Identification of polymorphisms and balancing selection in the male infertility candidate gene, ornithine decarboxylase antizyme 3

Abstract Background The antizyme family is a group of small proteins that play a role in cell growth and division by regulating the biosynthesis of polyamines (putrescine, spermidine, spermine). Antizymes regulate polyamine levels primarily through binding ornithine decarboxylase (ODC), an enzyme key to polyamine production, and targeting ODC for destruction by the 26S proteosome. Ornithine decarboxylase antizyme 3 (OAZ3) is a testis-specific antizyme paralog and the only antizyme expressed in the mid to late stages of spermatogenesis. Methods To see if mutations in the OAZ3 gene are responsible for some cases of male infertility, we sequenced and evaluated the genomic DNA of 192 infertile men, 48 men of known paternity, and 34 African aborigines from the Mbuti tribe in the Democratic Republic of the Congo. The coding sequence of OAZ3 was further screened for polymorphisms by SSCP analysis in the infertile group and an additional 250 general population controls. Identified polymorphisms in the OAZ3 gene were further subjected to a haplotype analysis using PHASE 2.02 and Arlequin 2.0 software programs. Results A total of 23 polymorphisms were identified in the promoter, exons or intronic regions of OAZ3. The majority of these fell within a region of less than two kilobases. Two of the polymorphisms, -239 A/G in the promoter and 4280 C/T, a missense polymorphism in exon 5, may show evidence of association with male infertility. Haplotype analysis identified 15 different haplotypes, which can be separated into two divergent clusters. Conclusion Mutations in the OAZ3 gene are not a common cause of male infertility. However, the presence of the two divergent haplotypes at high frequencies in all three of our subsamples (infertile, control, African) suggests that they have been maintained in the genome by balancing selection, which was supported by a test of Tajima's D statistic. Evidence for natural selection in this region implies that these haplotypes may be associated with a trait other than infertility. This trait may be related to another function of OAZ3 or a region in tight linkage disequilibrium to the gene.</p

Iterative focused screening with biological fingerprints identifies selective Asc-1 inhibitors distinct from traditional high throughput screening

N-methyl-d-aspartate receptors (NMDARs) mediate glutamatergic signaling that is critical to cognitive processes in the central nervous system, and NMDAR hypofunction is thought to contribute to cognitive impairment observed in both schizophrenia and Alzheimer’s disease. One approach to enhance the function of NMDAR is to increase the concentration of an NMDAR coagonist, such as glycine or d-serine, in the synaptic cleft. Inhibition of alanine–serine–cysteine transporter-1 (Asc-1), the primary transporter of d-serine, is attractive because the transporter is localized to neurons in brain regions critical to cognitive function, including the hippocampus and cortical layers III and IV, and is colocalized with d-serine and NMDARs. To identify novel Asc-1 inhibitors, two different screening approaches were performed with whole-cell amino acid uptake in heterologous cells stably expressing human Asc-1: (1) a high-throughput screen (HTS) of 3 M compounds measuring 35S l-cysteine uptake into cells attached to scintillation proximity assay beads in a 1536 well format and (2) an iterative focused screen (IFS) of a 45 000 compound diversity set using a 3H d-serine uptake assay with a liquid scintillation plate reader in a 384 well format. Critically important for both screening approaches was the implementation of counter screens to remove nonspecific inhibitors of radioactive amino acid uptake. Furthermore, a 15 000 compound expansion step incorporating both on- and off-target data into chemical and biological fingerprint-based models for selection of additional hits enabled the identification of novel Asc-1-selective chemical matter from the IFS that was not identified in the full-collection HTS

Extraordinary Late-Time Infrared Emission of Type IIn Supernovae

Near-Infrared (NIR) observations are presented for five Type IIn supernovae (SN 1995N, SN 1997ab, SN 1998S, SN 1999Z, and SN 1999el) that exhibit strong infrared excesses at late times (t >= 100 d). H- and K-band emission from these objects is dominated by a continuum that rises toward longer wavelengths. The data are interpreted as thermal emission from dust, probably situated in a pre-existing circumstellar nebula. The IR luminosities implied by single temperature blackbody fits are quite large,> 10^(41 - 42) erg s^-1, and the emission evolves slowly, lasting for years after maximum light. For SN 1995N, the integrated energy release via IR dust emission was 0.5 -- 1 * 10^50 erg. A number of dust heating scenarios are considered, the most likely being an infrared echo poweredby X-ray and UV emissions from the shock interaction with a dense circumstellar medium.Comment: 14 Pages, 3 Figures, Accecpted for publication in The Astrophysical Journa

Analysis of the Type IIn Supernova 1998S: Effects of Circumstellar Interaction on Observed Spectra

We present spectral analysis of early observations of the Type IIn supernova 1998S using the general non-local thermodynamic equilibrium atmosphere code \tt PHOENIX}. We model both the underlying supernova spectrum and the overlying circumstellar interaction region and produce spectra in good agreement with observations. The early spectra are well fit by lines produced primarily in the circumstellar region itself, and later spectra are due primarily to the supernova ejecta. Intermediate spectra are affected by both regions. A mass-loss rate of order $\dot M \sim 0.0001-0.001$\msol yr$^{-1}$ is inferred for a wind speed of 100-1000 \kmps. We discuss how future self-consistent models will better clarify the underlying progenitor structure.Comment: to appear in ApJ, 2001, 54

Chandra Observations of Type Ia Supernovae: Upper Limits to the X-ray Flux of SN 2002bo, SN 2002ic, SN 2005gj, and SN 2005ke

We set sensitive upper limits to the X-ray emission of four Type Ia supernovae (SNe Ia) using the Chandra X-ray Observatory. SN 2002bo, a normal, although reddened, nearby SN Ia, was observed 9.3 days after explosion. For an absorbed, high temperature bremsstrahlung model the flux limits are 3.2E-16 ergs/cm^2/s (0.5-2 keV band) and 4.1E-15 ergs/cm^2/s (2-10 keV band). Using conservative model assumptions and a 10 km/s wind speed, we derive a mass loss rate of \dot{M} ~ 2E-5 M_\odot/yr, which is comparable to limits set by the non-detection of Halpha lines from other SNe Ia. Two other objects, SN 2002ic and SN 2005gj, observed 260 and 80 days after explosion, respectively, are the only SNe Ia showing evidence for circumstellar interaction. The SN 2002ic X-ray flux upper limits are ~4 times below predictions of the interaction model currently favored to explain the bright optical emission. To resolve this discrepancy we invoke the mixing of cool dense ejecta fragments into the forward shock region, which produces increased X-ray absorption. A modest amount of mixing allows us to accommodate the Chandra upper limit. SN 2005gj is less well studied at this time. Assuming the same circumstellar environment as for SN 2002i, the X-ray flux upper limits for SN 2005gj are ~4 times below the predictions, suggesting that mixing of cool ejecta into the forward shock has also occurred here. Our reanalysis of Swift and Chandra data on SN 2005ke does not confirm a previously reported X-ray detection. The host galaxies NGC 3190 (SN 2002bo) and NGC 1371 (SN 2005ke) each harbor a low luminosity (L_X ~ 3-4E40 ergs/s) active nucleus in addition to wide-spread diffuse soft X-ray emission.Comment: 16 pages, to appear in ApJ (20 Nov 2007

Faint NUV/FUV Standards from Swift/UVOT, GALEX and SDSS Photometry

At present, the precision of deep ultraviolet photometry is somewhat limited by the dearth of faint ultraviolet standard stars. In an effort to improve this situation, we present a uniform catalog of eleven new faint (u sim17) ultraviolet standard stars. High-precision photometry of these stars has been taken from the Sloan Digital Sky Survey and Galaxy Evolution Explorer and combined with new data from the Swift Ultraviolet Optical Telescope to provide precise photometric measures extending from the Near Infrared to the Far Ultraviolet. These stars were chosen because they are known to be hot (20,000 < T_eff < 50,000 K) DA white dwarfs with published Sloan spectra that should be photometrically stable. This careful selection allows us to compare the combined photometry and Sloan spectroscopy to models of pure hydrogen atmospheres to both constrain the underlying properties of the white dwarfs and test the ability of white dwarf models to predict the photometric measures. We find that the photometry provides good constraint on white dwarf temperatures, which demonstrates the ability of Swift/UVOT to investigate the properties of hot luminous stars. We further find that the models reproduce the photometric measures in all eleven passbands to within their systematic uncertainties. Within the limits of our photometry, we find the standard stars to be photometrically stable. This success indicates that the models can be used to calibrate additional filters to our standard system, permitting easier comparison of photometry from heterogeneous sources. The largest source of uncertainty in the model fitting is the uncertainty in the foreground reddening curve, a problem that is especially acute in the UV.Comment: Accepted for publication in Astrophysical Journal. 31 pages, 13 figures, electronic tables available from ApJ or on reques

Detection of CO and Dust Emission in Near-Infrared Spectra of SN 1998S

Near-infrared spectra (0.95 -- 2.4 micron) of the peculiar Type IIn supernova 1998S in NGC 3877 from 95 to 355 days after maximum light are presented. K-band data taken at days 95 and 225 show the presence of the first overtone of CO emission near 2.3 micron, which is gone by day 355. An apparent extended blue wing on the CO profile in the day 95 spectrum could indicate a large CO expansion velocity (~2000 -- 3000 km/s). This is the third detection of infrared CO emission in nearly as many Type II supernovae studied, implying that molecule formation may be fairly common in Type II events, and that the early formation of molecules in SN 1987A may be typical rather than exceptional. Multi-peak hydrogen and helium lines suggest that SN 1998S is interacting with a circumstellar disk, and the fading of the red side of this profile with time is suggestive of dust formation in the ejecta, perhaps induced by CO cooling. Continuum emission that rises towards longer wavelengths (J -> K) is seen after day 225 with an estimated near-infrared luminosity >~ 10^40 erg/s. This may be related to the near-infrared excesses seen in a number of other supernovae. If this continuum is due to free-free emission, it requires an exceptionally shallow density profile. On the other hand, the shape of the continuum is well fit by a 1200 +- 150 K blackbody spectrum possibly due to thermal emission from dust. Interestingly, we observe a similar 1200 K blackbody-like, near-infrared continuum in SN 1997ab, another Type IIn supernova at an even later post-maximum epoch (day 1064+). A number of dust emission scenarios are discussed, and we conclude that the NIR dust continuum is likely powered by the interaction of SN 1998S with the circumstellar medium.Comment: 38 Pages, 12 Figures, Submitted to The Astronomical Journa

A very low mass of Ni-56 in the ejecta of SN 1994W

We present spectroscopic and photometric observations of the luminous narrow- line Type IIP (plateau) supernova 1994W. After the plateau phase (t >120 days), the light curve dropped by 3.5 mag in V in only 12 days. Between 125 and 197 days after explosion the supernova faded substantially faster than the decay rate of Co-56, and by day 197 it was 3.6 magnitudes less luminous in R compared to SN 1987A. The low R-luminosity could indicate less than 0.0026 {+0.0017}/ {-0.0011} Msun of Ni-56 ejected at the explosion, but the emission between 125 and 197 days must then have been dominated by an additional power source, pre- sumably circumstellar interaction. Alternatively, the late light curve was dominated by Co-56 decay. In this case, the mass of the ejected Ni-56 was 0.015 {+0.012}/{-0.008} Msun, and the rapid fading between 125 and 197 days was most likely due to dust formation. Though this value of the mass is higher than in the case with the additional power source, it is still lower than estimated for any previous Type II supernova. Only progenitors with M(ZAMS) = 8-10 Msun and M(ZAMS) > 25 Msun are expected to eject such low masses of Ni-56. If M(ZAMS) = 8-10 Msun, the plateau phase indicates a low explosion energy, while for a progenitor with M(ZAMS) > 25 Msun the energy can be the canonical 1.0E{51} ergs. As SN 1994W was unusually luminous, the low-mass explosion may require an uncomfortably high efficiency in converting explosion energy into radiation. This favors a M(ZAMS) > 25 Msun progenitor. The supernova's narrow (roughly 1000 km s^{-1}) emission lines were excited by the hot supernova spectrum, rather than a circumstellar shock. The thin shell from which the lines origi- nated was most likely accelerated by the radiation from the supernova.Comment: 19 pages AASTeX v.4.0, including 5 Postscript figures; ApJ, in pres

SN 2006bt: A Perplexing, Troublesome, and Possibly Misleading Type Ia Supernova

SN 2006bt displays characteristics unlike those of any other known Type Ia supernova (SN Ia). We present optical light curves and spectra of SN 2006bt which demonstrate the peculiar nature of this object. SN 2006bt has broad, slowly declining light curves indicative of a hot, high-luminosity SN, but lacks a prominent second maximum in the i band as do low-luminosity SNe Ia. Its spectra are similar to those of low-luminosity SNe Ia, containing features that are only present in cool SN photospheres. Light-curve fitting methods suggest that SN 2006bt is reddened by a significant amount of dust; however, it occurred in the outskirts of its early-type host galaxy and has no strong Na D absorption in any of its spectra, suggesting a negligible amount of host-galaxy dust absorption. C II is possibly detected in our pre-maximum spectra, but at a much lower velocity than other elements. The progenitor was likely very old, being a member of the halo population of a galaxy that shows no signs of recent star formation. SNe Ia have been very successfully modeled as a one-parameter family, and this is fundamental to their use as cosmological distance indicators. SN 2006bt is a challenge to that picture, yet its relatively normal light curves allowed SN 2006bt to be included in cosmological analyses. We generate mock SN Ia datasets which indicate that contamination by similar objects will both increase the scatter of a SN Ia Hubble diagram and systematically bias measurements of cosmological parameters. However, spectra and rest-frame i-band light curves should provide a definitive way to identify and eliminate such objects.Comment: ApJ, accepted. 13 pages, 13 figure