Magnesium isotopes of the bulk solar wind from Genesis diamond-like carbon films.

NASA's Genesis Mission returned solar wind (SW) to the Earth for analysis to derive the composition of the solar photosphere from solar material. SW analyses control the precision of the derived solar compositions, but their ultimate accuracy is limited by the theoretical or empirical models of fractionation due to SW formation. Mg isotopes are "ground truth" for these models since, except for CAIs, planetary materials have a uniform Mg isotopic composition (within ≤1‰) so any significant isotopic fractionation of SW Mg is primarily that of SW formation and subsequent acceleration through the corona. This study analyzed Mg isotopes in a bulk SW diamond-like carbon (DLC) film on silicon collector returned by the Genesis Mission. A novel data reduction technique was required to account for variable ion yield and instrumental mass fractionation (IMF) in the DLC. The resulting SW Mg fractionation relative to the DSM-3 laboratory standard was (-14.4‰, -30.2‰) ± (4.1‰, 5.5‰), where the uncertainty is 2Æ¡ SE of the data combined with a 2.5‰ (total) error in the IMF determination. Two of the SW fractionation models considered generally agreed with our data. Their possible ramifications are discussed for O isotopes based on the CAI nebular composition of McKeegan et al. (2011).

Electron Microprobe/SIMS Determinations of Al in Olivine: Applications to Solar Wind, Pallasites and Trace Element Measurements.

Electron probe microanalyzer measurements of trace elements with high accuracy are challenging. Accurate Al measurements in olivine are required to calibrate SIMS implant reference materials for measurement of Al in the solar wind. We adopt a combined EPMA/SIMS approach that is useful for producing SIMS reference materials as well as for EPMA at the ~100 µg g-1 level. Even for mounts not polished with alumina photoelectron spectroscopy shows high levels of Al surface contamination. In order to minimize electron beam current density, a rastered 50 × 100 µm electron beam was adequate and minimized sensitivity to small Al-rich contaminants. Reproducible analyses of eleven SIMS-cleaned spots on San Carlos olivine agreed at 69.3 ± 1.0 µg g-1• The known Al mass fraction was used to calibrate an Al implant into San Carlos. Accurate measurements of Al were made for olivines in the pallasites: lmilac, Eagle Station and Springwater. Our focus was on Al in olivine, but our technique could be refined to give accurate electron probe measurements for other contamination-sensitive trace elements. For solar wind, it is projected that the Al/Mg abundance ratio can be determined to 6%, a factor of 2 more precise than the solar spectroscopic ratio.

The future of Genesis science.

Solar abundances are important to planetary science since the prevalent model assumes that the composition of the solar photosphere is that of the solar nebula from which planetary materials formed. Thus, solar abundances are a baseline for planetary science. Previously, solar abundances have only been available through spectroscopy or by proxy (CI). The Genesis spacecraft collected and returned samples of the solar wind for laboratory analyses. Elemental and isotopic abundances in solar wind from Genesis samples have been successfully measured despite the crash of the re-entry capsule. Here we present science rationales for a set of 12 important (and feasible postcrash) Science and Measurement Objectives as goals for the future (Table 1). We also review progress in Genesis sample analyses since the last major review (Burnett 2013). Considerable progress has been made toward understanding elemental fractionation during the extraction of the solar wind from the photosphere, a necessary step in determining true solar abundances from solar wind composition. The suitability of Genesis collectors for specific analyses is also assessed. Thus far, the prevalent model remains viable despite large isotopic variations in a number of volatile elements, but its validity and limitations can be further checked by several Objectives.

DETERMINING THE ELEMENTAL AND ISOTOPIC COMPOSITION OF THE PRESOLAR NEBULA FROM GENESIS DATA ANALYSIS: THE CASE OF OXYGEN.

We compare element and isotopic fractionations measured in solar wind samples collected by NASA's Genesis mission with those predicted from models incorporating both the ponderomotive force in the chromosphere and conservation of the first adiabatic invariant in the low corona. Generally good agreement is found, suggesting that these factors are consistent with the process of solar wind fractionation. Based on bulk wind measurements, we also consider in more detail the isotopic and elemental abundances of O. We find mild support for an O abundance in the range 8.75 - 8.83, with a value as low as 8.69 disfavored. A stronger conclusion must await solar wind regime specific measurements from the Genesis samples.

The oxygen isotopic composition of the Sun inferred from captured solar wind.

All planetary materials sampled thus far vary in their relative abundance of the major isotope of oxygen, (16)O, such that it has not been possible to define a primordial solar system composition. We measured the oxygen isotopic composition of solar wind captured and returned to Earth by NASA's Genesis mission. Our results demonstrate that the Sun is highly enriched in (16)O relative to the Earth, Moon, Mars, and bulk meteorites. Because the solar photosphere preserves the average isotopic composition of the solar system for elements heavier than lithium, we conclude that essentially all rocky materials in the inner solar system were enriched in (17)O and (18)O, relative to (16)O, by ~7%, probably via non-mass-dependent chemistry before accretion of the first planetesimals.

A 15N-poor isotopic composition for the solar system as shown by Genesis solar wind samples.

The Genesis mission sampled solar wind ions to document the elemental and isotopic compositions of the Sun and, by inference, of the protosolar nebula. Nitrogen was a key target element because the extent and origin of its isotopic variations in solar system materials remain unknown. Isotopic analysis of a Genesis Solar Wind Concentrator target material shows that implanted solar wind nitrogen has a (15)N/(14)N ratio of 2.18 ± 0.02 × 10(-3) (that is, ≈40% poorer in (15)N relative to terrestrial atmosphere). The (15)N/(14)N ratio of the protosolar nebula was 2.27 ± 0.03 × 10(-3), which is the lowest (15)N/(14)N ratio known for solar system objects. This result demonstrates the extreme nitrogen isotopic heterogeneity of the nascent solar system and accounts for the (15)N-depleted components observed in solar system reservoirs.

Identification of a selective nonpeptide antagonist of the anaphylatoxin C3a receptor that demonstrates antiinflammatory activity in animal models.

The anaphylatoxin C3a is a potent chemotactic peptide and inflammatory mediator released during complement activation which binds to and activates a G-protein-coupled receptor. Molecular cloning of the C3aR has facilitated studies to identify nonpeptide antagonists of the C3aR. A chemical lead that selectively inhibited the C3aR in a high throughput screen was identified and chemically optimized. The resulting antagonist, N(2)-[(2,2-diphenylethoxy)acetyl]-L-arginine (SB 290157), functioned as a competitive antagonist of (125)I-C3a radioligand binding to rat basophilic leukemia (RBL)-2H3 cells expressing the human C3aR (RBL-C3aR), with an IC(50) of 200 nM. SB 290157 was a functional antagonist, blocking C3a-induced C3aR internalization in a concentration-dependent manner and C3a-induced Ca(2+) mobilization in RBL-C3aR cells and human neutrophils with IC(50)s of 27.7 and 28 nM, respectively. SB 290157 was selective for the C3aR in that it did not antagonize the C5aR or six other chemotactic G protein-coupled receptors. Functional antagonism was not solely limited to the human C3aR; SB 290157 also inhibited C3a-induced Ca(2+) mobilization of RBL-2H3 cells expressing the mouse and guinea pig C3aRS: It potently inhibited C3a-mediated ATP release from guinea pig platelets and inhibited C3a-induced potentiation of the contractile response to field stimulation of perfused rat caudal artery. Furthermore, in animal models, SB 290157, inhibited neutrophil recruitment in a guinea pig LPS-induced airway neutrophilia model and decreased paw edema in a rat adjuvant-induced arthritis model. This selective antagonist may be useful to define the physiological and pathophysiological roles of the C3aR.

Discovery of potent and selective phenylalanine derived CCR3 antagonists. Part 1.

The discovery of a series of phenylalanine derived CCR3 antagonists is reported. Parallel, solution-phase library synthesis has been utilized to delineate the structure-activity relationship leading to the synthesis of highly potent, CCR3-selective antagonists.

Identification of potent, selective non-peptide CC chemokine receptor-3 antagonist that inhibits eotaxin-, eotaxin-2-, and monocyte chemotactic protein-4-induced eosinophil migration.

Eosinophils have been implicated in the pathogenesis of asthma and other allergic diseases. Several CC chemokines including eotaxin (CCL-11), eotaxin-2 (CCL-24), RANTES (CCL-5), and monocyte chemotactic protein-3 (MCP-3, CCL-7) and 4 (MCP-4, CCL-13) are potent eosinophil chemotactic and activating peptides acting through CC chemokine receptor-3 (CCR3). Thus, antagonism of CCR3 could have a therapeutic role in asthma and other eosinophil-mediated diseases. A high throughput, cellular functional screen was configured using RBL-2H3 cells stably expressing CCR3 (RBL-2H3-CCR3) to identify non-peptide receptor antagonists. A small molecule CCR3 antagonist was identified, SK&F 45523, and chemical optimization led to the generation of a number of highly potent, selective CCR3 antagonists including SB-297006 and SB-328437. These compounds were further characterized in vitro and demonstrated high affinity, competitive inhibition of (125)I-eotaxin and (125)I-MCP-4 binding to human eosinophils. The compounds were potent inhibitors of eotaxin- and MCP-4-induced Ca(2+) mobilization in RBL-2H3-CCR3 cells and eosinophils. Additionally, SB-328437 inhibited eosinophil chemotaxis induced by three ligands that activate CCR3 with similar potencies. Selectivity was affirmed using a panel of 10 seven-transmembrane receptors. This is the first description of a non-peptide CCR3 antagonist, which should be useful in further elucidating the pathophysiological role of CCR3 in allergic inflammatory diseases.

Identification of a potent, selective non-peptide CXCR2 antagonist that inhibits interleukin-8-induced neutrophil migration.

Interleukin-8 (IL-8) and closely related Glu-Leu-Arg (ELR) containing CXC chemokines, including growth-related oncogene (GRO)alpha, GRObeta, GROgamma, and epithelial cell-derived neutrophil-activating peptide-78 (ENA-78), are potent neutrophil chemotactic and activating peptides, which are proposed to be major mediators of inflammation. IL-8 activates neutrophils by binding to two distinct seven-transmembrane (7-TMR) G-protein coupled receptors CXCR1 (IL-8RA) and CXCR2 (IL-8RB), while GROalpha, GRObeta, GROgamma, and ENA-78 bind to and activate only CXCR2. A chemical lead, which selectively inhibited CXCR2 was discovered by high throughput screening and chemically optimized. SB 225002 (N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea) is the first reported potent and selective non-peptide inhibitor of a chemokine receptor. It is an antagonist of 125I-IL-8 binding to CXCR2 with an IC50 = 22 nM. SB 225002 showed >150-fold selectivity over CXCR1 and four other 7-TMRs tested. In vitro, SB 225002 potently inhibited human and rabbit neutrophil chemotaxis induced by both IL-8 and GROalpha. In vivo, SB 225002 selectively blocked IL-8-induced neutrophil margination in rabbits. The present findings suggest that CXCR2 is responsible for neutrophil chemotaxis and margination induced by IL-8. This selective antagonist will be a useful tool compound to define the role of CXCR2 in inflammatory diseases where neutrophils play a major role.

Molecular cloning and characterization of the human anaphylatoxin C3a receptor.

In a human neutrophil cDNA library, an orphan G-protein-coupled receptor, HNFAG09, with 37% nucleotide identity to the C5a receptor (C5a-R, CD88) was identified. A novel feature of this gene, unlike C5a-R and other G-protein-coupled receptors, is the presence of an extraordinarily large predicted extracellular loop comprised of in excess of 160 amino acid residues between transmembrane domains 4 and 5. Northern blot analysis revealed that expression of mRNA for this receptor in human tissues, while similar, was distinct from C5a-R expression. Although there were differences in expression, transcripts for both receptors were detected in tissues throughout the body and the central nervous system. Mammalian cells stably expressing HNFAG09 specifically bound 125I-C3a and responded to a C3a carboxyl-terminal analogue synthetic peptide and to human C3a but not to rC5a with a robust calcium mobilization response. HNFAG09 encodes the human anaphylatoxin C3a receptor.

Design and evaluation of small peptides mapping the exposed surface of IL-8.

In an effort to determine which regions of IL-8 are involved in interactions with its receptors, eight peptides were designed to correspond to distinct exposed regions of the IL-8 monomer, using the proton NMR-derived structure of the dimer as a basis. The peptides were evaluated singularly, and as equimolar mixtures of two to six peptides, in an IL-8 receptor binding assay and found to have no binding interaction with either alpha or beta IL-8 receptor as single peptides or mixtures of two peptides. In contrast, one of these peptides having the sequence AVLPRSAKEL, which corresponds to the N-terminal 10 amino acid residues of the 77 amino acid form of IL-8, exhibited potent chemotactic activity in human neutrophils. These results indicate that there is no contiguous ligand that can be designed based on the NMR and X-ray determined structure of IL-8 and that there may be multiple receptors responsible for neutrophil activation and chemotaxis.

Reduced dose OKT3 prophylaxis in sensitised kidney recipients.

Prophylactic use of the monoclonal antibody OKT3 has been studied for the prevention of rejection in sensitised renal transplant recipients. Patients receiving a full dose (FD) regimen were compared to a subsequent consecutive group of patients receiving a reduced dose (RD) regimen. The characteristics of the two groups were not significantly different with regard to age, HLA mismatch and panel-reactive antibody (PRA) status. The number of days that OKT3 was given was 12.9 +/- 1.8 for the FD regimen and 11.3 +/- 2.8 for the RD regimen. The total dose of OKT3 given was 64.4 +/- 9 mg (FD) and 38.3 +/- 8.5 mg (RD). Patient survival at 12 months was 8/8 for FD and 17/17 for RD. Graft survival at 12 months was 7/8 for FD and 17/17 for RD. Creatinine at 24 months was 185 +/- 68 and 201 +/- 81 mumol/l for FD and RD, respectively. A reduced dose regimen of OKT3 produced excellent and comparable results to the standard recommended full-dose regimen. The cost per patient was reduced 40% from 5676 pounds for FD to 3344 pounds for RD.

Partial Melting of the Aliende (CV3) Meteorite: Implications for Origins of Basaltic Meteorites.

Eucrites and angrites are distinct types of basaltic meteorites whose origins are poorly known. Experiments in which samples of the Allende (CV3) carbonaceous chondrite were partially melted indicate that partial melts can resemble either eucrites or angrites, depending only on the oxygen fugacity (fo(2)). Melts are eucritic if thefo(2) is below that of the iron-wüstite buffer or angritic if above the fo(2) of that buffer. With changing pressure, the graphite-oxygen redox reaction can produce oxygen fugacities that are above or below those of the iron-wüstite buffer. Therefore, a single, homogeneous, carbonaceous planetoid >110 kilometers in radius could produce melts of drastically different composition, depending on the depth of melting.