External Reproducibility Research Articles

1059P - PD-L1 Detection and Assay Performance in Squamous Cell Carcinoma of the Head and Neck Using PD-L1 IHC 28-8 pharmDx

Background: Detecting PD-L1 protein expression by immunohistochemistry has shown to be effective in identifying patients who may benefit from treatment with PD-1 targeted immune checkpoint inhibitors. The PD-L1 IHC 28-8 pharmDx assay has been applied in formalin-fixed, paraffin-embedded (FFPE) squamous cell carcinoma of the head and neck (SCCHN) tissues for measuring PD-L1 expression and its associated treatment effect with nivolumab. Assay performance results of PD-L1 IHC 28-8 pharmDx in SCCHN, including validation in external reproducibility, are described. Methods: Antigen retrieval was conducted on Dako PT Link and automated staining was performed with Autostainer Link 48 platform using the PD-L1 IHC 28-8 pharmDx protocol, per instructions for use. The PD-L1 staining was assessed by tumor proportion score to report the percentage of PD-L1 expression in invasive SCCHN. Assay performance was validated at the ≥ 1% expression level on commercially procured FFPE SCCHN specimens. Results: PD-L1 expression was measured on 236 unique specimens originating from squamous cell carcinoma of the tongue, tonsil, nasopharynx, oropharynx, hypopharynx, and larynx. The assay demonstrated acceptable sensitivity and reported a large range of PD-L1 expression from 0 to 95% positive tumor cells and 0 to 3+ staining intensity. Acceptable correlation was observed between primary and metastatic specimens and between “sister” blocks from the same patient. Validation of assay precision and robustness (to target retrieval solution pH, target retrieval solution temperature, target retrieval time, and cut section thickness) demonstrated agreement estimates above 97.5% with the lower bound of two-sided 95 percent confidence intervals at 95% or higher. When tested in external sites, intra- and inter-site reproducibility, and intra- and inter-observer agreements were estimated above 94% with the lower bound of two-sided 95 percent confidence intervals at 88% or higher. Stability of PD-L1 staining in aged cut sections demonstrated interim stability at 4 months with ongoing evaluation. Conclusions: PD-L1 IHC 28-8 pharmDx has shown to be reproducible and robust in detecting PD-L1 expression in FFPE human SCCHN specimens using the Autostainer Link 48. Legal entity responsible for the study: Agilent Technologies, Inc. Funding: Agilent Technologies, Inc. and Bristol Myers Squibb Disclosure: S. Alvarez: Currently employed by a for-profit health care company, Agilent Technologies. Own stock in a for-profit health care company, Agilent Technologies. J. Chan, C. Felten: Employed, leader for, and has ownership in Gemini Diagnostics. Paid consultant for Agilent Technologies. J. William: Employed by a diagnostic laboratory, Neogenomics. Was in a paid consulting role for Agilent Technologies in the last 2 years. D.A. Hanks: Employed and holds leadership for Premier Pathology Laboratories, Inc. Employed by Agilent Technologies, Inc. Holds intellectual property relating to health and medicine in the last 2 years while working with Agilent Technologies. A. Northrup: Employed by Agilent Technologies and owns stock in Agilent technologies. Has been reimbursed for travel, accommodations, or other expenses by Agilent Technologies in the last 2 years. D. Jaiswal, M. Jansson, T. Phillips: Employed by Agilent technologies. And own stock in Agilent Technologies. A. Segal: Was employed by Agilent Technologies and owns stock in Agilent Technologies. I. Satnick, H. Little, B. Wynne, C. Pierce: Employed by Agilent Technologies. H. McDonald: Employed by Agilent Technologies. Was employed by Baster/Baxalta/Shire in the last two years. Owns stock in Shire, Inc. J. Carnahan: Employed by Agilent Technologies. Was employed by Agensys in the past 2 years and received research funding and paid travel expenses from Agensys. Owns stock in Amgen. S.Y. Reddy: Employed by Agilent and owns stock in Agilent Technologies. H.D. Inzunza: Was employed by Bristol-Myers Squibb and is employed by Halozyme. E. Oroudjev: Employed by Agilent Technologies. Is in leadership role for Agilent Technologies. Owns stock in Agilent Technologies.

Determination of Hf–Sr–Nd isotopic ratios by MC-ICP-MS using rapid acid digestion after flux-free fusion in geological materials

In this study, we established a rapid acid digestion for determining Hf–Sr–Nd isotopic ratios of geological samples by using MC-ICP-MS. Conditions of 1600 °C for 1 min and 1400 °C for 1 min were adopted for fusing intrusive rocks and extrusive rocks, respectively. The rapid acid digestion technique is superior in digestion time compared with high-pressure PTFE bomb method. The procedural blanks of the method were also lower than that flux fusion. Replicate analyses of international certified reference materials (CRMs) indicate that isotopic ratios of 176Hf/177Hf, 87Sr/86Sr and 143Nd/144Nd agree well with previously published data. The external reproducibility (2SD, n = 5) of ten CRMs are ±0.000030 for 87Sr/86Sr, ±0.000030 for 143Nd/144Nd, and ±0.000018 for 176Hf/177Hf.

A method for Se isotope analysis of low ng-level geological samples via double spike and hydride generation MC-ICP-MS

The isotopic signature of the chalcophile, redox-sensitive and moderately volatile element Se in geological materials may offer valuable new insights into the origin and evolution of volatiles in planetary systems. Here, we report a new method for Se isotope determination of low Se containing samples relevant to the Earth's mantle reservoir. We present a method that combines a double spike and hydride generation sample introduction system with a ThermoFisher Scientific® NeptunePlus™ MC-ICP-MS. The measurement routine takes advantage of methane injection in the instrument source during measurement, resulting in enhanced Se signals and suppression of polyatomic interferences. Purification of Se from natural samples was simplified by employing conventional ion exchange chromatography procedures. An external reproducibility of 0.15‰ (2σ) on δ82/76Se values for measurements performed on natural samples with Se abundances down to ~5ng is obtained. We demonstrate that our technique allows the determination of Se isotope signatures of low Se-bearing geological materials with complex matrices such as mafic igneous rocks, which is essential to extend the Se isotopic investigation to Se-depleted planetary reservoirs such as the Earth's mantle.

Tracing metal–silicate segregation and late veneer in the Earth and the ureilite parent body with palladium stable isotopes

Stable isotope studies of highly siderophile elements (HSE) have the potential to yield valuable insights into a range of geological processes. In particular, the strong partitioning of these elements into metal over silicates may lead to stable isotope fractionation during metal–silicate segregation, making them sensitive tracers of planetary differentiation processes. We present the first techniques for the precise determination of palladium stable isotopes by MC-ICPMS using a 106Pd–110Pd double-spike to correct for instrumental mass fractionation. Results are expressed as the per mil (‰) difference in the 106Pd/105Pd ratio (δ106Pd) relative to an in-house solution standard (Pd_IPGP) in the absence of a certified Pd isotopic standard. Repeated analyses of the Pd isotopic composition of the chondrite Allende demonstrate the external reproducibility of the technique of ±0.032‰ on δ106Pd. Using these techniques, we have analysed Pd stable isotopes from a range of terrestrial and extraterrestrial samples. We find that chondrites define a mean δ106Pdchondrite=−0.19±0.05‰. Ureilites reveal a weak trend towards heavier δ106Pd with decreasing Pd content, similar to recent findings based on Pt stable isotopes (Creech et al., 2017), although fractionation of Pd isotopes is significantly less than for Pt, possibly related to its weaker metal–silicate partitioning behaviour and the limited field shift effect. Terrestrial mantle samples have a mean δ106Pdmantle=−0.182±0.130‰, which is consistent with a late-veneer of chondritic material after core formation.

A multiple ion counter total evaporation (MICTE) method for precise analysis of plutonium by thermal ionization mass spectrometry

This paper presents a total evaporation method for the analysis of sub-picogram quantities of Pu, utilizing an array of multiple ion counters. Data from three standards are presented to assess the utility of the technique. An external precision of 1.5% RSD (2σ) was achieved on aliquots approaching 100 fg for the minor 240Pu isotope. Accurate analysis of <1 femtogram of 240Pu, is achievable, with an external reproducibility of better than 10% RSD (2σ). This new technique represents a significant advance in the total evaporation method and will allow routine measurement of femtogram sized Pu samples by thermal ionization mass spectrometry.

Tin stable isotope analysis of geological materials by double-spike MC-ICPMS

Tin is a volatile as well as chalcophile and siderophile element, and this geochemical behaviour gives rise to a broad range of potential applications for Sn as a stable isotope tracer in geological processes. We present the first high-precision method to analyse the stable isotopic composition of Sn in geological materials using ion-exchange chromatography and double-spike multi-collector inductively-coupled-plasma mass-spectrometry (MC-ICPMS). We apply these methods to analyse the Sn stable isotopic composition of four geological reference materials, including a number of replicate digestions of BHVO-2 and BCR-2 to assess the reproducibility of the technique. Tin was purified prior to analysis using TRU resin to remove matrix and interfering elements. Isotopic ratios were measured using a Thermo-Fischer Neptune Plus MC-ICPMS combined with a 117Sn–122Sn double-spike to correct for any mass dependent fractionation resulting from instrumental mass bias or incomplete yields from chemical purification. Results are expressed in delta notation as δ122/118Sn, representing the per mil (‰) difference in the 122/118Sn ratio of the sample relative to our in-house standard Sn_IPGP. Based on replicate analyses of the USGS reference materials BHVO-2 and BCR-2, we estimate the external reproducibility to be ca. ± 0.065‰ (2 sd) on the δ122/118Sn ratio, or ca. ± 0.016‰ per amu. Analyses of these plus two additional USGS reference materials, AGV-2 and GSP-2, show a large range (>0.2‰ on δ122/118Sn) of Sn stable isotopic compositions that are correlated with igneous differentiation indicators (e.g. SiO2 content), indicating that Sn isotopes are fractionated during igneous processes. These results indicate significant potential for Sn stable isotopes as a tracer of magmatic differentiation and the redox state of the mantle. In addition, Sn stable isotopes may prove useful in tracing diverse geological processes such as volatilisation/condensation and metal–silicate/metal–sulphide differentiation.

Overcoming Peak Overlaps in Titanium- and Vanadium-Bearing Materials with Multiple Linear Least Squares Fitting.

The evolution of the energy dispersive spectrometer (EDS) from the lithium-drifted silicon detector [Si(Li)] to the silicon drift detector (SDD) has created new opportunities in the field of electron probe X-ray microanalysis. The SDD permits operation at significantly higher count rates than the Si(Li) and also provides a more stable energy scale. X-ray spectra captured by EDS can now be analyzed qualitatively or quantitatively under the same beam conditions as used for wavelength dispersive spectrometry (WDS). Standards-based quantitative EDS (SB-Quant-EDS) can thus provide analyses that are accurate and precise for an ever growing number of materials measurement problems. In this study, we analyze NIST research glasses with "known" nominal concentrations of titanium (Ti) and vanadium (V) to evaluate the external reproducibility of the SB-Quant-EDS technique in the presence of severe peak overlaps. We additionally analyze several naturally occurring oxide minerals by WDS and EDS simultaneously and evaluate the outputs of these two methods when quantifying the same analytical volume within the sample.

Lead isotopes in deep-sea coral skeletons: Ground-truthing and a first deglacial Southern Ocean record

Past changes in seawater lead (Pb) isotopes record the temporal evolution of anthropogenic pollution, continental weathering inputs, and ocean current transport. To advance our ability to reconstruct this signature, we present methodological developments that allow us to make precise and accurate Pb isotope measurements on deep-sea coral aragonite, and apply our approach to generate the first Pb isotope record for the glacial to deglacial mid-depth Southern Ocean.Our refined methodology includes a two-step anion exchange chemistry procedure and measurement using a 207Pb–204Pb double spike on a Thermo Finnigan Triton TIMS instrument. By employing a 1012Ω resistor (in place of a 1011Ω resistor) to measure the low-abundance 204Pb ion beam, we improve the internal precision on 206,207,208Pb/204Pb for a 2ng load of NIST-SRM-981 Pb from typically ∼420ppm to ∼230ppm (2 s.e.), and the long term external reproducibility from ∼950ppm to ∼550ppm (2 s.d.). Furthermore, for a typical 500mg coral sample with low Pb concentrations (∼6–10ppb yielding ∼3–5ngPb for analysis), we obtain a comparable internal precision of ∼150–250ppm for 206,207,208Pb/204Pb, indicating a good sensitivity for tracing natural Pb sources to the oceans. Successful extraction of a seawater signal from deep-sea coral aragonite further relies on careful physical and chemical cleaning steps, which are necessary to remove anthropogenic Pb contaminants and obtain results that are consistent with ferromanganese crusts.Applying our approach to a collection of late glacial and deglacial corals (∼12–40kaBP) from south of Tasmania at ∼1.4–1.7km water depth, we generated the first intermediate water Pb isotope record from the Southern Ocean. That record reveals millennial timescale variability, controlled by binary mixing between two Pb sources, but no distinct glacial-interglacial Pb isotope shift. Mixing between natural endmembers is fully consistent with our data and points to a persistence of the same Pb sources through time, although we cannot rule out a minor influence from recent anthropogenic Pb. Whereas neodymium (Nd) isotopes in the Southern Ocean respond to global ocean circulation changes between glacial and interglacial periods, Pb isotopes record more localised mixing within the Antarctic Circumpolar Current, potentially further modulated by climate through changing terrestrial inputs from southern Africa or Australia. Such decoupling between Pb and Nd isotopes in the Southern Ocean highlights their potential to provide complementary insights into past oceanographic variability.Keywords: Southern Ocean; Tasmania; Deglaciation; Climate change; Ocean circulation; Weathering; Isotope tracers; Pb isotopes; Deep-sea corals

The gallium isotopic composition of the bulk silicate Earth

We report a new method for precise analysis of gallium (Ga) isotopic composition in geological samples. The purification of Ga is achieved by a three-step ion exchange chromatography to remove matrix and interfering elements. The 71Ga/69Ga ratios are analyzed by multi-collector inductively-coupled-plasma mass-spectrometer (MC-ICP-MS). The external reproducibility of the measurements (0.05‰, 2 s.d.) was assessed by replicate analyses of the USGS BCR-2 and BHVO-2 standards. This newly developed technique was then used to investigate the extent of Ga isotopic fractionation during igneous processes by analyzing well-characterized samples from the Kilauea Iki lava lake, USA. These samples were formed in a closed system and have MgO contents ranging from 26.9 to 2.4wt.%. We found that igneous processes do not fractionate Ga isotopes within the analytical uncertainty and that the Ga isotopic composition of mafic-ultramafic lavas can be used to estimate the composition of their mantle source. Twelve ocean island basalts, two mid-ocean-ridge basalts, one continental flood basalt and one komatiite have homogeneous and nearly identical Ga isotopic compositions within analytical uncertainties averaging 0.00±0.06‰ (2s.d.). This value represents the best estimate for the Ga isotopic composition of the bulk silicate Earth

Direct lead isotope analysis in Hg-rich sulfides by LA-MC-ICP-MS with a gas exchange device and matrix-matched calibration

In situ Pb isotope data of sulfide samples measured by LA-MC-ICP-MS provide valuable geochemical information for studies of the origin and evolution of ore deposits. However, the severe isobaric interference of 204Hg on 204Pb and the lack of matrix-matched sulfide reference materials limit the precision of Pb isotopic analyses for Hg-rich sulfides. In this study, we observe that Hg forms vapor and can be completely removed from sample aerosol particles produced by laser ablation using a gas exchange device. Additionally, this device does not influence the signal intensities of Pb isotopes. The within-run precision, the external reproducibility and the analytical accuracy are significantly improved for the Hg-rich sulfide samples using this mercury-vapor-removing device. Matrix effects are observed when using silicate glass reference materials as the external standards to assess the relationship of mass fractionation factors between Tl and Pb in sulfide samples, resulting in a maximum deviation of ∼0.20% for 20xPb/204Pb. Matrix-matched reference materials are therefore required for the highly precise and accurate Pb isotope analyses of sulfide samples. We investigated two sulfide samples, MASS-1 (the Unites States Geological Survey reference materials) and Sph-HYLM (a natural sphalerite), as potential candidates. Repeated analyses of the two proposed sulfide reference materials by LA-MC-ICP-MS yield good external reproducibility of <0.04% (RSD, k = 2) for 20xPb/206Pb and <0.06% (RSD, k = 2) for 20xPb/204Pb with the exception of 20xPb/204Pb in MASS-1, which provided an external reproducibility of 0.24% (RSD, k = 2). Because the concentration of Pb in MASS-1 (76 μg g−1) is ∼5.2 times lower than that in Sph-HYLM (394 ± 264 μg g−1). The in situ analytical results of MASS-1 and Sph-HYLM are consistent with the values obtained by solution MC-ICP-MS, demonstrating the reliability and robustness of our analytical protocol.

High-precision molybdenum isotope analysis by negative thermal ionization mass spectrometry

Procedures for the separation, purification, and high-precision analysis of mass-independent isotopic variations in molybdenum (Mo) using negative thermal ionization mass spectrometry are reported. Separation and purification of Mo from silicate and metal matrices are achieved using a two-stage anion exchange chromatographic procedure. Molybdenum is ionized as the MoO3− species using a double filament assembly. The MoO3− ion beams are collected using Faraday cup detectors equipped with a mixed array of amplifiers utilizing 1011 and 1012Ω resistors, which allows for in situ measurement and correction of oxygen isobars. The long-term external reproducibility of 97Mo/96Mo, the most precisely measured Mo isotope ratio, is ±5.4ppm (2SD), based on the repeated analyses of the Alfa Aesar Specpure® Mo plasma standard and using 98Mo/96Mo for fractionation correction. The long-term external reproducibilities of 92Mo/96Mo, 94Mo/96Mo, 95Mo/96Mo, and 100Mo/96Mo are ±107, 37, 23, and 32ppm (2SD), respectively. With this precision, smaller differences in Mo isotopic compositions can be resolved than have been previously possible.

Precise titanium isotope compositions of refractory inclusions in the Allende CV3 chondrite by LA-MC-ICPMS

We present here analyses of mass-independent effects in the Ti isotope ratios of 17 coarse-grained (compact Type A and Type B) calcium–aluminum-rich inclusions (CAIs) from the Allende CV3 chondrite utilizing a method developed for rapid measurement of Ti isotopes by laser ablation multi-collector inductively coupled plasma mass spectrometry (LA-MC-ICPMS). Based on the analyses of the synthetic CMAS glasses doped with varying amounts of Ca, Cr and V, an empirical scheme for correction of potential isobaric interferences and matrix effects was developed. Using this scheme, mass-independent variations of the Ti isotope ratios 46Ti/47Ti, 48Ti/47Ti and 50Ti/47Ti were measured with external reproducibilities (2SD) of ±0.4, ±0.5, and ±1.8 for ε46Ti, ε48Ti, and ε50Ti, respectively, based on repeat measurements of standard glasses. The Ti isotope compositions of the 17 Allende refractory inclusions analyzed here show that most of these CAIs are “normal” with limited variation in their mass-independent Ti isotope composition. One CAI (designated as CMS-1) has a significantly larger mass-independent ε50Ti anomaly and is identified as having Fractionation and Unidentified Nuclear (FUN) effects. The limited range in the Ti isotope compositions of normal CAIs (ε50Ti excesses ranging from 2.9 to 11.4) suggests that they originated from a nebular reservoir that was relatively well-mixed, although not completely homogenized (at the level of precision of the analyses reported here), in its isotopic composition. The distinctive isotopic composition of the FUN CAI CMS-1 indicates that it formed from a reservoir in the protoplanetary disk that was spatially or temporally distinct from that from which the normal CAIs were formed.

Refinement of high precision Ru isotope analysis using negative thermal ionization mass spectrometry

A refined method for the isolation, purification, and high precision measurement of Ru isotope compositions in natural samples by negative thermal ionization mass spectrometry (N-TIMS) is reported. After chemical purification of Ru using ion exchange chromatography and microdistillation techniques, the Ru isotopic composition is measured as RuO3− via N-TIMS. Data are corrected for oxide interferences using the simultaneously measured oxygen isotope composition, and subsequently for mass fractionation using an exponential law. Repeat analyses of an Alfa Aesar Ru standard solution demonstrate external reproducibility of 100Ru/101Ru to ±6.4ppm (2SD). This level of precision is more than two times better than prior techniques. Repeat analyses of gravimetrically prepared mixtures of a natural Alfa Aesar Ru standard and a 100Ru enriched spike show that isotopic differences of ≥13ppm can be resolved by single measurements of a material using this method. Repeat analyses of diverse terrestrial materials (chromitites and Os-Ir-Ru alloys) are characterized by compositions that are identical to the Alfa Aesar standard, and the external reproducibility for these materials is also identical to that of the chemically pure standard, demonstrating that chemical separation/purification methods introduce no bias to the analysis. These materials likely define the Ru isotopic composition of the Earth's mantle.

High-Precision Tungsten Isotopic Analysis by Multicollection Negative Thermal Ionization Mass Spectrometry Based on Simultaneous Measurement of W and 18O/16O Isotope Ratios for Accurate Fractionation Correction

Determination of the (182)W/(184)W ratio to a precision of ± 5 ppm (2σ) is desirable for constraining the timing of core formation and other early planetary differentiation processes. However, WO3(-) analysis by negative thermal ionization mass spectrometry normally results in a residual correlation between the instrumental-mass-fractionation-corrected (182)W/(184)W and (183)W/(184)W ratios that is attributed to mass-dependent variability of O isotopes over the course of an analysis and between different analyses. A second-order correction using the (183)W/(184)W ratio relies on the assumption that this ratio is constant in nature. This may prove invalid, as has already been realized for other isotope systems. The present study utilizes simultaneous monitoring of the (18)O/(16)O and W isotope ratios to correct oxide interferences on a per-integration basis and thus avoid the need for a double normalization of W isotopes. After normalization of W isotope ratios to a pair of W isotopes, following the exponential law, no residual W-O isotope correlation is observed. However, there is a nonideal mass bias residual correlation between (182)W/(i)W and (183)W/(i)W with time. Without double normalization of W isotopes and on the basis of three or four duplicate analyses, the external reproducibility per session of (182)W/(184)W and (183)W/(184)W normalized to (186)W/(183)W is 5-6 ppm (2σ, 1-3 μg loads). The combined uncertainty per session is less than 4 ppm for (183)W/(184)W and less than 6 ppm for (182)W/(184)W (2σm) for loads between 3000 and 50 ng.

High-precision zircon U/Pb geochronology by ID-TIMS using new 1013 ohm resistors

Accessory mineral U–Pb geochronology by isotope dilution thermal ionization mass spectrometry (ID-TIMS) requires precise and accurate determinations of parent–daughter isotope ratios.

Can one find External Source Input Expressions for which there exist Map Reduce Configurations?

An intention of MapReduce Sets for External Source Input expressions analysis has to suggest criteria how External Source Input expressions in External Source Input data can be defined in a meaningful way and how they should be compared. Similitude based MapReduce Sets for External Source Input Expression Analysis and MapReduce Sets for Assignment is expected to adhere to fundamental principles of the scientific External Source Input process that are expressiveness of External Source Input models and reproducibility of their External Source Input inference. External Source Input expressions are assumed to be elements of a External Source Input expression space or Conjecture class and External Source Input data provide “information” which of these External Source Input expressions should be used to interpret the External Source Input data. An inference External Source Input algorithm constructs the mapping between External Source Input data and External Source Input expressions, in particular by a External Source Input cost minimization process. Fluctuations in the External Source Input data often limit the External Source Input precision, which we can achieve to uniquely identify a single External Source Input expression as interpretation of the External Source Input data. We advocate an information theoretic perspective on External Source Input expression analysis to resolve this dilemma where the tradeoff between External Source Input informativeness of statistical inference External Source Input and their External Source Input stability is mirrored in the information-theoretic External Source Input optimum of high External Source Input information rate and zero communication expression error. The inference External Source Input algorithm is considered as an outlier object External Source Input path, which naturally limits the resolution of the External Source Input expression space given the uncertainty of the External Source Input data.

Determination of cupric ion concentrations in marine waters: an improved procedure and comparison with other speciation methods

Environmental context A Cu ion-selective electrode is potentially an excellent tool for cupric ion measurements in salt water, but it is prone to poor reproducibility. We show that dramatic improvements can be obtained by using a Cu ion-selective electrode and a one-point calibration method that corrects for electrode fouling. The method shows promise to be used to collect data on toxic cupric ion concentrations in saltwater environments. Abstract Free Cu is often used as an indicator for potential Cu toxicity. Free ionic Cu2+ was measured using a flow-through ion-selective electrode (ISE). Four different marine samples were collected from various locations and analysed during a fixed-pH Cu titration using an external standard calibration ISE method. Free cupric determinations in the range 10–12 to 10–7molL–1 were consistent with published literature but replicate measures showed up to four orders of magnitude variability. To improve reproducibility, an internal calibration method was developed. The new method was validated using artificial seawater with added tryptophan as the model ligand. The free Cu measured using the improved method showed the same trends as the external calibration data but reproducibility increased to an order of magnitude or better. The potential applicability of this new method was also highlighted in that it matches, in the environmentally and regulatory significant range of total Cu, with a fluorescence quenching method applied to one of the four samples. The ISE data do not agree with free ion concentrations estimated from anodic stripping voltammetry (ASV) though. This suggests that, at least for these samples, ASV responded to a larger fraction of total Cu than simply the inorganic complexes. Caution should be exercised when using ASV as a proxy for bioavailability because the trends in ASV-derived free Cu did not match the free Cu as estimated by ISE. This ability to more reliably measure free Cu is significant for predicting and measuring toxicity on Cu exposure.

A new global database of δ98Mo in molybdenites: A literature review and new data

Isotopic compositions of Mo in molybdenites were used for deciphering a possible genetic link between isotopic variations and mineralizing processes, based on a worldwide molybdenite databank. We compared the δ98/95Mo (hereafter referred as δ98MoNIST) of 391 molybdenite samples (193 from the literature, 198 for this study) from different localities, different types of occurrences and different ages. The 198 molybdenite samples we analysed represent various types of mineralization in 6 granites, 11 pegmatites, 6 perigranitic veins, 2 greisen, 28 porphyry deposits, 5 skarns, 1 IOCG, and 9 Alpine-type fissure veins, with ages varying from 5Ma to 2.7Ga. The Mo isotopic composition was determined with an MC-ICP-MS Neptune after aqua regia dissolution and adjustment to [Mo]=1μg·ml−1. Mass bias was corrected by using Zr as dopant and standard-sample-standard bracketing. The δ98MoNIST ratios were normalized to NIST3134. External reproducibility is 0.07‰ (2σ). The overall range of the δ98MoNIST ratio in the 391 molybdenite samples varied from −1.62 to 2.27‰, being higher for molybdenite formed in Alpine-type veins, greisen, perigranitic veins and IOCG, than for that in granite, pegmatite, porphyry deposits and skarns. The crystallization temperature can explain some of these differences, as polymetallic Alpine-type fissure veins broadly crystallize at lower temperatures than granite, pegmatite and porphyry deposits. For some occurrences the δ98MoNIST was determined on several molybdenite samples, showing variability at occurrence scale. For example, in the Azegour skarn (Morocco) the δ98MoNIST varies from −0.60 to 0.42‰ (n=29), and in “Ravin de la Ruine” Alpine-type fissure veins (France) the variation is from −0.08 to 0.77‰ (n=3). No correlation is seen between δ98MoNIST and the age of the deposits.

Characterization of Randomized External Source Output Map Reduce Expressions

intention of MapReduce Sets for External Source Output expressions analysis has to suggest criteria how External Source Output expressions in External Source Output data can be defined in a meaningful way and how they should be compared. Similitude based MapReduce Sets for External Source Output Expression Analysis and MapReduce Sets for Assignment is expected to adhere to fundamental principles of the scientific External Source Output process that are expressiveness of External Source Output models and reproducibility of their External Source Output inference. External Source Output expressions are assumed to be elements of a External Source Output expression space or Conjecture class and External Source Output data provide which of these External Source Output expressions should be used to interpret the External Source Output data. An inference External Source Output algorithm constructs the mapping between External Source Output data and External Source Output expressions, in particular by a External Source Output cost minimization process. Fluctuations in the External Source Output data often limit the External Source Output precision, which we can achieve to uniquely identify a single External Source Output expression as interpretation of the External Source Output data. We advocate an information theoretic perspective on External Source Output expression analysis to resolve this dilemma where the tradeoff between External Source Output informativeness of statistical inference External Source Output and their External Source Output stability is mirrored in the information-theoretic External Source Output optimum of high External Source Output information rate and zero communication expression error. The inference External Source Output algorithm is considered as an outlier object External Source Output path, which naturally limits the resolution of the External Source Output expression space given the uncertainty of the External Source Output data. KeywordsExternal Source Output expressions, kernel function.

In situ lithium and boron isotope determinations in mica, pyroxene, and serpentine by LA-MC-ICP-MS

Boron and Li are light, incompatible elements that preferentially partition into the liquid phase, whether melt or aqueous fluid, and thus are useful for tracking fluid-related processes in rocks. Most of the Li isotopic data presently available on subduction-related rocks are from whole-rock analyses; and the B isotopic analyses of subduction material have been carried out either on whole-rocks or in-situ on an accessory phase, such as tourmaline. The new method presented here couples an ESI New Wave UP-193-FX ArF* (193nm) excimer laser-ablation microscope with a Neptune Plus (Thermo Scientific) MC-ICP-MS aiming to measure both Li and B isotopes in situ with good spatial resolution (metamorphic minerals are commonly chemically zoned, and whole-rock analyses lose this detail). The data thus obtained are compared with SIMS analyses on the same mineral samples for B, and with MC-ICP-MS analyses on whole-rock or mineral separates from the same sample for Li. Additionally, data acquired on tourmaline standards were compared to SIMS values. The results show that for B concentrations above 5μg/g, the data obtained by LA-MC-ICP-MS and by SIMS are identical within error, for mica (phengitic muscovite), pyroxene (jadeite), serpentine (antigorite), and tourmaline. For Li concentrations above 10μg/g, the data obtained by LA-MC-ICP-MS and by MC-ICP-MS are also identical, within error, for mica (phengitic muscovite), and pyroxene (jadeite). However, analyses of tourmaline standards have shown significant differences with reference values, so LA-MC-ICP-MS does not yet appear to be an appropriate method to analyze Li isotopes in tourmalines. Thus, LA-MC-ICP-MS is a suitable method to measure Li and B isotopes with good spatial resolution in major rock-forming silicates from subduction-related rocks where concentrations exceed 10μg/g and 5μg/g, respectively, with an error on individual measurements equal to or less than previously used methods, but obtainable in a significantly shorter amount of time. The external reproducibility is ±2.88 to 3.31‰ for B and ±1.50 to 1.75‰ for Li, which is lower than or equal to the variations encountered within a given chemically zoned sample (up to 10‰ of variation within a given natural sample).