In Situ Ti Isotopic Measurements by Laser Ablation MC-ICP-MS

We have been developing Laser Ablation Multi-Collector Inductively Coupled Plasma Mass Spectrometry (MC-ICP-MS) technique to measure titanium isotopic composition in situ. A principal aim of this work is to search for isotopic heterogeneities larger than the few epsilons (e, in parts in 10^4) of the solar system. Our analytical precision of the ratios of 46Ti, 48Ti, and 50Ti to 49Ti after exponential-law mass discrimination correction normalizing 47Ti/49Ti to 1.33375 were about 2.5 £` (2£m). Mixture solutions were prepared by adding the expected level of Ca, Cr, Mg, and Alto the Ti solutions to demonstrate that our interference correction is effective. We then applied our technique with 213 nm Nd-YAG laser ablation to five Ti-rich terrestrial solids, and all of them also showed titanium isotopic composition that was consistent with one an other and agreed with that for the solution standard. It appears that the in situ laser technique did not significantly in crease the long-term reproducibility be yond the 2.5 established using the solution method. This is an order of magnitude better than the typical precision of a few permil for secondary ion mass spectrometry (SIMS). The combination of the ability to perform in situ analysis on 30 mm spots with e level precision is a niche for LA-MC-ICP-MS. We also ablated two lines on a fassaite grain from a large well studied CAI Egg-6 of the Allende meteorite. After the mass discrimination was corrected by normalizing 47Ti/49Ti, the 46Ti and 48Ti are nor mal within about 2 £ while 50Ti/49Ti shows a 9 £ excess. These data are in excellent agreement with thermalion ization mass spectrometry (TIMS) results. Comparing our ICP-MS results against the results from TIMS studies, we found that our normal titanium isotopic ratios were closest to the less precise data of Heydegger et al. (1979) who measured Ti+. We support the proposal to IUPAC to change the accepted Ti abundance to that measured by ICP-MS and TIMS without using Ti oxides

Japanese encephalitis virus induces matrix metalloproteinase-9 expression via a ROS/c-Src/PDGFR/PI3K/Akt/MAPKs-dependent AP-1 pathway in rat brain astrocytes

<p>Abstract</p> <p>Background</p> <p>Japanese encephalitis virus (JEV) infection is a major cause of acute encephalopathy in children, which destroys central nervous system (CNS) cells, including astrocytes and neurons. Matrix metalloproteinase (MMP)-9 has been shown to degrade components of the basal lamina, leading to disruption of the blood-brain barrier (BBB) and to contribute to neuroinflammatory responses in many neurological diseases. However, the detailed mechanisms of JEV-induced MMP-9 expression in rat brain astrocytes (RBA-1 cells) are largely unclear.</p> <p>Methods</p> <p>In this study, the effect of JEV on expression of MMP-9 was determined by gelatin zymography, western blot analysis, RT-PCR, and promoter assay. The involvement of AP-1 (c-Jun and c-Fos), c-Src, PDGFR, PI3K/Akt, and MAPKs in these responses were investigated by using the selective pharmacological inhibitors and transfection with siRNAs.</p> <p>Results</p> <p>Here, we demonstrate that JEV induces expression of pro-form MMP-9 via ROS/c-Src/PDGFR/PI3K/Akt/MAPKs-dependent, AP-1 activation in RBA-1 cells. JEV-induced MMP-9 expression and promoter activity were inhibited by pretreatment with inhibitors of AP-1 (tanshinone), c-Src (PP1), PDGFR (AG1296), and PI3K (LY294002), and by transfection with siRNAs of c-Jun, c-Fos, PDGFR, and Akt. Moreover, JEV-stimulated AP-1 activation was inhibited by pretreatment with the inhibitors of c-Src, PDGFR, PI3K, and MAPKs.</p> <p>Conclusion</p> <p>From these results, we conclude that JEV activates the ROS/c-Src/PDGFR/PI3K/Akt/MAPKs pathway, which in turn triggers AP-1 activation and ultimately induces MMP-9 expression in RBA-1 cells. These findings concerning JEV-induced MMP-9 expression in RBA-1 cells imply that JEV might play an important role in CNS inflammation and diseases.</p

Evolution of the upper mantle of the Earth's Moon: Neodymium and strontium isotopic constraints from high-Ti mare basalts

Isotopic studies of mare basalts have led workers to conclude that their sources are heterogeneous on both large and small scales. Furthermore, these studies have led workers to postulate that depletion within the lunar mantle occurred early in its evolution and was a result of accumulation of mafic minerals from a LREE-enriched magma ocean. High-Ti basalts from the Apollo 11 and 17 landing sites and ilmenite basalts from Apollo 12 are secondary evidence of this extreme, early depletion event. KREEPy rocks are the complementary enriched component in the Moon.A total of fourteen high-Ti basalts have now been analyzed from the Apollo 11 landing site for neodymium and strontium isotopes. A Sm-Nd internal isochron on basalt 10058 yields an age of 3.70 +/- 0.06 Ga, similar to 40Ar/39Ar ages of other Group B1 basalts. A compilation of all previously determined ages on Apollo 11 high-Ti basalts indicates four distinct phases of volcanism at 3.85 +/- 0.02 Ga (Group B2), 3.71 +/- 0.02 Ga (Group B3), 3.67 +/- 0.02 Ga (Group B1), and 3.59 +/- 0.04 Ga (Group A). Wholerock Sm-Nd isotopic data for all Apollo 11 high-Ti basalts form a linear array, which yields the age of the Moon (4.55 +/- 0.30 Ga). A similar regression of all uncontaminated high-Ti basalts from the Moon (both Apollo 11 and Apollo 17) yields an age of 4.46 +/- 0.17 Ga. Both arrays are interpreted as average source ages of the high-Ti basalts and are consistent with the formation of these sources by precipitation of cumulates from a magma ocean early in the history of the Moon.These new strontium and neodymium isotopic data, coupled with previously published data, are consistent with a two component model for the upper mantle of the Moon. These two-components include mafic adcumulates precipitated from a magma ocean prior to 4.4 Ga and small amounts (147Sm/144Nd = 0.318 and 87Rb/86Sr = 0.005 to extremely radiogenic neodymium isotopic ratios and very unradiogenic strontium isotopic ratios. The KREEPy trapped liquid has a 147Sm/144Nd = 0.168 and 87Rb/86Sr = 0.235 and thus, evolves toward very unradiogenic neodymium and radiogenic strontium isotopic ratios. Because the KREEPy trapped liquid is enriched in both rubidium and the REEs by over an order of magnitude compared to the mafic adcumulate, trapping of even small proportions of this liquid in the adcumulate will control the radiogenic isotopic composition of the source. The apparent heterogeneity in the source regions of mare basalts could be caused by trapping of variable, yet small, proportions of this LILE-enriched liquid in the cumulate pile.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31245/1/0000151.pd

A strontium and neodymium isotopic study of Apollo 17 high-Ti mare basalts: Resolution of ages, evolution of magmas, and origins of source heterogeneities

A combined Sr and Nd isotopic study of 15 Apollo 17 high-Ti mare basalts was undertaken to investigate geochronological and compositional differences between previously identified magma types (A, B1, B2, and C). Whole-rock and mineral separates for one of the least-evolved Type B1 basalts, 70139, yield Sm-Nd and Rb-Sr isochron ages of 3.71 +/- 0.12 Ga and 3.65 +/- 0.13 Ga, respectively. A more-evolved, Type A basalt, 71539, exhibits a slightly older Sm-Nd isochron age of 3.75 +/- 0.07 Ga and a Rb-Sr isochron age of 3.67 +/-0.10 Ga. Although these two ages are non-resolvable by themselves, compilation of all available geochronological data allows resolution of Type A and B1/B2 ages at high levels of confidence (&gt;99%). The most reliably dated samples, classified according to their geochemical type, yield weighted average ages of 3.75 +/- 0.02 Ga for Type A (N = 4) and 3.69 +/- 0.02 Ga for Type B1/B2 (N = 3) basalts. Insufficient geochronological data are available to place the rare, Type C basalts within this stratigraphy. We propose that age differences correlate with geochemical magma type, and that early magmatism was dominated by eruption of Type A basalts while later activity was dominated by effusion of Type B1 and B2 basalts.Whole-rock isotopic data yield distinct differences in initial Sr and Nd isotopic compositions between Types A, B1, B2, and C basalts. Types A, B1, and C exhibit restricted intra-group compositional variations and lie along well-defined whole-rock isochrons. These data are consistent with petrogenetic models involving closed-system fractionation of observed microphenocrysts from chemically and isotopically distinct parental magmas. In contrast, a wide range of Type B2 initial isotopic compositions indicates mixing of several distinct components during magma evolution.The Sm-Nd whole-rock isochron age for Type A, Bl, and C basalts of 3.79 +/- 0.15 Ga is within error of Apollo 17 eruptive activity. However, the very well-defined Sr whole-rock isochron age of 4.02 +/- 0.05 Ga is 270 to 330 Ma older than eruptive ages. Isotopic and petrological arguments indicate that extensive Rb/Sr fractionation did not occur at the time of melt generation. Therefore, the 4.0 Ga Sr whole-rock isochron age records a significant event at which time geochemical heterogeneities were established within the originally homogeneous basalt source regions. Types A and C sources were enriched in Rb/Sr, with little or no concurrent modification of 87Sr/86Sr, Sm/Nd, or 143Nd/144Nd. Infiltration of similar-aged KREEP magmas into mantle cumulate sources cannot explain both Sr and Nd isotopic data. Instead, we suggest a metasomatic origin in which Rb, transported as a chloride complex in halogen-rich fluids, was preferentially mobilized relative to Sr and the REEs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29272/1/0000331.pd

Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist

High-resolution spatial and genomic characterization of coral-associated microbial aggregates in the coral Stylophora pistillata

Bacteria commonly form aggregates in a range of coral species [termed coral-associated microbial aggregates (CAMAs)], although these structures remain poorly characterized despite extensive efforts studying the coral microbiome. Here, we comprehensively characterize CAMAs associated with Stylophora pistillata and quantify their cell abundance. Our analysis reveals that multiple Endozoicomonas phylotypes coexist inside a single CAMA. Nanoscale secondary ion mass spectrometry imaging revealed that the Endozoicomonas cells were enriched with phosphorus, with the elemental compositions of CAMAs different from coral tissues and endosymbiotic Symbiodiniaceae, highlighting a role in sequestering and cycling phosphate between coral holobiont partners. Consensus metagenome--assembled genomes of the two dominant Endozoicomonas phylotypes confirmed their metabolic potential for polyphosphate accumulation along with genomic signatures including type VI secretion systems allowing host association. Our findings provide unprecedented insights into Endozoicomonas-dominated CAMAs and the first direct physiological and genomic linked evidence of their biological role in the coral holobiont

Nature of the Earth's earliest crust from hafnium isotopes in single detrital zircons

Continental crust forms from, and thus chemically depletes, the Earth's mantle. Evidence that the Earth's mantle was already chemically depleted by melting before the formation of today's oldest surviving crust has been presented in the form of Sm-Nd isotope studies of 3.8-4.0 billion years old rocks from Greenland(1-5) and Canada(5-7). But this interpretation has been questioned because of the possibility that subsequent perturbations may have re-equilibrated the neodymium-isotope compositions of these rocks(8). Independent and more robust evidence for the origin of the earliest crust and depletion of the Archaean mantle can potentially be provided by hafnium-isotope compositions of zircon, a mineral whose age can be precisely determined by U-Pb dating, and which can survive metamorphisms(4). But the amounts of hafnium in single zircon grains are too small for the isotopic composition to be precisely analysed by conventional methods. Here we report hafnium-isotope data, obtained using the new technique of multiple-collector plasma-source mass spectrometry(9), for 37 individual grains of the oldest known terrestrial zircons (from the Narryer Gneiss Complex, Australia, with U-Pb ages of up to 4.14 Gyr (refs 10-13)). We find that none of the grains has a depleted mantle signature, but that many were derived from a source with a hafnium-isotope composition similar to that of chondritic meteorites. Furthermore, more than half of the analysed grains seem to have formed by remelting of significantly older crust, indicating that crustal preservation and subsequent reworking might have been important processes from earliest times.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62681/1/399252a0.pd

NADPH oxidase-mediated redox signal contributes to lipoteichoic acid-induced MMP-9 upregulation in brain astrocytes

<p>Abstract</p> <p>Background</p> <p>Lipoteichoic acid (LTA) is a component of gram-positive bacterial cell walls and may be elevated in the cerebrospinal fluid of patients suffering from meningitis. Among matrix metalloproteinases (MMPs), MMP-9 has been observed in patients with brain inflammatory diseases and may contribute to the pathology of brain diseases. Moreover, several studies have suggested that increased oxidative stress is implicated in the pathogenesis of brain inflammation and injury. However, the molecular mechanisms underlying LTA-induced redox signal and MMP-9 expression in brain astrocytes remain unclear.</p> <p>Objective</p> <p>Herein we explored whether LTA-induced MMP-9 expression was mediated through redox signals in rat brain astrocytes (RBA-1 cells).</p> <p>Methods</p> <p>Upregulation of MMP-9 by LTA was evaluated by zymographic and RT-PCR analyses. Next, the MMP-9 regulatory pathways were investigated by pretreatment with pharmacological inhibitors or transfection with small interfering RNAs (siRNAs), Western blotting, and chromatin immunoprecipitation (ChIP)-PCR and promoter activity reporter assays. Moreover, we determined the cell functional changes by migration assay.</p> <p>Results</p> <p>These results showed that LTA induced MMP-9 expression via a PKC(α)-dependent pathway. We further demonstrated that PKCα stimulated p47^phox/NADPH oxidase 2 (Nox2)-dependent reactive oxygen species (ROS) generation and then activated the ATF2/AP-1 signals. The activated-ATF2 bound to the AP-1-binding site of MMP-9 promoter, and thereby turned on MMP-9 gene transcription. Additionally, the co-activator p300 also contributed to these responses. Functionally, LTA-induced MMP-9 expression enhanced astrocytic migration.</p> <p>Conclusion</p> <p>These results demonstrated that in RBA-1 cells, activation of ATF2/AP-1 by the PKC(α)-mediated Nox(2)/ROS signals is essential for upregulation of MMP-9 and cell migration enhanced by LTA.</p

Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets