Measurements of rhenium isotopic composition in low-abundance samples

Rhenium (Re) is a trace element whose redox chemistry makes it an ideal candidate to trace a range of geochemical processes. In particular, fractionation of its isotopes 187Re (62.6% abundance) and 185Re (37.4%) may be used to improve our understanding of redox reactions during weathering, both in the modern day and in geological archives. Published methods for measurement of Re isotopic composition are limited by the requirements of Re mass to reach a desirable precision, making the analysis of many geological materials unfeasible at present. Here we develop new methods which allow us to measure Re isotope ratios (reported as δ187Re) with improved precision: ±0.10‰ (2σ) for a mass of Re of ∼1 ng to ±0.03‰ (2σ) for a mass of Re of >10 ng. This is possible due to the combination of a modified column chemistry procedure and the use of 1013 Ω amplifiers for measurement via multicollector inductively coupled plasma mass spectrometry (MC-ICP-MS). For river water samples (with Re concentrations typically ∼10−12 g g−1) we design a field-based pre-concentration of Re that can be used with large volumes of filtered water (5–20 L) shortly after sample collection to provide abundant Re for isotope analysis. As a result of these developments we provide new measurements of δ187Re in standards reference materials (δ187Re values range from −0.06 ± 0.07‰ to +0.19 ± 0.05‰) and a seawater standard (δ187Re = +0.10 ± 0.04‰), providing impetus for further exploration of the Re isotope system

Integrated Petrological and Fe-Zn Isotopic Modelling of Plutonic Differentiation

The upper continental crust is formed from chemically diverse granitic plutons. Active debate surrounds the range of physical conditions (P-T-X-fO2) and differentiation processes which occur in mush bodies that solidify to form plutons. Transition metal stable isotopes are increasingly employed to trace magmatic processes in both extrusive lavas and intrusive plutonic suites, with a focus on analysis of whole rock powders. However, studies of plutonic suites often overlook the complex textures represented within coarse grained samples, and how these will influence whole rock isotopic compositions. Here we examine the calc-alkaline Boggy Plain Zoned Pluton, SE Australia, which closely approximates closed system behaviour during magmatic differentiation. We combine petrological examination with Fe and Zn isotopic analysis of biotite, hornblende and magnetite mineral separates and whole rock powders. Whole rock Fe isotopic composition (as δ56Fe) increases from 0.038‰ to 0.171‰ with decreasing MgO content, while mineral separates display heavy Fe isotope enrichment in the order magnetite > biotite = hornblende > pyroxene. A lack of correlation between whole rock Fe and Zn isotopic compositions suggests that the Fe isotopic variation is predominantly driven by closed system fractional crystallisation: specifically by the balance between crystallisation of isotopically heavy magnetite, and isotopically light silicates. To demonstrate this quantitatively, temperature dependent mineral-melt fractionation factors were derived from the mineral separate data (Δ56Femag-melt = 0.17x106/T2 and Δ56Febt/hbd-melt = -0.12x106/T2) and used to construct models that successfully reproduce the observed Fe isotopic variation during fractional crystallisation. These fractionation factors are compared to theoretical and empirical estimates from previous studies. We highlight that accurate determinations of temperature and modal mineralogy are critical when modelling Fe isotopic variations in plutonic suites. Successful interpretation of equilibrium Fe isotopic fractionation in a relatively simple calc-alkaline suite like the Boggy Plain Zoned Pluton paves the way for Fe isotopes to be used to investigate more complex mush bodies

Weathering fluxes and sediment provenance on the SW Scottish shelf during the last deglaciation

The reconstruction of past ice sheet dynamics can shed a light on long-term ice stream activity, and in turn provide constraints on the response of modern ice sheets to climate change. The Hebrides Ice Stream (HIS) flowed across part of the western Scottish shelf to the shelf-break during the last glacial cycle and drained a large portion of the northern sector of the British Irish-Ice Sheet. To investigate the deglacial dynamics of the HIS following the Last Glacial Maximum, lead (Pb) isotope records were extracted from the FeMn oxyhydroxide and detrital fractions of recovered laminated glacimarine mud sequences to monitor the changing activity of HIS during its retreat. These provide timing and some source information of glacially weathered inputs to the marine environment. The FeMn oxyhydroxide fraction in the samples is dominated by allochthonous particles (pre-formed) and shows a marked decrease from radiogenic (≤ 20.05 206Pb/204Pb) at ~ 21 cal ka BP to less radiogenic Pb isotope compositions (~ 19.48) towards the Windermere Interstadial (15.4–13 ka). This decrease represents a reduction in the flux of subglacially-derived radiogenic Pb to the continental shelf is interpreted as being associated with the break-up of the ice-stream in western Scotland around that time. The Pb, Sr and Nd isotopic signatures of the detrital fraction indicate a preponderance of Moine-sourced fine sediments (originated from the NW Highlands) in the core locations from ~ 21 to 15 cal ka BP (Dimlington Stadial - Windermere Interstadial), most likely dictated by the orientation of ice flow, tidal and oceanic current directions and sediment delivery. In contrast, ice rafted debris in a ~ 21 cal ka BP old basal diamicton contains volcanic-derived material, suggesting different provenance for different grain sizes. The FeMn oxyhydroxide 208Pb/204Pb ratio shows an unusual inversion relative to the other Pb isotope ratios, and is attributed to the introduction of secondary weathering phases from a source with contrasting 208Pb/204Pb but similar 206Pb/204Pb and 207Pb/204Pb. In the detrital fraction, the inversions are constrained to periodic spikes, which may indicate an increased contribution from a high Th/U source, potentially the neighbouring Archaean amphibolitic Lewisian basement in the Outer Hebrides. This study demonstrates how geochemical investigation on continental shelves can be used to constrain the timing, activity and flow sources of palaeo-ice streams

Vanadium isotope fractionation during plutonic differentiation and implications for the isotopic composition of the upper continental crust

The analysis of emerging stable isotopic systems in clastic sedimentary rocks is increasingly used to determine the average composition of the upper continental crust through geological time. Any temporal variations can then be linked to global-scale processes such as the oxygenation of the atmosphere or onset of plate tectonics. Given that clastic sediments are ultimately eroded from the upper continental crust, knowledge of the potential isotopic variability in the plutonic rocks which make up the crust is vital for interpreting these sedimentary records. Here we focus on the multi-valent transition metal element vanadium (V) and present the first investigation of the V isotopic composition of an upper crustal granitic pluton and its mineral separates. We use well-characterised samples from the calc-alkaline Boggy Plain Zoned Pluton, Australia. Whole rock samples and mineral separates show increases in δ51V during magmatic differentiation, similar to what has been documented for extrusive differentiation suites. However, whole rock δ51V is scattered, reflecting variations in the modal mineralogy and demonstrating the typical heterogeneity generated when dealing with coarse grained igneous rocks. In contrast, mineral separates show well-defined trends in δ51V, where mineral-melt fractionation factors are largely controlled by bonding environment rather than direct redox variations. We interpret the increase in δ51V during magmatic differentiation to be driven by crystallisation of isotopically light magnetite, biotite and hornblende, in contrast with previous interpretations from extrusive lavas that oxide crystallisation alone is the main driver of V isotopic fractionation. The overall range of whole rock samples and their mineral separates is > 0.6 ‰ within this single plutonic body. The range highlights that the upper continental crust can have extremely heterogeneous V isotopic composition over small geographic areas. This detailed examination of V isotopes in a simple system may shed light on the discrepancy between interpretations of the timing of felsic crust formation derived from the V and Ti isotopic compositions of glacial diamictites

The status of the world's land and marine mammals: diversity, threat, and knowledge

Knowledge of mammalian diversity is still surprisingly disparate, both regionally and taxonomically. Here, we present a comprehensive assessment of the conservation status and distribution of the world's mammals. Data, compiled by 1700+ experts, cover all 5487 species, including marine mammals. Global macroecological patterns are very different for land and marine species but suggest common mechanisms driving diversity and endemism across systems. Compared with land species, threat levels are higher among marine mammals, driven by different processes (accidental mortality and pollution, rather than habitat loss), and are spatially distinct (peaking in northern oceans, rather than in Southeast Asia). Marine mammals are also disproportionately poorly known. These data are made freely available to support further scientific developments and conservation action

Patient-derived xenograft (PDX) models in basic and translational breast cancer research

Patient-derived xenograft (PDX) models of a growing spectrum of cancers are rapidly supplanting long-established traditional cell lines as preferred models for conducting basic and translational preclinical research. In breast cancer, to complement the now curated collection of approximately 45 long-established human breast cancer cell lines, a newly formed consortium of academic laboratories, currently from Europe, Australia, and North America, herein summarizes data on over 500 stably transplantable PDX models representing all three clinical subtypes of breast cancer (ER+, HER2+, and "Triple-negative" (TNBC)). Many of these models are well-characterized with respect to genomic, transcriptomic, and proteomic features, metastatic behavior, and treatment response to a variety of standard-of-care and experimental therapeutics. These stably transplantable PDX lines are generally available for dissemination to laboratories conducting translational research, and contact information for each collection is provided. This review summarizes current experiences related to PDX generation across participating groups, efforts to develop data standards for annotation and dissemination of patient clinical information that does not compromise patient privacy, efforts to develop complementary data standards for annotation of PDX characteristics and biology, and progress toward "credentialing" of PDX models as surrogates to represent individual patients for use in preclinical and co-clinical translational research. In addition, this review highlights important unresolved questions, as well as current limitations, that have hampered more efficient generation of PDX lines and more rapid adoption of PDX use in translational breast cancer research

Re-Os isotope characteristics of postorogenic lavas: Implications for the nature of young lithospheric mantle and its contribution to basaltic magmas

Re-Os isotopes have been measured on postorogenic potassic lavas from the Tibetan Plateau, the Betic domain of southeastern Spain, and the Colorado Plateau of the southwestern United States. Previous work has established that these lavas were all derived from parts of the subcontinental lithospheric mantle that had undergone metasomatic enrichment in incompatible elements, following various degrees of melt depletion. Cratonic depleted subcontinental lithospheric mantle peridotites typically have subchondritic 187Os/188Os; however, the postorogenic lavas are characterized by radiogenic 187Os/188Os ratios (0.139-0.559). Simple modeling shows that only very large degrees of melt depletion (>25-30) can lower source Re/Os ratios sufficiently to permit time-integrated development of subchondritic 187Os/188Os ratios. Such processes may have been largely restricted to the older Precambrian, and the peridotite component of the postorogenic lavas source was probably depleted by <25. The more radiogenic values may reflect increasing contributions from metasomatic components or possibly crustal contamination. Our findings imply the need for caution in the use of Os isotopes as a diagnostic tracer of subcontinental lithospheric mantle contributions to lavas erupted through younger Proterozoic and Phanerozoic lithosphere

Titanium stable isotope investigation of magmatic processes on the Earth and Moon

We present titanium stable isotope measurements of terrestrial magmatic samples and lunar mare basalts with the aims of constraining the composition of the lunar and terrestrial mantles and evaluating the potential of Ti stable isotopes for understanding magmatic processes. Relative to the OL–Ti isotope standard, the δ49Ti values of terrestrial samples vary from −0.05 to +0.55‰, whereas those of lunar mare basalts vary from −0.01 to +0.03‰ (the precisions of the double spike Ti isotope measurements are ca. ±0.02‰ at 95% confidence). The Ti stable isotope compositions of differentiated terrestrial magmas define a well-defined positive correlation with SiO2 content, which appears to result from the fractional crystallisation of Ti-bearing oxides with an inferred isotope fractionation factor of View the MathML sourc

Activated platelets in the tumor microenvironment for targeting of antibody-drug conjugates to tumors and metastases

Rationale: Platelets are increasingly recognized as mediators of tumor growth and metastasis. Hypothesizing that activated platelets in the tumor microenvironment provide a targeting epitope for tumor-directed chemotherapy, we developed an antibody-drug conjugate (ADC), comprised of a single-chain antibody (scFv) against the platelet integrin GPIIb/IIIa (scFvGPIIb/IIIa) linked to the potent chemotherapeutic microtubule inhibitor, monomethyl auristatin E (MMAE). Methods: We developed an ADC comprised of three components: 1) A scFv which specifically binds to the high affinity, activated integrin GPIIb/IIIa on activated platelets. 2) A highly potent microtubule inhibitor, monomethyl auristatin E. 3) A drug activation/release mechanism using a linker cleavable by cathepsin B, which we demonstrate to be abundant in the tumor microenvironment. The scFvGPIIb/IIIa-MMAE was first conjugated with Cyanine7 for in vivo imaging. The therapeutic efficacy of the scFvGPIIb/IIIa-MMAE was then tested in a mouse metastasis model of triple negative breast cancer. Results: In vitro studies confirmed that this ADC specifically binds to activated GPIIb/IIIa, and cathepsin B-mediated drug release/activation resulted in tumor cytotoxicity. In vivo fluorescence imaging demonstrated that the newly generated ADC localized to primary tumors and metastases in a mouse xenograft model of triple negative breast cancer, a difficult to treat tumor for which a selective tumor-targeting therapy remains to be clinically established. Importantly, we demonstrated that the scFvGPIIb/IIIa-MMAE displays marked efficacy as an anti-cancer agent, reducing tumor growth and preventing metastatic disease, without any discernible toxic effects. Conclusion: Here, we demonstrate the utility of a novel ADC that targets a potent cytotoxic drug to activated platelets and specifically releases the cytotoxic agent within the confines of the tumor. This unique targeting mechanism, specific to the tumor microenvironment, holds promise as a novel therapeutic approach for the treatment of a broad range of primary tumors and metastatic disease, particularly for tumors that lack specific molecular epitopes for drug targeting