An early-time infrared and optical study of the Type Ia Supernova 1998bu in M96

We present first-season infrared (IR) and optical photometry and spectroscopy of the Type Ia Supernova 1998bu in M96. We also report optical polarimetry of this event. SN 1998bu is one of the closest type Ia supernovae of modern times, and the distance of its host galaxy is well determined. We find that SN 1998bu is both photometrically and spectroscopically normal. However, the extinction to this event is unusually high, with A(V) = 1.0 +/- 0.11. We find that SN 1998bu peaked at an intrinsic M-V = -19.37 +/- 0.23. Adopting a distance modulus of 30.25 (Tanvir et al.) and using Phillips et al.'s relations for the Hubble constant, we obtain H-0 = 70.4 +/- 4.3 km s(-1) Mpc(-1). Combination of our IR photometry with those of Jha et al. provides one of the most complete early-phase IR light curves for a SN Ia published so far. In particular, SN 1998bu is the first normal SN Ia for which good pre-t(Bmax) IR coverage has been obtained. It reveals that the J, H and K light curves peak about 5 days earlier than the flux in the B-band curve.

Environmental Regulation in a Transitional Society

12,430 words Submitted for peer review

HIF-2alpha Associated Familial Erythrocytosis Supports the PHD2-HIF2-alpha-VHL Axis as the Major Regulator of Erythropoietin Production

Transcriptionally erythropoietin (Epo) synthesis is tightly regulated by the hypoxia inducible factor (HIF), which is composed of one alpha and one beta subunit that are constitutively expressed. The beta subunit is non-variable, but three different alpha subunits give rise to three isoforms of HIF. The alpha subunit is proteasomally regulated in the presence of oxygen by hydroxylation of the proline in the LXXLAP motif of the oxygen dependent degradation (ODD) domain of HIFalpha, catalysed by members of the prolyl hydroxylase domain (PHD) family of enzymes. This allows the von Hippel Lindau (VHL) protein to associate with the alpha subunit, which is subsequently tagged with ubiquitin and degraded by the proteasome. Any defect in the oxygen sensing pathway that allows the alpha subunit to escape proteasomal regulation leads to elevated expression of HIF target genes.

Recently mutations in both VHL and PHD2 have been identified in a cohort of patients with erythrocytosis, but no mutations were found in the ODD domain of HIF1alpha. Instead, investigation of the homologous region in HIF-2alpha revealed four different mutations, Pro534Leu, Met535Val, Gly537Arg and Gly537Trp in seven individuals/families. Affected individuals presented at a young age with elevated serum Epo. Several individuals have a clinical history of thrombosis, but no evidence of a von Hippel Lindau-like syndrome.

To define how the four mutations relate to the erythrocytosis phenotype functional assays were performed in vitro. Binding of PHD2 to the four HIF-2alpha mutants was impaired to varying degrees, with both the Gly537 mutants showing the greatest reduction. The association of VHL with the hydroxylated Met535Val mutant peptide was similar to wild type HIF- 2alpha, but was decreased in the other three HIF-2alpha mutants. Expression of three HIF- 2alpha target genes, adrenomedullin, NDRG1 and VEGF, was significantly up-regulated in cells stably transfected with the mutants under normoxia compared to wild type HIF-2alpha. Mutations in the ODD domain of HIF-2alpha disrupt proteasomal regulation by reducing the association with PHD2 and hence hydroxylation. Furthermore the binding of VHL is also impaired, even when HIF-2alpha is hydroxylated. Examination of the three-dimensional structure of hydroxylated HIF-1alpha bound to VHL confirms that amino acids close to site of hydroxylation (Pro-531 in isoform 2) are important for this association. These observations, together with recent studies utilising murine models of erythrocytosis, support the PHD2-HIF-2alpha-VHL axis as the major regulator of erythropoietin.

The Family of Love in English Society, 1550-1630

A detailed investigation of an outlawed mystical religious fellowship in early modern England.