Restoration of Sp4 in Forebrain GABAergic Neurons Rescues Hypersensitivity to Ketamine in Sp4 Hypomorphic Mice.

BackgroundKetamine produces schizophrenia-like behavioral phenotypes in healthy people. Prolonged ketamine effects and exacerbation of symptoms after the administration of ketamine have been observed in patients with schizophrenia. More recently, ketamine has been used as a potent antidepressant to treat patients with major depression. The genes and neurons that regulate behavioral responses to ketamine, however, remain poorly understood. Sp4 is a transcription factor for which gene expression is restricted to neuronal cells in the brain. Our previous studies demonstrated that Sp4 hypomorphic mice display several behavioral phenotypes relevant to psychiatric disorders, consistent with human SP4 gene associations with schizophrenia, bipolar disorder, and major depression. Among those behavioral phenotypes, hypersensitivity to ketamine-induced hyperlocomotion has been observed in Sp4 hypomorphic mice.MethodsIn the present study, we used the Cre-LoxP system to restore Sp4 gene expression, specifically in either forebrain excitatory or GABAergic inhibitory neurons in Sp4 hypomorphic mice. Mouse behavioral phenotypes related to psychiatric disorders were examined in these distinct rescue mice.ResultsRestoration of Sp4 in forebrain excitatory neurons did not rescue deficient sensorimotor gating nor ketamine-induced hyperlocomotion. Restoration of Sp4 in forebrain GABAergic neurons, however, rescued ketamine-induced hyperlocomotion, but did not rescue deficient sensorimotor gating.ConclusionsOur studies suggest that the Sp4 gene in forebrain GABAergic neurons regulates ketamine-induced hyperlocomotion

The Relationship Between Luminosity and Broad-Line Region Size in Active Galactic Nuclei

We reinvestigate the relationship between the characteristic broad-line region size (R_blr) and the Balmer emission-line, X-ray, UV, and optical continuum luminosities. Our study makes use of the best available determinations of R_blr for a large number of active galactic nuclei (AGNs) from Peterson et al. Using their determinations of R_blr for a large sample of AGNs and two different regression methods, we investigate the robustness of our correlation results as a function of data sub-sample and regression technique. Though small systematic differences were found depending on the method of analysis, our results are generally consistent. Assuming a power-law relation R_blr \propto L^\alpha, we find the mean best-fitting \alpha is about 0.67+/-0.05 for the optical continuum and the broad H\beta luminosity, about 0.56+/-0.05 for the UV continuum luminosity, and about 0.70+/-0.14 for the X-ray luminosity. We also find an intrinsic scatter of about 40% in these relations. The disagreement of our results with the theoretical expected slope of 0.5 indicates that the simple assumption of all AGNs having on average same ionization parameter, BLR density, column density, and ionizing spectral energy distribution, is not valid and there is likely some evolution of a few of these characteristics along the luminosity scale.Comment: 11 pages, 2 figures, emulateapj, accepted for publication in The Astrophysical Journa

The Clustering of Extragalactic Extremely Red Objects

We have measured the angular and spatial clustering of 671 K5 Extremely Red Objects (EROs) from a 0.98 square degree sub-region of the NOAO Deep Wide-Field Survey (NDWFS). Our study covers nearly 5 times the area and has twice the sample size of any previous ERO clustering study. The wide field of view and BwRIK passbands of the NDWFS allow us to place improved constraints on the clustering of z=1 EROs. We find the angular clustering of EROs is slightly weaker than in previous measurements, and w(1')=0.25+/-0.05 for K<18.40 EROs. We find no significant correlation of ERO spatial clustering with redshift, apparent color or absolute magnitude, although given the uncertainties, such correlations remain plausible. We find the spatial clustering of K5 EROs is well approximated by a power-law, with r_0=9.7+/-1.1 Mpc/h in comoving coordinates. This is comparable to the clustering of 4L* early-type galaxies at z<1, and is consistent with the brightest EROs being the progenitors of the most massive ellipticals. There is evidence of the angular clustering of EROs decreasing with increasing apparent magnitude, when NDWFS measurements of ERO clustering are combined with those from the literature. Unless the redshift distribution of K>20 EROs is very broad, the spatial clustering of EROs decreases from r_0=9.7+/-1.1 Mpc/h for K20 EROs.Comment: Accepted for publication in the ApJ. 29 pages with 10 figures. The NOAO Deep Wide-Field Survey Bootes data release is available online at http://www.noao.edu/noao/noaodeep

Chandra Observations of the QSO Pair Q2345+007: Binary Quasar or Massive Dark Lens?

The components of the wide (7.3") separation quasar pair Q2345+007A,B (z=2.15) have the most strikingly similar optical spectra seen to date (Steidel & Sargent 1991) yet no detected lensing mass, making this system the best candidate known for a massive (1e14 Msun) dark matter lens system. Here we present results from a 65ksec Chandra observation designed to investigate whether it is a binary quasar or a gravitational lens. We find no X-ray evidence for a lensing cluster to a (0.5-2keV) flux limit of 2e-15 cgs, which is consistent with lensing only for a reduced baryon fraction. Using the Chandra X-ray observations of the quasars themselves, together with new and published optical measurements, we use the observed emission properties of the quasars for further tests between the lens and binary hypotheses. Assuming similar line-of-sight absorption to the images, we find that their X-ray continuum slopes are inconsistent (Gamma_A=2.30 and Gamma_B=0.83) as are their X-ray to optical flux ratios. The probability that B suffers absorption sufficient to account for these spectral differences is negligible. We present new optical evidence that the flux ratio of the pair is variable, so the time-delay in a lens scenario could cause some of the discrepancies. However, adequately large variations in overall spectral energy distribution are rare in individual QSOs. All new evidence here weighs strongly toward the binary interpretation. Q2345+007 thus may represent the highest redshift example known of interaction-triggered but as-yet unmerged luminous AGN.Comment: 15 pages, Latex, emulateapj style, including 3 tables and 5 figures. Accepted Feb 1, 2002 for publication in ApJ Main Journal. See also http://hea-www.harvard.edu/~pgreen/Papers.htm

Dynamics and Selection of Giant Spirals in Rayleigh-Benard Convection

For Rayleigh-Benard convection of a fluid with Prandtl number \sigma \approx 1, we report experimental and theoretical results on a pattern selection mechanism for cell-filling, giant, rotating spirals. We show that the pattern selection in a certain limit can be explained quantitatively by a phase-diffusion mechanism. This mechanism for pattern selection is very different from that for spirals in excitable media

Dopa-Responsive Dystonia: Functional Analysis of Single Nucleotide Substitutions within the 5’ Untranslated GCH1 Region

Background: Mutations in the GCH1 gene are associated with childhood onset, dopa-responsive dystonia (DRD). Correct diagnosis of DRD is crucial, given the potential for complete recovery once treated with L-dopa. The majority of DRD associated mutations lie within the coding region of the GCH1 gene, but three additional single nucleotide sequence substitutions have been reported within the 5’ untranslated (5’UTR) region of the mRNA. The biologic significance of these 5’UTR GCH1 sequence substitutions has not been analyzed. Methodology/Principal Findings Luciferase reporter assays, quantitative real time PCR and RNA decay assays, combined with bioinformatics, revealed a pathogenic 5’UTR GCH1 substitution. The +142C>T single nucleotide 5’UTR substitution that segregates with affected status in DRD patients, substantially attenuates translation without altering RNA expression levels or stability. The +142C>T substitution disrupts translation most likely by creating an upstream initiation start codon (uAUG) and an upstream open reading frame (uORF). Conclusions/Significance: This is the first GCH1 regulatory substitution reported to act at a post-transcriptional level, increasing the list of genetic diseases caused by abnormal translation and reaffirming the importance of investigating potential regulatory substitutions in genetic diseases

Nanobodies Raised against Monomeric α-Synuclein Distinguish between Fibrils at Different Maturation Stages

AbstractNanobodies are single-domain fragments of camelid antibodies that are emerging as versatile tools in biotechnology. We describe here the interactions of a specific nanobody, NbSyn87, with the monomeric and fibrillar forms of α-synuclein (αSyn), a 140-residue protein whose aggregation is associated with Parkinson's disease. We have characterized these interactions using a range of biophysical techniques, including nuclear magnetic resonance and circular dichroism spectroscopy, isothermal titration calorimetry and quartz crystal microbalance measurements. In addition, we have compared the results with those that we have reported previously for a different nanobody, NbSyn2, also raised against monomeric αSyn. This comparison indicates that NbSyn87 and NbSyn2 bind with nanomolar affinity to distinctive epitopes within the C-terminal domain of soluble αSyn, comprising approximately amino acids 118–131 and 137–140, respectively. The calorimetric and quartz crystal microbalance data indicate that the epitopes of both nanobodies are still accessible when αSyn converts into its fibrillar structure. The apparent affinities and other thermodynamic parameters defining the binding between the nanobody and the fibrils, however, vary significantly with the length of time that the process of fibril formation has been allowed to progress and with the conditions under which formation occurs, indicating that the environment of the C-terminal domain of αSyn changes as fibril assembly takes place. These results demonstrate that nanobodies are able to target forms of potentially pathogenic aggregates that differ from each other in relatively minor details of their structure, such as those associated with fibril maturation

Mean flow and spiral defect chaos in Rayleigh-Benard convection

We describe a numerical procedure to construct a modified velocity field that does not have any mean flow. Using this procedure, we present two results. Firstly, we show that, in the absence of mean flow, spiral defect chaos collapses to a stationary pattern comprising textures of stripes with angular bends. The quenched patterns are characterized by mean wavenumbers that approach those uniquely selected by focus-type singularities, which, in the absence of mean flow, lie at the zig-zag instability boundary. The quenched patterns also have larger correlation lengths and are comprised of rolls with less curvature. Secondly, we describe how mean flow can contribute to the commonly observed phenomenon of rolls terminating perpendicularly into lateral walls. We show that, in the absence of mean flow, rolls begin to terminate into lateral walls at an oblique angle. This obliqueness increases with Rayleigh number.Comment: 14 pages, 19 figure