trophic level on subsequent breeding outcome. Repeatability among feathers of the same individual was moderate in δ13C and low in δ15N. This cross‐sectional study demonstrates high variability in the foraging and migration strategies of this albatross population

Evolution of Structure in the Intergalactic Medium and the Nature of the Ly-alpha Forest

We have performed a detailed statistical study of the evolution of structure in a photoionized intergalactic medium (IGM) using analytical simulations to extend the calculation into the mildly non-linear density regime found to prevail at z = 3. Our work is based on a simple fundamental conjecture: that the probability distribution function of the density of baryonic diffuse matter in the universe is described by a lognormal (LN) random field. The LN field has several attractive features and follows plausibly from the assumption of initial linear Gaussian density and velocity fluctuations at arbitrarily early times. Starting with a suitably normalized power spectrum of primordial fluc- tuations in a universe dominated by cold dark matter (CDM), we compute the behavior of the baryonic matter, which moves slowly toward minima in the dark matter potential on scales larger than the Jeans length. We have computed two models that succeed in matching observations. One is a non-standard CDM model with Omega=1, h=0.5 and \Gamma=0.3, and the other is a low density flat model with a cosmological constant(LCDM), with Omega=0.4, Omega_Lambda=0.6 and h=.65. In both models, the variance of the density distribution function grows with time, reaching unity at about z=4, where the simulation yields spectra that closely resemble the Ly-alpha forest absorption seen in the spectra of high z quasars. The calculations also successfully predict the observed properties of the Ly-alpha forest clouds and their evolution from z=4 down to at least z=2, assuming a constant intensity for the metagalactic UV background over this redshift range. However, in our model the forest is not due to discrete clouds, but rather to fluctuations in a continuous intergalactic medium. (This is an abreviated abstract; the complete abstract is included with the manuscript.)Comment: Wrong Fig. 10 is corrected. Our custom made postscript is available at ftp://hut4.pha.jhu.edu/incoming/igm, or contact Arthur Davidsen ([email protected]) for nice hardcopies; accepted for publication in Ap

Systematic review of dietary salt reduction policies: Evidence for an effectiveness hierarchy?

Background: Non-communicable disease (NCD) prevention strategies now prioritise four major risk factors: food, tobacco, alcohol and physical activity. Dietary salt intake remains much higher than recommended, increasing blood pressure, cardiovascular disease and stomach cancer. Substantial reductions in salt intake are therefore urgently needed. However, the debate continues about the most effective approaches. To inform future prevention programmes, we systematically reviewed the evidence on the effectiveness of possible salt reduction interventions. We further compared “downstream, agentic” approaches targeting individuals with “upstream, structural” policy-based population strategies. Methods: We searched six electronic databases (CDSR, CRD, MEDLINE, SCI, SCOPUS and the Campbell Library) using a pre-piloted search strategy focussing on the effectiveness of population interventions to reduce salt intake. Retrieved papers were independently screened, appraised and graded for quality by two researchers. To facilitate comparisons between the interventions, the extracted data were categorised using nine stages along the agentic/structural continuum, from “downstream”: dietary counselling (for individuals, worksites or communities), through media campaigns, nutrition labelling, voluntary and mandatory reformulation, to the most “upstream” regulatory and fiscal interventions, and comprehensive strategies involving multiple components. Results: After screening 2,526 candidate papers, 70 were included in this systematic review (49 empirical studies and 21 modelling studies). Some papers described several interventions. Quality was variable. Multi-component strategies involving both upstream and downstream interventions, generally achieved the biggest reductions in salt consumption across an entire population, most notably 4g/day in Finland and Japan, 3g/day in Turkey and 1.3g/day recently in the UK. Mandatory reformulation alone could achieve a reduction of approximately 1.45g/day (three separate studies), followed by voluntary reformulation (-0.8g/day), school interventions (-0.7g/day), short term dietary advice (-0.6g/day) and nutrition labelling (-0.4g/day), but each with a wide range. Tax and community based counselling could, each typically reduce salt intake by 0.3g/day, whilst even smaller population benefits were derived from health education media campaigns (-0.1g/day). Worksite interventions achieved an increase in intake (+0.5g/day), however, with a very wide range. Long term dietary advice could achieve a -2g/day reduction under optimal research trial conditions; however, smaller reductions might be anticipated in unselected individuals. Conclusions: Comprehensive strategies involving multiple components (reformulation, food labelling and media campaigns) and “upstream” population-wide policies such as mandatory reformulation generally appear to achieve larger reductions in population-wide salt consumption than “downstream”, individually focussed interventions. This ‘effectiveness hierarchy’ might deserve greater emphasis in future NCD prevention strategies