Genomic and epigenomic mapping of leptin-responsive neuronal populations involved in body weight regulation.

Genome wide association studies (GWAS) in obesity have identified a large number of noncoding loci located near genes expressed in the central nervous system. However, due to the difficulties in isolating and characterizing specific neuronal subpopulations, few obesity-associated SNPs have been functionally characterized. Leptin responsive neurons in the hypothalamus are essential in controlling energy homeostasis and body weight. Here, we combine FACS-sorting of leptin-responsive hypothalamic neuron nuclei with genomic and epigenomic approaches (RNA-seq, ChIP-seq, ATAC-seq) to generate a comprehensive map of leptin-response specific regulatory elements, several of which overlap obesity-associated GWAS variants. We demonstrate the usefulness of our leptin-response neuron regulome, by functionally characterizing a novel enhancer near Socs3, a leptin response-associated transcription factor. We envision our data to serve as a useful resource and a blueprint for functionally characterizing obesity-associated SNPs in the hypothalamus

Analysis of lead levels in deciduous teeth from children in Clark County, Nevada.

Background: Elevated blood lead levels (EBLL) are declining in the United States, although some population subgroups continue to exhibit significant health disparities. A childhood lead poisoning prevention program was recently started in Nevada, and many efforts have been made to support this program and increase the screening rates. Methods: To expand the potential pool of children screened for EBLLs, a pilot study was performed to evaluate lead concentrations in extracted deciduous teeth using Graphic Furnace Atomic Absorption Spectrometry (GFAAS), Inductively Coupled Plasma Mass Spectrometry (ICP-MS), and X-Ray Fluorescence (XRF) analysis. Results: Lead concentrations as determined by GFAAS and ICP-MS were found to be within normal ranges (0.585 ppm ± 0.022) and were similar to previous studies. Hispanic patients exhibited higher lead levels (0.580 ppm ± 0.032) than Black (0.478 ppm ± 0.051) patients, and were significantly higher than White (0.275 ppm ± 0.035) patients (p \u3c 0.05). Analysis of a small number of matched saliva samples, however, found no evidence for acute lead poisoning. Although limited by a small initial sample size (n=22), this pilot study provides evidence that teeth can be effectively used to reveal lead exposure in pediatric dentistry patients

Hubble Space Telescope Evidence for an Intermediate-Mass Black Hole in the Globular Cluster M15: II. Kinematical Analysis and Dynamical Modeling

We analyze HST/STIS spectra (see Paper I) of the central region of the dense globular cluster M15. We infer the velocities of 64 individual stars, two-thirds of which have their velocity measured for the first time. This triples the number of stars with measured velocities in the central 1 arcsec of M15 and doubles the number in the central 2 arcsec. Combined with existing ground-based data we obtain the radial profiles of the projected kinematical quantities. The RMS velocity sigma_RMS rises to 14 km/s in the central few arcsec, somewhat higher than the values of 10-12 km/s inferred previously from ground-based data. To interpret the results we construct dynamical models based on the Jeans equation, which imply that M15 must have a central concentration of non-luminous material. If this is due to a single black hole, then its mass is M_BH = (3.9 +/- 2.2) x 10^3 solar masses. This is consistent with the relation between M_BH and sigma_RMS that has been established for galaxies. Also, the existence of intermediate-mass black holes in globular clusters is consistent with several scenarios for globular cluster evolution proposed in the literature. Therefore, these results may have important implications for our understanding of the evolution of globular clusters, the growth of black holes, the connection between globular cluster and galaxy formation, and the nature of the recently discovered `ultra-luminous' X-ray sources in nearby galaxies. Instead of a single black hole, M15 could have a central concentration of dark remnants (e.g., neutron stars) due to mass segregation. However, the best-fitting Fokker-Planck models that have previously been constructed for M15 do not predict a central mass concentration that is sufficient to explain the observed kinematics.[ABRIDGED]Comment: 43 pages, LaTeX, with 14 PostScript figures. Astronomical Journal, in press (Dec 2002). Please note that the results reported here are modified by the Addendum available at astro-ph/0210158 (Astronomical Journal, in press, Jan 2003). This second version submitted to astro-ph is identical to first, with the exception of the preceeding remar

The Spectral Energy Distribution of Dust Emission in the Edge-on spiral galaxy NGC 4631 as seen with Spitzer and the James Clerk Maxwell telescope

We explore variations in dust emission within the edge-on Sd spiral galaxy NGC 4631 using 3.6-160 μm Spitzer Space Telescope data and 450-850 μm JCMT data with the goals of understanding the relation between PAHs and dust emission, studying the variations in the colors of the dust emission, and searching for possible excess submillimeter emission compared to what is expected from dust models extrapolated from far-infrared wavelengths. The 8 μm PAH emission correlates best with 24 μm hot dust emission on 1.7 kpc scales, but the relation breaks down on 650 pc scales, possibly because of differences in the mean free paths between photons that excite the PAHs and photons that heat the dust and possibly because the PAHs are destroyed by the hard radiation fields within some star formation regions. The ratio of 8 μm PAH emission to 160 μm cool dust emission appears to vary as a function of radius. The 70 μm/160 μm and 160 μm/450 μm flux density ratios are remarkably constant even though the surface brightnesses vary by factors of 25, which suggests that the emission is from dust heated by a nearly uniform radiation field. Globally, we find an excess of 850-1230 μm emission relative to what would be predicted by dust models. The 850 μm excess is highest in regions with low 160 μm surface brightnesses, although the magnitude depends on the model fit to the data. We rule out variable emissivity functions or ~4 K dust as the possible origins of this 850 μm emission, but we do discuss the other possible mechanisms that could produce the emission

Large-area NbN superconducting nanowire avalanche photon detectors with saturated detection efficiency

Superconducting circuits comprising SNSPDs placed in parallel—superconducting nanowire avalanche photodetectors, or SNAPs—have previously been demonstrated to improve the output signal-to-noise ratio (SNR) by increasing the critical current. In this work, we employ a 2-SNAP superconducting circuit with narrow (40 nm) niobium nitride (NbN) nanowires to improve the system detection efficiency to near-IR photons while maintaining high SNR. Additionally, while previous 2-SNAP demonstrations have added external choke inductance to stabilize the avalanching photocurrent, we show that the external inductance can be entirely folded into the active area by cascading 2-SNAP devices in series to produce a greatly increased active area. We fabricated series-2-SNAP (s2-SNAP) circuits with a nanowire length of 20 μm with cascades of 2-SNAPs providing the choke inductance necessary for SNAP operation. We observed that (1) the detection efficiency saturated at high bias currents, and (2) the 40 nm 2-SNAP circuit critical current was approximately twice that for a 40 nm non-SNAP configuration.United States. Dept. of Defense. Assistant Secretary of Defense for Research & Engineering (United States. Air Force Contract FA8721-05-C-0002

Occurrence of testicular microlithiasis in androgen insensitive hypogonadal mice

<b>Background</b>: Testicular microliths are calcifications found within the seminiferous tubules. In humans, testicular microlithiasis (TM) has an unknown etiology but may be significantly associated with testicular germ cell tumors. Factors inducing microlith development may also, therefore, act as susceptibility factors for malignant testicular conditions. Studies to identify the mechanisms of microlith development have been hampered by the lack of suitable animal models for TM.<BR/> <b>Methods</b>: This was an observational study of the testicular phenotype of different mouse models. The mouse models were: cryptorchid mice, mice lacking androgen receptors (ARs) on the Sertoli cells (SCARKO), mice with a ubiquitous loss of androgen ARs (ARKO), hypogonadal (hpg) mice which lack circulating gonadotrophins, and hpg mice crossed with SCARKO (hpg.SCARKO) and ARKO (hpg.ARKO) mice.<BR/> <b>Results</b>: Microscopic TM was seen in 94% of hpg.ARKO mice (n=16) and the mean number of microliths per testis was 81 +/- 54. Occasional small microliths were seen in 36% (n=11) of hpg testes (mean 2 +/- 0.5 per testis) and 30% (n=10) of hpg.SCARKO testes (mean 8 +/- 6 per testis). No microliths were seen in cryptorchid, ARKO or SCARKO mice. There was no significant effect of FSH or androgen on TM in hpg.ARKO mice.<BR/> <b>Conclusions</b>: We have identified a mouse model of TM and show that lack of endocrine stimulation is a cause of TM. Importantly, this model will provide a means with which to identify the mechanisms of TM development and the underlying changes in protein and gene expression

Enhancer Interaction Networks as a Means for Singular Olfactory Receptor Expression

SummaryThe transcriptional activation of one out of ∼2800 olfactory receptor (OR) alleles is a poorly understood process. Here, we identify a plethora of putative OR enhancers and study their in vivo activity in olfactory neurons. Distinguished by an unusual epigenetic signature, candidate OR enhancers are characterized by extensive interchromosomal interactions associated with OR transcription and share a similar pattern of transcription factor footprints. In particular, we establish the role of the transcription factor Bptf as a facilitator of both enhancer interactions and OR transcription. Our observations agree with the model whereby OR transcription occurs in the context of multiple interacting enhancers. Disruption of these interchromosomal interactions results in weak and multigenic OR expression, suggesting that the rare coincidence of numerous enhancers over a stochastically chosen OR may account for the singularity and robustness in OR transcription

Step-Indexed Normalization for a Language with General Recursion

The Trellys project has produced several designs for practical dependently typed languages. These languages are broken into two fragments-a_logical_fragment where every term normalizes and which is consistent when interpreted as a logic, and a_programmatic_fragment with general recursion and other convenient but unsound features. In this paper, we present a small example language in this style. Our design allows the programmer to explicitly mention and pass information between the two fragments. We show that this feature substantially complicates the metatheory and present a new technique, combining the traditional Girard-Tait method with step-indexed logical relations, which we use to show normalization for the logical fragment.Comment: In Proceedings MSFP 2012, arXiv:1202.240