Description: The 46-million-ounce Ladolam gold deposit, the largest alkalic epithermal gold deposit in the world in terms of contained gold, is composed of four ore zones: Minifie, Lienetz, Kapit, and Coastal. This detailed lithofacies study of the Minifie ore zone recognized three evolutionary stages: (1) volcanosedimentary strata (part of an alkalic composite volcanic island), (2) a porphyry-style breccia dike, and (3) epithermal-style breccias. The Plio-Pleistocene volcanosedimentary stratigraphy reflects the transition from subaerial deposition of pyroclastic surge deposits close to vent to a subaqueous, quiet depositional environment into which a cryptodome was emplaced. The stratigraphy is predominantly composed of polymictic, matrix-supported breccia and sandstone interbedded with lavas and shallow intrusions. The Minifie strata have a shallow southward dip as a result of Quaternary uplift. Overprinting the volcanosedimentary stratigraphy are three hydrothermally cemented breccia facies—one deposited in the porphyry environment and two deposited in the epithermal environment. Porphyry-style alteration assemblages and a 3- to 5-m-wide biotite-K-feldspar-calcite-anhydrite–cemented breccia dike are focused around the central "Minifie shear" fault. The porphyry alteration assemblages are overprinted by shallow-level and deeper-level epithermal-style features. The deeper-level (below the present mining surface; 〉140 m below sea level) epithermal vein stockwork is composed of quartz-calcite-adularia-anhydrite–cemented breccias and shallowly northward to near-horizontal dipping veins that have gold grades of 1 to 〉60 g/t Au. Shallow-level epithermal facies (adularia-quartz-pyrite–cemented breccias, veins, and associated alteration) host the bulk mineable gold ore, and typically yield 〉4 g/t Au over 12-m blast hole samples.

Description: Suppressor/Enhancer of Lin-12-like (Sel1L) is an adaptor protein for the E3 ligase hydroxymethylglutaryl reductase degradation protein 1 (Hrd1) involved in endoplasmic reticulum-associated degradation (ERAD). Sel1L’s physiological importance in mammalian ERAD, however, remains to be established. Here, using the inducible Sel1L knockout mouse and cell models, we show that Sel1L is...

Description: High-grade serous ovarian cancers (HGSCs) are characterized by a high frequency of TP53 mutations, BRCA1/2 inactivation, homologous recombination dysfunction, and widespread copy number changes. Cyclin E1 (CCNE1) gene amplification has been reported to occur independently of BRCA1/2 mutation, and it is associated with primary treatment failure and reduced patient survival....

Description: The Late Triassic Galore Creek porphyry district is the largest accumulation of Cu-Au prospects in British Columbia, Canada, in terms of contained metal. The principal economic resource is the Central zone deposit. It comprises three high-grade centers: the Au-rich North and South gold lenses and the Cu-dominated Central replacement zone. Alteration footprints, ore shells, and porphyry intrusions in these centers dip 45° to 60° to the west in the North gold lens and southwest in the South gold lens and Central replacement zone, indicative of significant postmineral tilting. This inclination created an oblique vertical expression of the Central zone at surface and at depth, providing a +700-m depth profile through the deposit. Galore Creek is considered to be the end-member of the silica-undersaturated class of alkalic porphyry Cu-Au deposits. It displays a unique hydrothermal alteration footprint, generally devoid of quartz veining. Despite the lack of crosscutting veins, a paragenetic sequence of several discrete potassic and calcic alteration events has been established. During main-stage alteration, two mineralization events occurred that formed the economic resource in the Central zone. Highly oxidizing fluids derived from porphyritic syenite to monzonite intrusions produced initial potassic alteration and sulfide mineralization in the North gold lens and South gold lens. Cu-Au ore shells are characterized by a gold-rich core dominated by bornite associated with hematite-dusted orthoclase, specular hematite, and anhydrite. The second period of hydrothermal activity caused brecciation and calcic alteration in the Central replacement zone. The calcic fluids formed hydrothermal cement grading from Ti-rich andraditic to grossularitic garnet in the core of the breccia to a diopside and magnetite-dominated assemblage at the margins. Calcic alteration also formed in the surrounding host rock. This alteration event was followed by potassic alteration and mineralization, characterized by biotite, anhydrite, and chalcopyrite in the Cu-rich ore shell of the Central replacement zone. Most of the Au is hosted in bornite that is spatially associated with oxidized (reddened) rock units dominated by an alteration assemblage of orthoclase ± hematite ± specular hematite ± garnet ± anhydrite. High-grade Cu in the Central zone is related to abundant chalcopyrite that has commonly replaced an assemblage of biotite ± magnetite ± diopside. This distinct spatial separation strongly suggests that the local redox environment within the wall rocks governed sulfide and gold distributions. The switch from early Au-rich mineralization to late-stage Cu-dominated mineralization appears to have been controlled by varying redox conditions within the magma. The change from more oxidized alteration assemblages (Fe 3+ 〉 Fe 2+ ) to more reduced assemblages (Fe 3+ ≤ Fe 2+ ) is indicative of a change in oxidation potential that may have propelled sulfide saturation in the magma and, thus, the subsequent depletion of most of the Au.

Description: Endeavour 41 is a deep-level, structurally controlled epithermal gold deposit hosted by Early Ordovician subaqueous volcanosedimentary rocks. Calc-alkalic to shoshonitic, mafic to intermediate sills, dikes, and stocks intruded the volcanosedimentary units in the Middle Ordovician. The most felsic intrusions, together with pyroxene-bearing dikes, are temporally related to gold mineralization. Postmineralization intrusions are exclusively of mafic character. Endeavour 41 evolved from early, high-temperature porphyry-style veins and alteration to lower-temperature epithermal-style gold mineralization. Early magnetite and garnet-bearing veins (stage 1 and 2, respectively) associated with actinolite, magnetite, and biotite-bearing alteration assemblages have been cut by gold-bearing veins and associated alteration assemblages. There were two main epithermal-style gold mineralizing events: (1) quartz-pyrite ± calcite ± adularia ± chlorite veins (stage 3) and (2) carbonate-base metal sulfide veins (calcite, ankerite, quartz, pyrite, sphalerite, galena, chalcopyrite, Ag tellurides, arsenopyrite, apatite, hematite, illite-muscovite, and chlorite [stage 4]). Gold occurs principally as a refractory phase in pyrite. It also occurs as grains of Au-Ag tellurides and as inclusions of free gold in pyrite, sphalerite, and chalcopyrite. Hydrothermal alteration associated with gold-mineralized veins produced early epidote and K-feldspar-epidote–bearing alteration halos and later-stage illite-muscovite-K-feldspar and calcite-rich alteration halos. The highest gold grades are associated with muscovite and illite alteration. Stable isotope analyses and fluid inclusion data provide evidence of a magmatic-hydrothermal component to the mineralizing fluids. Fluid inclusion data suggest that gold precipitated from boiling saline waters (~9.0 wt % NaCl) at temperatures of about 310°C. Stage 3 veins are estimated to have formed approximately 1 km below the paleosurface at hydrostatic pressure (~90 bars). Stage 4 illite formed at temperatures below ~280°C. Stage 3 calcite has 13 C calcite and 18 O calcite values that range from –5.2 to –4.6 and from 11.6 to 12.1, respectively. Calculated fluids for these mineral values at 300°C ( 13 C fluid = –3; 18 O fluid = 6) are consistent with a magmatic-hydrothermal source of carbon and oxygen during stage 3. A component of meteoric waters is inferred for stage 4, because 13 C carbonate and 18 O carbonate values range from –6.9 to –0.5 and from 10.9 to 30.1, respectively, corresponding to 13 C fluid and 18 O fluid values of –5 and –2 at 200° to 250°C. The 34 S sulfide values for early vein stages range between –4.9 and –0.5. Stage 3 has 34 S sulfide values ranging from –5.2 to +0.8 with the most 34 S enriched values deposited away from the mineralized center. Stage 4 sulfides have isotopic compositions from –7.5 to +2.5. The negative isotopic values are consistent with oxidized (sulfate-predominant) magmatic-hydrothermal fluids. Sulfur isotopic zonation patterns show that the most negative 34 S values correlate with gold-enriched domains and also with areas that contain high-temperature, porphyry-style alteration facies. The negative sulfur isotope values define zones of upflow for the mineralizing magmatic-hydrothermal fluids. The paragenetic history of Endeavour 41 records a transition from deep-level to shallow-level magmatic-hydrothermal activity. This transition implies erosion and unroofing of the system synchronous with mineralization. High-temperature assemblages (e.g., actinolite-magnetite, biotite, and K-feldspar-epidote) indicate that epithermal mineralization occurred proximal to a magmatic-hydrothermal center and that there is potential for the discovery of porphyry copper-gold mineralization below the current level of diamond drilling.

Description: The macrophage migration inhibitory factor (MIF), an inflammatory cytokine, is overexpressed in many solid tumors and is associated with poor prognosis. We previously identified inhibitors of MIF within a class of natural products with demonstrated anti-cancer activities. We therefore sought to determine how MIF contributes to tumor growth and progression. We show in this study that in murine tumors including the 4T1 model of aggressive, spontaneously metastatic breast cancer in immunologically intact mice, tumor-derived MIF promotes tumor growth and pulmonary metastasis through control of inflammatory cells within the tumor. Specifically, MIF increases the prevalence of a highly immune suppressive subpopulation of myeloid-derived suppressor cells (MDSCs) within the tumor. In vitro, MIF promotes differentiation of myeloid cells into the same population of MDSCs. Pharmacologic inhibition of MIF reduces MDSC accumulation in the tumor similar to MIF depletion and blocks the MIF-dependent in vitro differentiation of MDSCs. Our results demonstrate that MIF is a therapeutically targetable mechanism for control of tumor growth and metastasis through regulation of the host immune response and support the potential utility of MIF inhibitors, either alone or in combination with standard tumor-targeting therapeutic or immunotherapy approaches.

Description: Serotonin (5-HT) plays a key role in early brain development, and manipulation of 5-HT levels during this period can have lasting neurobiological and behavioral consequences. It is unclear how perinatal exposure to drugs, such as selective serotonin reuptake inhibitors (SSRIs), impacts cortical neural network function and what mechanism(s) may elicit the disruption of normal neuronal connections/interactions. In this article, we report on cortical wiring organization after pre- and postnatal exposure to the SSRI citalopram. We show that manipulation of 5-HT during early development in both in vitro and in vivo models disturbs characteristic chemoarchitectural and electrophysiological brain features, including changes in raphe and callosal connections, sensory processing, and myelin sheath formation. Also, drug-exposed rat pups exhibit neophobia and disrupted juvenile play behavior. These findings indicate that 5-HT homeostasis is required for proper brain maturation and that fetal/infant exposure to SSRIs should be examined in humans, particularly those with developmental dysfunction, such as autism.

Description: Diurnal variation in inflammatory and immune function is evident in the physiology and pathology of humans and animals, but molecular mechanisms and mediating cell types that provide this gating remain unknown. By screening cytokine responses in mice to endotoxin challenge at different times of day, we reveal that the magnitude of response exhibited pronounced temporal dependence, yet only within a subset of proinflammatory cytokines. Disruption of the circadian clockwork in macrophages (primary effector cells of the innate immune system) by conditional targeting of a key clock gene (bmal1) removed all temporal gating of endotoxin-induced cytokine response in cultured cells and in vivo. Loss of circadian gating was coincident with suppressed rev-erbα expression, implicating this nuclear receptor as a potential link between the clock and inflammatory pathways. This finding was confirmed in vivo and in vitro through genetic and pharmacological modulation of REV-ERBα activity. Circadian gating of endotoxin response was lost in rev-erbα−/− mice and in cultured macrophages from these animals, despite maintenance of circadian rhythmicity within these cells. Using human macrophages, which show circadian clock gene oscillations and rhythmic endotoxin responses, we demonstrate that administration of a synthetic REV-ERB ligand, or genetic knockdown of rev-erbα expression, is effective at modulating the production and release of the proinflammatory cytokine IL-6. This work demonstrates that the macrophage clockwork provides temporal gating of systemic responses to endotoxin, and identifies REV-ERBα as the key link between the clock and immune function. REV-ERBα may therefore represent a unique therapeutic target in human inflammatory disease.

Description: Author(s): V. M. Acosta, C. Santori, A. Faraon, Z. Huang, K.-M. C. Fu, A. Stacey, D. A. Simpson, K. Ganesan, S. Tomljenovic-Hanic, A. D. Greentree, S. Prawer, and R. G. Beausoleil We report electrical tuning by the Stark effect of the excited-state structure of single nitrogen-vacancy (NV) centers located ≲100  nm from the diamond surface. The zero-phonon line (ZPL) emission frequency is controllably varied over a range of 300 GHz. Using high-resolution emission spectroscopy,... [Phys. Rev. Lett. 108, 206401] Published Mon May 14, 2012