CD18-dependent activation of the neutrophil NADPH oxidase during phagocytosis of Escherichia coli or Staphylococcus aureus is regulated by class III but not class I or II PI3Ks

Phagocytosis and activation of the NADPH oxidase are important mechanisms by which neutrophils and macrophages engulf and kill microbial pathogens. We investigated the role of PI3K signaling pathways in the regulation of the oxidase during phagocytosis of Staphylococcus aureus and Escherichia coli by mouse and human neutrophils, a mouse macrophage-like cell line and a human myeloid-like cell line. Phagocytosis of these bacteria was promoted by serum, independent of serum-derived antibodies, and effectively abolished in mouse neutrophils lacking the beta(2)-integrin common chain, CD18. A combination of PI3K isoform-selective inhibitors, mouse knock-outs, and RNA-interference indicated CD18-dependent activation of the oxidase was independent of class I and II PI3Ks, but substantially dependent on the single class III isoform (Vps34). Class III PI3K was responsible for the synthesis of PtdIns( 3) P on phagosomes containing either bacteria. The use of mouse neutrophils carrying an appropriate knock-in mutation indicated that PtdIns(3) P binding to the PX domain of their p40(phox) oxidase subunit is important for oxidase activation in response to both S aureus and E coli. This interaction does not, however, account for all the PI3K sensitivity of these responses, particularly the oxidase response to E coli, suggesting that additional mechanisms for PtdIns( 3) P-regulation of the oxidase must exist. ( Blood. 2008; 112: 5202-5211)

Early-time Spitzer observations of the type II plateau supernova SN 2004dj

We present mid-infrared observations with the Spitzer Space Telescope of the nearby Type II-P supernova SN 2004dj at epochs of 89 - 129 days. We have obtained the first mid-IR spectra of any supernova apart from SN 1987A. A prominent [Ni II] 6.64 mu m line is observed, from which we deduce that the mass of stable nickel must be at least 2.2 x 10(-4) M-.. We also observe the red wing of the CO fundamental band. We relate our findings to possible progenitors and favor an evolved star, most likely a red supergiant, with a probable initial mass between similar to 10 and 15 M-..

The Yellow Supergiant Progenitor of the Type II Supernova 2011dh in M51

We present the detection of the putative progenitor of the Type IIb SN 2011dh in archival pre-explosion Hubble Space Telescope images. Using post-explosion Adaptive Optics imaging with Gemini NIRI+ALTAIR, the position of the supernova (SN) in the pre-explosion images was determined to within 23 mas. The progenitor candidate is consistent with an F8 supergiant star (logL/L sun = 4.92 ± 0.20 and T eff = 6000 ± 280 K). Through comparison with stellar evolution tracks, this corresponds to a single star at the end of core C-burning with an initial mass of M ZAMS = 13 ± 3 M sun. The possibility of the progenitor source being a cluster is rejected, on the basis of: (1) the source not being spatially extended, (2) the absence of excess Ha emission, and (3) the poor fit to synthetic cluster spectral energy distributions (SEDs). It is unclear if a binary companion is contributing to the observed SED, although given the excellent correspondence of the observed photometry to a single star SED we suggest that the companion does not contribute significantly. Early photometric and spectroscopic observations show fast evolution similar to the transitional Type IIb SN 2008ax and suggest that a large amount of the progenitor's hydrogen envelope was removed before explosion. Late-time observations will reveal if the yellow supergiant or the putative companion star were responsible for this SN explosion.

Sequential C-H and C-Ru bond formation and cleavage during the thermally induced rearrangement of aryl ruthenium(II) complexes with [C6H3(CH2NMe2)(2)-2,6](-) as a bidentate eta(2)-C,N coordinated ligand. The crystal structures of the isomeric pairs [RuCl{eta(6)-C10H14}{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,n}] (n = 4 or 6) and [Ru(eta(5)-C5H5){(eta(2)-C,N-C6H3(CH2NMe2)(2)-2,n} (PPH3)] (n = 4 or 6)

New air-stable ruthenium(II) complexes that contain the aryldiamine ligand [C6H3(CH2-NMe2)(2)-2,6](-) (NCN) are described. These complexes are [RuCl{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,6}(eta(6)-C10H14)] (2; C10H14 = p-cymene = C6H4Me-Pr-i-4), [Ru{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,6}(eta(5)-C5H5)(PPh3)] (5), and their isomeric forms [RuCl{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,4}(eta(6)-C10H14)] (3) and [Ru{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,4}(eta(5)-C5H5)(PPh3)] (6), respectively. Complex 2 has been prepared from the reaction of [Li(NCN)](2) with [RuCl2(eta(6)-C10H14)](2), whereas complex 5 has been prepared by the treatment of [RuCl{eta(3)-N,C,N-C6H3(CH2NMe2)(2)-2,6}(PPh3)] (4) with [Na(C5H5)](n). Both 2 and 5 are formally 18-electron ruthenium(II) complexes in which the monoanionic potentially tridentate coordinating ligand NCN is eta(2)-C,N-bonded, In solution (halocarbon solvent at room temperature or in aromatic solvents at elevated temperature), the intramolecular rearrangements of 2 and 5 afford complexes 3 and 6, respectively. This is a result of a shift of the metal-C-aryl bond from position-1 to position-3 on the aromatic ring of the NCN ligand. The mechanism of the isomerization is proposed to involve a sequence of intramolecular oxidative addition and reductive elimination reactions of both aromatic and aliphatic C-H bonds. This is based on results from deuterium labeling, spectroscopic studies, and some kinetic experiments. The mechanism is proposed to contain fully reversible steps in the case of 5, but a nonreversible step involving oxidative addition of a methyl NCH2-H bond in the case of 2. The solid-state structures of complexes 2, 3, 5, and 6 have been determined by single-crystal X-ray diffraction. A new dinuclear 1,4-phenylene-bridged bisruthenium(II) complex, [1,4-{RuCl(eta(6)-C10H14)}(2){C-6(CH2NMe2)(4)-2,3,5,6-C,N,C',N'}] (9) has also been prepared from the dianionic ligand [C-6(CH2NMe2)(4)-2,3,5,6](2-) (C2N4). The C2N4 ligand is in an eta(2)-C,N-eta(2)-C',N'-bis(bidentate) bonding mode. Compound 9 does not isomerize in solution (halocarbon solvent), presumably because of the absence of an accessible C-aryl-H bond. Complex 9 could not be isolated in an analytically pure form, probably because of its high sensitivity to air and very low solubility, which precludes recrystallization.

Resonance Raman probing of the interaction between dipyridophenazine complexes of Ru(II) and DNA

Resonance Raman (RR) spectroscopy has been used to probe the interaction between dipyridophenazine (dppz) complexes of ruthenium(II), [Ru(L)(2)(dppz)](2+) (L = 1,10-phenanthroline (1) and 2,2-bipyridyl (2)), and calf-thymus DNA. Ground electronic state RR spectra at selected probe wavelengths reveal enhancement patterns which reflect perturbation of the dppz-centered electronic transitions in the UV-vis spectra in the presence of DNA. Comparison of the RR spectra recorded of the short-lived MLCT excited states of both complexes in aqueous solution with those of the longer-lived states of the complexes in the DNA environment reveals changes to excited state modes, suggesting perturbation of electronic transitions of the dppz ligand in the excited state as a result of intercalation. The most prominent feature, at 1526 cm(-1), appears in the spectra of both 1 and 2 and is a convenient marker band for intercalation. For 1, the excited state studies have been extended to the A and A enantiomers. The marker band appears at the same frequency for both but with different relative intensities. This is interpreted as reflecting the distinctive response of the enantiomers to the chiral environment of the DNA binding sites. The results, together with some analogous data for other potentially intercalating complexes, are considered in relation to the more general application of time-resolved RR spectroscopy for investigation of intercalative interactions of photoexcited metal complexes with DNA.

Resonance-Raman probing of the interaction between dipyridophenazine complexes of ruthenium(II) and DNA

The resonance-Raman spectroscopic technique is an effective probe of the interaction between dipyridophenazine (dppz) complexes of ruthenium(II) and calf-thymus DNA, providing evidence that DNA addition results in changes to electronic transitions of the intercalating dppz ligand in both ground and excited states.

PHOTOPERTURBATION OF THE (1)A-][-(5)T SPIN EQUILIBRIUM IN AN IRON(II) COMPLEX IN SOLUTION VIA LIGAND-FIELD EXCITATION

Variable-temperature magnetic susceptibility measurements in the solid state of the bis complex of tris(1-pyrazolyl)-methane with Fe(II), [Fe(tpm)2](ClO4)2, suggest the existence of singlet-quintet spin crossover with the singlet isomer largely favored at room temperature. In acetonitrile solution, measurement of the absorption spectrum as a function of temperature reveals a spin equilibrium with the quintet population varying from ca. 6% at 233 K to ca. 30% at 295 K. When the complex in solution is irradiated with a laser pulse at wavelengths within the ligand field absorption band of the singlet isomer, ground-state depletion occurs within the pulse duration followed by fast recovery to the original absorbance level with a time constant of 25 +/- 5ns. The recovery time is virtually independent of temperature over the range +23 to -43-degrees-C, but the signal:noise ratio of the transient signals increases with decreasing temperature. The effect was observable at several monitoring wavelengths spanning the LF and MLCT absorption regions of the complex but only when the irradiation wavelength fell within the LF absorption region. Irradiation within the MLCT band produced no effect other than that of laser pulse scatter. The observations are interpreted in terms of photoperturbation of the singlet-quintet spin state equilibrium, which in this case occurs solely through excitation in the ligand field absorption region of the complex and is the first reported instance of this type for a spin-crossover complex in solution.

On the nature of the progenitors of three Type II-P supernovae: 2004et, 2006my and 2006ov

The pre-explosion observations of the Type II-P supernovae 2006my, 2006ov and 2004et are re-analysed. In the cases of supernovae 2006my and 2006ov we argue that the published candidate progenitors are not coincident with their respective supernova sites in pre-explosion Hubble Space Telescope observations. We therefore derive upper luminosity and mass limits for the unseen progenitors of both these supernovae, assuming they are red supergiants: 2006my (log L/L-circle dot = 4.51; m

Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead

This Letter describes the synthesis and SAR of two mGluR4 positive allosteric modulator leads, 6 and 7. VU001171 (6) represents the most potent (EC50 = 650 nM), efficacious (141% Glu Max) and largest fold shift (36-fold) of any mGluR4 PAM reported to date. However, this work highlights the challenges in hit-to-lead for mGluR4 PAMs, with multiple confirmed HTS hits displaying little or no tractable SAR. (C) 2008 Elsevier Ltd. All rights reserved.