DISPLAYING THE HETEROGENEITY OF THE SN 2002cx-LIKE SUBCLASS OF TYPE Ia SUPERNOVAE WITH OBSERVATIONS OF THE Pan-STARRS-1 DISCOVERED SN 2009ku

SN 2009ku, discovered by Pan-STARRS-1, is a Type Ia supernova (SN Ia), and a member of the distinct SN 2002cx-like class of SNe Ia. Its light curves are similar to the prototypical SN 2002cx, but are slightly broader and have a later rise to maximum in g. SN 2009ku is brighter (similar to 0.6 mag) than other SN 2002cx-like objects, peaking at M-V = -18.4 mag, which is still significantly fainter than typical SNe Ia. SN 2009ku, which had an ejecta velocity of similar to 2000 km s(-1) at 18 days after maximum brightness, is spectroscopically most similar to SN 2008ha, which also had extremely low-velocity ejecta. However, SN 2008ha had an exceedingly low luminosity, peaking at M-V = -14.2 mag, similar to 4 mag fainter than SN 2009ku. The contrast of high luminosity and low ejecta velocity for SN 2009ku is contrary to an emerging trend seen for the SN 2002cx class. SN 2009ku is a counterexample of a previously held belief that the class was more homogeneous than typical SNe Ia, indicating that the class has a diverse progenitor population and/or complicated explosion physics. As the first example of a member of this class of objects from the new generation of transient surveys, SN 2009ku is an indication of the potential for these surveys to find rare and interesting objects.

Context-Dependent Pharmacology Exhibited by Negative Allosteric Modulators of Metabotropic Glutamate Receptor 7

Phenotypic studies of mice lacking metabotropic glutamate receptor subtype 7 (mGluR7) suggest that antagonists of this receptor may be promising for the treatment of central nervous system disorders such as anxiety and depression. Suzuki et al. (J Pharmacol Exp Ther 323: 147-156, 2007) recently reported the in vitro characterization of a novel mGluR7 antagonist called 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), which noncompetitively inhibited the activity of orthosteric and allosteric agonists at mGluR7. We describe that MMPIP acts as a noncompetitive antagonist in calcium mobilization assays in cells coexpressing mGluR7 and the promiscuous G protein G alpha(15). Assessment of the activity of a small library of MMPIP-derived compounds using this assay reveals that, despite similar potencies, compounds exhibit differences in negative co-operativity for agonist-mediated calcium mobilization. Examination of the inhibitory activity of MMPIP and analogs using endogenous G(i/o)-coupled assay readouts indicates that the pharmacology of these ligands seems to be context-dependent, and MMPIP exhibits differences in negative cooperativity in certain cellular backgrounds. Electrophysiological studies reveal that, in contrast to the orthosteric antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxyclycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), MMPIP is unable to block agonist-mediated responses at the Schaffer collateral-CA1 synapse, a location at which neurotransmission has been shown to be modulated by mGluR7 activity. Thus, MMPIP and related compounds differentially inhibit coupling of mGluR7 in different cellular backgrounds and may not antagonize the coupling of this receptor to native G(i/o) signaling pathways in all cellular contexts. The pharmacology of this compound represents a striking example of the potential for context-dependent blockade of receptor responses by negative allosteric modulators.

Clinical consequences of mast cell heterogeneity

The heterogeneous morphological, biochemical and functional characteristics of mast cells from different species and from different tissue sites in the same species have been described for over 30 years. Far from being mere histochemical or pharmacological curiosities these differences have far reaching implications for therapeutic practice. This review concentrates on two important areas affected by mast cell heterogeneity, those of adverse reactions to therapeutic agents and the efficacy of anti-allergy therapy.