The laurentian record of neoproterozoic glaciation, tectonism, and eukaryotic evolution in Death Vally, California

Neoproterozoic strata in Death Valley, California contain eukaryotic microfossils and glacial deposits that have been used to assess the severity of putative Snowball Earth events and the biological response to extreme environmental change. These successions also contain evidence for syn-sedimentary faulting that has been related to the rifting of Rodinia, and in turn the tectonic context of the onset of Snowball Earth. These interpretations hinge on local geological relationships and both regional and global stratigraphic correlations. Here we present new geological mapping, measured stratigraphic sections, carbon and strontium isotope chemostratigraphy, and micropaleontology from the Neoproterozoic glacial deposits and bounding strata in Death Valley. These new data enable us to refine regional correlations both across Death Valley and throughout Laurentia, and construct a new age model for glaciogenic strata and microfossil assemblages. Particularly, our remapping of the Kingston Peak Formation in the Saddle Peak Hills and near the type locality shows for the first time that glacial deposits of both the Marinoan and Sturtian glaciations can be distinguished in southeastern Death Valley, and that beds containing vase-shaped microfossils are slump blocks derived from the underlying strata. These slump blocks are associated with multiple overlapping unconformities that developed during syn-sedimentary faulting, which is a common feature of Cyrogenian strata along the margin of Laurentia from California to Alaska. With these data, we conclude that all of the microfossils that have been described to date in Neoproterozoic strata of Death Valley predate the glaciations and do not bear on the severity, extent or duration of Neoproterozoic Snowball Earth events

MRD dynamics during maintenance for improved prognostication of 1280 patients with myeloma in the TOURMALINE-MM3 and -MM4 trials

Measurable residual disease (MRD) evaluation may help to guide treatment duration in multiple myeloma (MM). Paradoxically, limited longitudinal data exist on MRD during maintenance. We investigated the prognostic value of MRD dynamics in 1280 transplant-eligible and -ineligible patients from the TOURMALINE-MM3 and -MM4 randomized placebo-controlled phase 3 studies of 2-year ixazomib maintenance. MRD status at randomization showed independent prognostic value (median progression-free survival [PFS], 38.6 vs 15.6 months in MRD− vs MRD+ patients; HR, 0.47). However, MRD dynamics during maintenance provided more detailed risk stratification. A 14-month landmark analysis showed prolonged PFS in patients converting from MRD+ to MRD− status vs those with persistent MRD+ status (76.8% vs 27.6% 2-year PFS rates). Prolonged PFS was observed in patients with sustained MRD− status vs those converting from MRD− to MRD+ status (75.0% vs 34.2% 2-year PFS rates). Similar results were observed at a 28-month landmark analysis. Ixazomib maintenance vs placebo improved PFS in patients who were MRD+ at randomization (median, 18.8 vs 11.6 months; HR, 0.65) or at the 14-month landmark (median, 16.8 vs 10.6 months; HR, 0.65); no difference was observed in patients who were MRD−. This is the largest MM population undergoing yearly MRD evaluation during maintenance reported to date. We demonstrate the limited prognostic value of a single–time point MRD evaluation, because MRD dynamics over time substantially impact PFS risk. These findings support MRD− status as a relevant end point during maintenance and confirm the increased progression risk in patients converting to MRD+ from MRD− status. These trials were registered at www.clinicaltrials.gov as #NCT02181413 and #NCT02312258

A phase 1/2 trial of HQK-1001, an oral fetal globin inducer, in sickle cell disease

Therapeutics which reduce the pathology in sickle cell syndromes are needed, particularly non-cytotoxic therapeutics. Fetal hemoglobin (HbF, α2γ2) is established as a major regulator of disease severity; increased HbF levels correlate with milder clinical courses and improved survival. Accordingly, sodium dimethylbutyrate (HQK-1001), an orally-bioavailable, promoter-targeted fetal globin gene-inducing agent, was evaluated in a randomized, blinded, dose-ranging Phase I/II trial in 24 adult patients with HbSS or S/β thalassemia, to determine safety and tolerability of three escalating dose levels. The study therapeutic was administered once daily for two 6-week cycles, with a 2-week interim dose holiday. Twenty-one patients completed the study. Five patients received study drug at 10 or 20 mg/kg doses, seven patients received study drug at 30 mg/kg/dose, and 4 patients received placebo. HQK-1001 was well-tolerated with no unexpected drug-related adverse events; a dose-limiting toxicity was not identified. Plasma drug levels were sustained above targeted levels for 24 hours. Increases in HbF above baseline were observed particularly with 30 mg/kg/day doses; in five of seven treated patients, a mean absolute increase in HbF of 0.2 g/dl and a mean increase in total hemoglobin (Hgb) of 0.83 g/dl above baseline were observed, whereas no increases occurred in placebo-treated controls. These findings of favorable PK profiles, tolerability, early rises in HbF and total Hgb indicate that trials of longer duration appear warranted to more definitively evaluate the therapeutic potential of HQK-1001 in sickle cell disease

Reaction mechanism for the replacement of calcite by dolomite and siderite: Implications for geochemistry, microstructure and porosity evolution during hydrothermal mineralisation

Carbonate reactions are common in mineral deposits due to CO2-rich mineralising fluids. This study presents the first in-depth, integrated analysis of microstructure and microchemistry of fluid-mediated carbonate reaction textures at hydrothermal conditions. In doing so, we describe the mechanisms by which carbonate phases replace one another, and the implications for the evolution of geochemistry, rock microstructures and porosity. The sample from the 1.95 Moz Junction gold deposit, Western Australia, contains calcite derived from carbonation of a metamorphic amphibole—plagioclase assemblage that has further altered to siderite and dolomite. The calcite is porous and contains iron-rich calcite blebs interpreted to have resulted from fluid-mediated replacement of compositionally heterogeneous amphiboles. The siderite is polycrystalline but nucleates topotactically on the calcite. As a result, the boundaries between adjacent grains are low-angle boundaries (<10°), which are geometrically similar to those formed by crystal–plastic deformation and recovery. Growth zoning within individual siderite grains shows that the low-angle boundaries are growth features and not due to deformation. Low-angle boundaries develop due to the propagation of defects at grain faces and zone boundaries and by impingement of grains that nucleated with small misorientations relative to each other during grain growth.The cores of siderite grains are aligned with the twin planes in the parent calcite crystal showing that the reactant Fe entered the crystal along the twin boundaries. Dolomite grains, many of which appear to in-fill space generated by the siderite replacement, also show alignment of cores along the calcite twin planes, suggesting that they did not grow into space but replaced the calcite. Where dolomite is seen directly replacing calcite, it nucleates on the Fe-rich calcite due to the increased compatibility of the Fe-bearing calcite lattice relative to the pure calcite. Both reactions are interpreted as fluid-mediated replacement reactions which use the crystallography and elemental chemistry of the calcite. Experiments of fluid-mediated replacement reactions show that they proceed much faster than diffusion-based reactions. This is important when considering the rates of reactions relative to fluid flow in mineralising systems

Excess Silica in Omphacite and the Formation of Free Silica in Eclogite

Silica lamellae in eclogitic clinopyroxene are widely interpreted as evidence of exsolution during decompression of eclogite. However, mechanisms other than exsolution might produce free silica, and the possible mechanisms depend in part on the nature and definition of excess silica. ‘Excess’ silica may occur in both stoichiometric and non-stoichiometric pyroxene. Although the issue has been debated, we show that all common definitions of excess silica in non-stoichiometric clinopyroxene are internally consistent, interchangeable, and therefore equivalent. The excess silica content of pyroxene is easily illustrated in a three-component, condensed composition space and may be plotted directly from a structural formula unit or recalculated end-members. In order to evaluate possible mechanisms for the formation of free silica in eclogite, we examined the net-transfer reactions in model eclogites using a Thompson reaction space. We show that there are at least three broad classes of reactions that release free silica in eclogite: (i) vacancy consumption in non-stoichiometric pyroxene; (ii) dissolution of Ti-phases in pyroxene or garnet; (iii) reactions between accessory phases and either pyroxene or garnet. We suggest that reliable interpretation of the significance of silica lamellae in natural clinopyroxene will require the evaluation not only of silica solubility, but also of titanium solubility, and the possible roles of accessory phases and inclusions on the balance of free silica

Microstructural records of multiple retrograde local H2O supplement in the pelitic gneiss, Lützow-Holm Complex at Akarui Point, East Antarctica

The alkali-feldspar and biotite in the sillimanite-biotite-garnet gneiss from East Antarctica preserves characteristic microstructural evidence of multi-stage H2O supplement during the retrograde metamorphism. The first microstructural evidence is the "zoned feldspar, " in which the mesoperthitic zone, the anti-perthitic zone, and lamella-free plagioclase zone coexist within a single crystal. They are occasionally found next to biotite, and are always depleted in orthoclase (Or) component toward the biotite. The formation process of this microstructure could be explained by the diffusion that oversteps the solvus. The second microstructural evidence is the serrate boundary between alkali-feldspar and biotite. The projections of biotite are selectively developed next to Or lamellae of alkali-feldspar every 3–5 μm. These two microstructures would have formed as the biotite grew by consuming potash in alkali-feldspar when H2O-bearing fluid locally passed through the grain boundaries. The former microstructure was formed at 825–900 °C before lamella formation, and the latter microstructure was formed after the lamella formation. These microstructures are the indicators of fluid pathways formed under two different temperature conditions. The common coexistence of these microstructures implies that the fluid used similar pathways during the retrograde metamorphism