Subduction zone magmatism is a major control of volcanism, the generation of modern continental crust and the formation of economically important porphyry Cu-(Mo-Au) deposits. Reading the magmatic record of individual arc segments and constraining the rates of magmatic changes are critical in order to fully understand and quantify the processes that drive magma evolution in subduction settings during arc growth. This study focuses on the San Francisco Batholith and the Rio Blanco-Los Bronces porphyry deposit cluster in central Chile, which provides an igneous rock record over similar to 13.5 Myr of arc evolution. We use whole-rock geochemistry, zircon geochronology and Hf isotope geochemistry to track changes in the crustal magmatic system of this arc segment during crustal thickening and porphyry Cu deposit formation. By combining the analytical dataset with Monte Carlo fractional crystallisation and assimilation fractional crystallisation modelling, we test a model for significant crustal involvement during magma evolution. Systematic and continuous increases in Dy/Yb, La/Yb, V/Sc and Sr/Y in the magmas over time indicate a transition in the main fractionation assemblage from plagioclase-dominated to amphibole-dominated that reflects deeper crystallisation and/or a higher meltwater content. Concomitant decreases in epsilon Hf and Th/La as well as increasing Ba/Th are best explained by assimilation of progressively deeper crustal lithologies from low (Chilenia) to high Ba/Th (Cuyania) basement terranes. Our study highlights that an increasingly hydrous magma and a deepening locus of crustal magma differentiation and assimilation, driven by crustal thickening contemporaneous with increased tectonic convergence and ingression of the aseismic Juan Fernandez ridge, can account for all investigated aspects of the multi-Myr magmatic evolution leading up to the formation of the Rio Blanco-Los Bronces porphyry Cu deposits. Our findings corroborate the importance of high-pressure differentiation of hydrous magma for the formation of Andean-style porphyry deposits. Once magmas favourable for porphyry Cu mineralisation were generated in the lower crust, multiple episodes of efficient magma migration into the upper crust fed several, discrete, shallow magmatic-hydrothermal systems over similar to 3.5 Myr to form the world's largest known Cu resource at Rio Blanco-Los Bronces.

Volatile saturation influences the physicochemical behavior of magmas and is essential for the sequestration of metals in porphyry copper deposits. Tracking the evolution of volatile components (F, Cl, H2O, S) in arc systems is complicated by their mobility and tendency to rapidly re-equilibrate with late-stage melts. We demonstrate that accurate measurements of volatile concentrations in apatite offer a reliable method for identifying the occurrence of volatile saturation. Fluorine, Cl, S, and calculated OH concentrations in apatite obtained by scanning electron microscope-energy-dispersive X-ray spectroscopy and electron microprobe analysis were used to compare two end-member volcanic systems in the West Luzon Arc (Philippines): Pinatubo (a fluid-saturated analogue for porphyry copper deposits) and Taal (a barren and fluid-undersaturated comparator). Apatites from Pinatubo are S-rich (0.04-0.64 wt%) and show a progressive decrease in X-Cl/X-OH (0.6-0.25) and an increase in X-F/X-Cl (1.5-8) and X-F/X-OH (0.75-1.2) during crystallization. Modeling indicates that these changes result from efficient partitioning of Cl into a continuously saturated H2O-rich fluid, while high regions of S in apatite reflect episodic flushing by a separate S-rich flux. Little S is evident in apatites from Taal (<300 ppm), which show increasing X-Cl/X-OH and X-F/X-OH together with constant X-F/X-Cl during crystallization. This cannot be explained using an H2O-saturated model, and instead reflects fluid-undersaturated crystallization and cooling in a reduced and/or S-depleted system. Measured volatiles in apatite therefore effectively discriminate volatile-saturated and undersaturated magmatic systems, providing an important 'fertility' filter for porphyry exploration.

The Ratagain Complex is an enigmatic Late Caledonian granitic intrusion and a member of the high Ba-Sr Northern Highlands granite (NHG) suite that has been related to slab failure. Slab failure magmatism explains varying contributions of mafic and felsic magmas in post-collision orogenic settings. It is therefore of major importance in understanding crustal accretion. However, the source and nature of any mantle derived contri-bution is poorly understood. This study reveals that Ratagain is not only transitional in nature between the high Ba-Sr calc-alkaline granites and syenite intrusions of the Northern Highlands Terrane, but overlaps with the entire compositional range of the NHG suite. New lithogeochemical data from Ratagain confirm remarkably high Sr (>1600 ppm) and Ba (>2200 ppm) contents, high LREEs, notable depletions in Nb, U, P and Ti, low HREEs and negligible Eu anomalies, associated with high initial 87Sr/86Sr (0.7055 to 0.7062) and low epsilon Nd (-11.8 to-13.3). Although mafic parts of the complex have strong elemental and isotopic similarities with broadly coeval lamprophyres, signalling derivation from enriched mantle sources, details of the isotope array with respect to local crustal reservoirs indicate a significant Lewisian component. Such geochemical characteristics, combined with tectonic and petrological evidence, may be attributable to long-lived, incremental emplacement of suc-cessive magma batches originating from the same enriched mantle but differing in age and extent of assimilation -fractionation crystallisation. We therefore propose that some of the age dates for the Late Caledonian intrusions, particularly those obtained from older geochronology studies, are in need of review as they may record early crystallisation in the deep crust and not be a valid proxy for granite emplacement.

Magmatic Ni-Cu-platinum group element (PGE) deposits are commonly located in tectonically active regions that typically undergo significant deformation and metamorphism and subsequent reworking of sulfide. The Munali Ni deposit is hosted by a dynamic intrusive mafic-ultramafic system situated within the Zambezi belt in southern Zambia. The deposit comprises Fe-Ni–dominant magmatic sulfides, present as a number of lenticular massive sulfide bodies that display a variety of magmatic and metamorphic sulfide textures. The sulfide lenses are uniformly deficient in iridium subgroup PGEs (IPGEs), Au, and Cu, with unusual but characteristically high bulk Ni/Cu ratios (~10) and a consistent precious metal mineral assemblage dominated by Pd and Pt tellurides. On a centimeter to meter scale, Cu tenors and Ni/Cu ratios are extremely variable (Ni/Cu between 0.1 and 71.5), while Ni and Pd tenors are consistent, indicative of the high mobility and variable concentrations of Cu sulfide within the deposit. Sulfur isotope signatures of the ore sulfides (δ34S ~6‰; Δ33S ~0‰) indicate a local crustal S contaminant from host marbles yet display S/Se ratios suggestive of a postmagmatic overprint. The consistent geochemical similarities of the bulk sulfide throughout the complex and the absence of primary silicate-sulfide textures suggest that the Munali ores were not sourced from a parental magma directly represented by units within the complex. Instead, it is suggested that the sulfide liquid was introduced from elsewhere in the magmatic system during the later stages of the emplacement of the complex. Fractional crystallization of the sulfide liquid during emplacement resulted in the primary segregation of a Cu-rich residual liquid that migrated away from the bulk of the Fe-Ni sulfide, accounting for the high bulk Ni/Cu ratio, with the potential for the accumulation of a separate and thus far undiscovered Cu orebody. In addition, intense deformation during the Pan-African orogeny and interaction with hydrothermal fluids have locally overprinted some of the primary magmatic textures, resulting in localized sulfide mobilization and the extreme variations of Ni/Cu ratio between sulfide samples. Munali therefore represents a complex dynamic deposit showcasing a variety of mechanisms for sulfide fractionation of an Ni-Cu-PGE orebody by both syn- and postmagmatic processes.

Magmatic arcs are terrestrial environments where lithospheric cycling and recycling of metals and volatiles is enhanced. However, the first-order mechanism permitting the episodic fluxing of these elements from the mantle through to the outer Earth’s spheres has been elusive. To address this knowledge gap, we focus on the textural and minero-chemical characteristics of metal-rich magmatic sulfides hosted in amphibole-olivine-pyroxene cumulates in the lowermost crust. We show that in cumulates that were subject to increasing temperature due to prolonged mafic magmatism, which only occurs episodically during the complex evolution of any magmatic arc, Cu-Au-rich sulfide can exist as liquid while Ni-Fe rich sulfide occurs as a solid phase. This scenario occurs within a ‘Goldilocks’ temperature zone at ~1100–1200 °C, typical of the base of the crust in arcs, which permits episodic fractionation and mobilisation of Cu-Au-rich sulfide liquid into permeable melt networks that may ascend through the lithosphere providing metals for porphyry and epithermal ore deposits.

Advanced computational techniques and mathematical modeling have become more and more important to the study of cardiac electrophysiology. In this review, we provide a brief history of the evolution of cardiomyocyte electrophysiology models and highlight some of the most important ones that had a major impact on our understanding of the electrical activity of the myocardium and associated transmembrane ion fluxes in normal and pathological states. We also present the use of these models in the study of various arrhythmogenesis mechanisms, particularly the integration of experimental pharmacology data into advanced humanized models for in silico proarrhythmogenic risk prediction as an essential component of the Comprehensive in vitro Proarrhythmia Assay (CiPA) drug safety paradigm.

Chloroquine and hydroxychloroquine have been proposed recently as therapy for SARS-CoV-2-infected patients, but during 3 months of extensive use concerns were raised related to their clinical effectiveness and arrhythmogenic risk. Therefore, we estimated for these compounds several proarrhythmogenic risk predictors according to the Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm. Experiments were performed with either CytoPatch™2 automated or manual patch-clamp setups on HEK293T cells stably or transiently transfected with hERG1, hNav1.5, hKir2.1, hKv7.1+hMinK, and on Pluricyte® cardiomyocytes (Ncardia), using physiological solutions. Dose-response plots of hERG1 inhibition fitted with Hill functions yielded IC50 values in the low micromolar range for both compounds. We found hyperpolarizing shifts of tens of mV, larger for chloroquine, in the voltage-dependent activation but not inactivation, as well as a voltage-dependent block of hERG current, larger at positive potentials. We also found inhibitory effects on peak and late INa and on IK1, with IC50 of tens of μM and larger for chloroquine. The two compounds, tested on Pluricyte® cardiomyocytes using the β-escin-perforated method, inhibited IKr, ICaL, INa peak, but had no effect on If. In current-clamp they caused action potential prolongation. Our data and those from literature for Ito were used to compute proarrhythmogenic risk predictors Bnet (Mistry HB, 2018) and Qnet (Dutta S et al., 2017), with hERG1 blocking/unblocking rates estimated from time constants of fractional block. Although the two antimalarials are successfully used in autoimmune diseases, and chloroquine may be effective in atrial fibrillation, assays place these drugs in the intermediate proarrhythmogenic risk group.

Super-eruptions are amongst the most extreme events to affect Earth's surface, but too few examples are known to assess their global role in crustal processes and environmental impact. We demonstrate a robust approach to recognize them at one of the best-preserved intraplate large igneous provinces, leading to the discovery of two new super-eruptions. Each generated huge and unusually hot pyroclastic density currents that sterilized extensive tracts of Idaho and Nevada in the United States. The ca. 8.99 Ma McMullen Creek eruption was magnitude 8.6, larger than the last two major eruptions at Yellowstone (Wyoming). Its volume exceeds 1700 km(3), covering >= 12,000 km(2). The ca. 8.72 Ma Grey's Landing eruption was even larger, at magnitude of 8.8 and volume of >= 2800 km(3). It covers >= 23,000 km(2) and is the largest and hottest documented eruption from the Yellowstone hotspot. The discoveries show the effectiveness of distinguishing and tracing vast deposit sheets by combining trace-element chemistry and mineral compositions with field and paleomagnetic characterization. This approach should lead to more discoveries and size estimates, here and at other provinces. It has increased the number of known super-eruptions from the Yellowstone hotspot, shows that the temporal framework of the magmatic province needs revision, and suggests that the hotspot may be waning.

The comprehensive in vitro pro-arrhythmia assay (CiPA) in silico working group developed a computational assay for proarrhythmogenic risk prediction based on numeric integration runs of the O'Hara-Rudy 2011 human ventricular cardiomyocyte mathematical model (with default parameters for subendocardial cardiomyocytes), including a Markov model for hERG channels (human ether-à-go-go related gene) that conduct the rapid delayed rectifier K+ current IKr (named ORd-IKr dynamic model, Li et al. 2017 Circ Arrhythm Electrophysiol. 10(2):e004628). A subsequent study (Dutta et al. 2017 Front Physiol. 8:616) used the ORd-IKr dynamic model with pharmacological inhibition data for a panel of 12 drugs with low, intermediate, and high proarrhythmogenic risk to assess the effectiveness of multiple proarrhythmogenic risk predictors based on action potential (AP) and intracellular calcium dynamics during AP, as well as the newly defined predictors cQinward and Qnet, concluding that Qnet represents the most reliable predictor. We reproduced these simulations for the 12-compound panel based on published pharmacological inhibition data using the ORd model with default parameters for midmyocardial cardiomyocytes. Using the classical (Hodgkin-Huxley-type) IKr model we found good predictability of early afterdepolarizations (EADs) development (their detection can be itself a good predictor), while with the Markov IKr model no EADs were detected in the range 1-25x Cmax (maximal therapeutic plasma concentration), except for dofetilide. Therefore we modified the hERG blocking and unblocking rates for cisapride, quinidine, terfenadine and bepridil according to our own experimental pharmacology results in whole-cell patch-clamp experiments on HEK293 cells stably transfected with hERG1, applying an onset-of-block kinetics analysis of the currents recorded with a simplified Milnes protocol with 10-s depolarizing steps to 0 mV repeated at 35-s intervals, obtaining direct EAD generation for all these compounds with the ORd-IKr dynamic model.

The 'fertility' of arc magmas to form porphyry Cu-Au deposits in the upper crust is dependant on a number of processes occurring within the source-pathway-sink framework of the evolution of any particular magmatic system. One of the first barriers to fertility is the so-called 'sulfide trap' whereby sulfides in lower crustal cumulates will sequester metals such as Cu and Au, thus rendering any subsequent upper crustal melts infertile. Textural evidence from the Ivrea zone in Italy, alongside numerical modelling for lower crustal cumulate complexes, shows that although sulfides may be present in these rocks, they are not necessarily a 'trap' as such. Instead, the typical temperatures of these systems allows for incongruent melting and potentially mobilization of Cu-Au sulfide associated with melt networks within these cumulate intrusions. This allows for a mechanism whereby partially molten Cu-Au-rich sulfide can be fractionated from solid Ni-Fe-rich sulfide, which could potentially be mobilized into the upper crust and ultimately supply metals to form porphyry-fertile intrusions.

Enhancing our understanding of the processes that lead to the formation of fertile magmas is key to the identification of robust new fertility proxies indicative of porphyry Cu deposits. Once the essential magmatic and hydrothermal processes have been identified, their resulting characteristic geochemical signatures can provide a fast and cost-efficient mean to distinguish between potentially fertile or barren igneous suites. We aim to utilise whole rock and mineral chemistry data from the spatially extensive intrusive suite that hosts the Rio Blanco-Los Bronces deposit cluster to reconstruct the magmatic evolution leading up to the formation of Earth's largest known porphyry Cu system. The associated intrusive complex was emplaced over more than 10 My of barren and ultimately fertile magmatism, making it an ideal site to develop and test fertility indicators. Temporally resolved whole-rock data reveals the composite nature of the intrusive complex suggested incremental assembly from potentially different source magmas. Next steps include the application integrated accessory mineral petrochronology to reconstruct processes such as emplacement rates and the injection of mafic melts. The influence of these factors on the fertility of the system will be evaluated and potentially useful geochemical signatures in pristine magmatic accessory minerals will be identified.

INTRODUCTION:The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative proposes a three-step approach to evaluate proarrhythmogenic liability of drug candidates: effects on individual ion channels in heterologous expression systems, integrating these data into in-silico models of the electrical activity of human cardiomyocytes, and comparison with experiments on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Here we introduce patch-clamp electrophysiology techniques on hiPSC-CM to combine two of the CiPA steps in one assay. METHODS:We performed automated patch-clamp experiments on hiPSC-CM (Cor.4U®, Ncardia) using the CytoPatch™2 platform in ruptured whole-cell and β-escin-perforated-patch configurations. A combination of three voltage-clamp protocols allowed recording of five distinct ion current components (voltage-gated Na+ current, L-type Ca2+ current, transient outward K+ current, delayed rectifier K+ current, and "funny" hyperpolarization-activated current) from the same cell. We proved their molecular identity by either Na+ replacement with choline or by applying specific blockers: nifedipine, cisapride, chromanol 293B, phrixotoxin-1, ZD7288. We developed a C++ script for automated analysis of voltage-clamp recordings and computation of ion current/conductance surface density for these five cardiac ion currents. RESULTS:The distributions from n = 54 hiPSC-CM in "ruptured" patch-clamp vs. n = 35 hiPSC-CM in β-escin-perforated patch-clamp were similar for membrane capacitance, access resistance, and ion current/conductance surface densities. The β-escin-perforated configuration resulted in improved stability of action potential (AP) shape and duration over a 10-min interval, with APD90 decay rate 0.7 ± 1.6%/min (mean ± SD, n = 4) vs. 4.6 ± 1.1%/min. (n = 3) for "ruptured" approach (p = 0.0286, one-tailed Mann-Whitney test). DISCUSSION:The improved stability obtained here will allow development of CiPA-compliant automated patch-clamp assays on hiPSC-CM. Future applications include the study of multi ion-channel blocking properties of drugs using dynamic-clamp protocols, adding a valuable new tool to the arsenal of safety-pharmacology.

The lupin alkaloid sparteine is a well-known chiral diamine with a range of applications in asymmetric synthesis, as well as a blocker of voltage-gated sodium channels (VGSCs). However, there is only scarce information on the VGSC-blocking activity of sparteine derivatives where the structure of the parent alkaloid is retained. Building on the recent renewed availability of sparteine and derivatives we report herein how modification of sparteine at position2 produces irreversible blockers of VGSCs. These compounds could be clinically envisaged as long-lasting local anesthetics.

In this paper, we present paleomagnetic, geochemical, mineralogical, and geochronologic evidence for correlation of the mid‐Miocene Cougar Point Tuff (CPT) in southwest Snake River Plain (SRP) of Idaho. The new stratigraphy presented here significantly reduces the frequency and increases the scale of known SRP ignimbrite eruptions. The CPT section exposed at the Black Rock Escarpment along the Bruneau River has been correlated eastward to the Brown's Bench escarpment (six common eruption units) and Cassia Mountains (three common eruption units) regions of southern Idaho. The CPT records an unusual pattern of geomagnetic field directions that provides the basis for robust stratigraphic correlations. Paleomagnetic characterization of eruption units based on geomagnetic field variation has a resolution on the order of a few centuries, providing a strong test of whether two deposits could have been emplaced from the same eruption or from temporally separate events. To obtain reliable paleomagnetic directions, the anisotropy of anhysteretic remanence was measured to correct for magnetic anisotropy, and an efficient new method was used to remove gyroremanence acquired during alternating field demagnetization.