ALBERT

Description: Elucidating the key signal transduction pathways essential for both antipsychotic efficacy and side-effect profiles is essential for developing safer and more effective therapies. Recent work has highlighted noncanonical modes of dopamine D2 receptor (D2R) signaling via β-arrestins as being important for the therapeutic actions of both antipsychotic and antimanic agents. We thus sought to create unique D2R agonists that display signaling bias via β-arrestin–ergic signaling. Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands. These compounds also represent unprecedented β-arrestin–biased ligands for a Gi-coupled G protein–coupled receptor (GPCR). Significantly, UNC9975, UNC0006, and UNC9994 are simultaneously antagonists of Gi-regulated cAMP production and partial agonists for D2R/β-arrestin-2 interactions. Importantly, UNC9975 displayed potent antipsychotic-like activity without inducing motoric side effects in inbred C57BL/6 mice in vivo. Genetic deletion of β-arrestin-2 simultaneously attenuated the antipsychotic actions of UNC9975 and transformed it into a typical antipsychotic drug with a high propensity to induce catalepsy. Similarly, the antipsychotic-like activity displayed by UNC9994, an extremely β-arrestin–biased D2R agonist, in wild-type mice was completely abolished in β-arrestin-2 knockout mice. Taken together, our results suggest that β-arrestin signaling and recruitment can be simultaneously a significant contributor to antipsychotic efficacy and protective against motoric side effects. These functionally selective, β-arrestin–biased D2R ligands represent valuable chemical probes for further investigations of D2R signaling in health and disease.

Description: The Yinachang deposit in the Kangdian Fe-Cu metallogenic province, Southwest China, contains approximately 20 Mt ore @ 41.9 to 44.5 wt % Fe and 15 Mt ore @ 0.85 to 0.97 wt % Cu, with potentially significant REEs. Orebodies are hosted in the late Paleoproterozoic Dongchuan Group, and consist mainly of massive and banded replacement ores. The paragenetic sequence of this deposit includes pre-ore Na-(Fe) alteration (stage I), Fe-(REE) mineralization dominated by magnetite and siderite with subsidiary apatite and fluorite (stage II), and Cu-(REE) mineralization with chalcopyrite, ankerite, biotite, and subordinate apatite, fluorite, allanite, and synchysite (stage III). This sequence is similar to those of many iron oxide copper-gold (IOCG) deposits elsewhere. There are two distinct types of fluid inclusions within apatite of both stages II and III. Type 1 fluid inclusions with liquid and vapor phases have relatively low homogenization temperatures (98°–345°C) and salinities (4.7–16.2 wt % NaCl equiv), whereas type 2 fluid inclusions with one or more solid phases, a liquid phase, and a vapor phase have higher homogenization temperatures (273°–〉500°C) and salinities (36.2–〉59.8 wt % NaCl equiv). Fluids in sulfur isotope equilibrium with chalcopyrite of stages III have 34 S CDT values ranging from –2.8 to +2.7, consistent with a magmatic origin for the sulfur. Thus, sulfur isotopie compositions imply that magmatic-hydrothermal fluids, probably represented by the hot and saline type 2 fluid inclusions, were involved in the ore-forming process, although 34 S close to 0 might also mean that sulfur was leached from igneous rocks by nonmagmatic fluids. Siderite of stage II and ankerite of stage III have 13 C PDB values ranging from –12.4 to –7.5 and from –8.5 to –4.4, respectively. The large variation of 13 C PDB values reveals a strong interaction between the magmatic-hydrothermal fluids and the dolostone in the ore-hosting sequence. Calculated 18 O SMOW values of the fluids in stages II and III are broadly similar, and vary from 11.1 to 17.1 (avg = 13.5). Such values are higher than that of magmatic-hydrothermal fluids and thus, may indicate extensive fluid–wall-rock interaction and/or mixing of magmatic-hydrothermal fluids with shallow-level nonmagmatic fluids. This interpretation is consistent with the radiogenic Sr isotope compositions of bulk ores (( 87 Sr/ 86 Sr) i = 0.710404–0.734034) and fluorite separated from ores (( 87 Sr/ 86 Sr) i = 0.709851–0.723658). These nonmagmatic fluids are probably representative of the type 1 fluid inclusions. Bulk ores and mineral separates have Nd(t) values ranging from –8.1 to +0.4 (mostly –0.9 to +0.4), similar to the coeval mafic intrusions in the region (+2.0 to +2.8). This similarity suggests that REEs in the Yinachang deposit might have been derived dominantly from mantle-derived magmas. On the other hand, relatively low Nd(t) values (–5.5 and –8.1) of some samples indicate insignificant REE contributions from wall rocks. The Yinachang deposit is temporally associated with regional mantle-derived mafic magmatism, and may have a genetic relationship with it. Fluids derived from deep-seated magmas may have supplied abundant sulfur and carbon as well as some of the ore metals in this deposit. The mafic magmatism could also have provided heat to induce the shallow level nonmagmatic fluids to interact with the sedimentary-volcanic sequence, thus leaching additional ore metals into the ore-forming system. Fluid mixing can effectively trigger saturation and deposition of ore minerals. Our work highlights that nonmagmatic fluids are not a prerequisite for Cu-(Au-REE) mineralization, but may facilitate metal deposition in magmatic-hydrothermal IOCG systems.

Description: An Al-20Mg-4Si high Mg containing alloy has been produced and its characteristics investigated. The as-cast alloy revealed primary Mg 2 Si particles evenly distributed throughout an α-Al matrix with a β-Al 3 Mg 2 fully divorced eutectic phase observed in interdendritic regions. The Mg 2 Si particles displayed octahedral, truncated octahedral, and hopper morphologies. Additions of Sb, Ti and Zr had a refining influence reducing the size of the Mg 2 Si from 52 ± 4 μm to 25 ± 0.1 μm, 35 ± 1 μm and 34 ± 1 μm respectively. HPDC tensile test samples could be produced with a 0.6 wt.% Mn addition which prevented die soldering. Solution heating for 1 hr was found to dissolve the majority of the Al 3 Mg 2 eutectic phase with no evidence of any effect on the primary Mg 2 Si. Preliminary results indicate that the heat treatment has a beneficial effect on the elongation and the UTS.

Description: Multiphase solid inclusions within cumulus silicates, particularly olivine, in Fe–Ti oxide ores from the Lower Zone of the Baima intrusion, Emeishan large igneous province, SW China, have been identified for the first time using 2-D scanning electron microscope and 3-D high-resolution X-ray computed tomography. These inclusions are spherical to subspherical and range from 100 to 300 µm in diameter. They are composed dominantly of titanomagnetite and ilmenite with minor apatite, hornblende, phlogopite and pyrrhotite. The titanomagnetite in the inclusions has a low Cr content (〈700 ppm) similar to the interstitial titanomagnetite, suggesting that these inclusions cannot be early crystallized mineral aggregates. In contrast, the spherical shape of these inclusions provides evidence of early trapped liquids from which these minerals crystallized. Based on the composition and modal proportions of the daughter mineral phases within the inclusions, the trapped liquids are estimated to have 82·1–59·6 wt % FeO T , 11·4–18·5 wt % TiO 2 , 2·69–6·12 wt % Al 2 O 3 , 1·40–4·47 wt % MgO, 0·87–4·93 wt % SiO 2 and ~1 wt % volatiles including F, S, Cl, P and H 2 O. Such a liquid composition deviates substantially from that of the slightly evolved ferrobasaltic magmas inferred to be parental to the Fe–Ti–(V) oxide-bearing mafic–ultramafic intrusions of the Emeishan large igneous province. It is thus speculated that these trapped liquids are immiscible Fe–Ti-rich melts formed upon cooling of ferrobasaltic magma. The net-textured and disseminated oxide ores have titanomagnetite compositions similar to those in the inclusions, suggesting that the oxide ores of the Baima intrusion also formed from Fe–Ti-rich melts immiscibly separated from ferrobasaltic magmas. We propose that immiscible Fe–Ti-rich liquids with high density percolated down through crystal-bearing silicate magma and crystallized an interconnected Fe–Ti oxide network interstitial to olivine, plagioclase and clinopyroxene. This study highlights that immiscible separation of Fe–Ti-rich liquids from ferrobasaltic magmas is an important mechanism in the formation of magmatic Fe–Ti–(V) oxide deposits hosted in mafic–ultramafic layered intrusions.

Description: In this paper, a high speed reconfigurable control bits generation algorithm for cyclic shift operations is proposed. The algorithm utilizes the characteristics of routing information when Inverse Butterfly multi level network supports cyclic shift. Moreover, it also integrates a kind of cyclic shift operations together, including cyclic shift and sub-word cyclic shift based on a bit width of 2 i (i = 1, 2, …). Based on this, the shifter is implemented, and the logic synthesis is realized in the SMIC 65nm process. The results show that when the proposed unit only supports cyclic shift operations, enhances the frequency by 3.6% ∼ 8.6% and reduces the area by1.4% ∼ 32%, compared with previously proposed solutions. When achieving a variety of cyclic shift operations, the frequency of our unit enhances the frequency by 5% and reduces the area by 6%.

Description: Both prograde and retrograde skarns from the Tengtie iron deposit, South China, contain rounded, euhedral, and anhedral zircon grains. Rounded grains were originally derived from detritus in carbonate rocks and were incorporated into the skarns. Euhedral and anhedral crystals are intergrown with various skarn minerals and are clearly hydrothermal in origin. These hydrothermal grains have low (Sm/La) N ratios and high La contents relative to typical magmatic ones and display flat LREE and subdued flattening of HREE chondrite-normalized patterns, similar to those of zircon crystallized from Zr-saturated fluids. Prograde skarns also contain baddeleyite rimed by zircon, which record a period of low Si activity during prograde skarnization relative to original magmatic-hydrothermal fluids. Hydrothermal zircon grains from Tengtie have variable Eu anomalies and slightly positive Ce anomalies, indicating that they may have crystallized from highly heterogeneous, but generally reducing fluids. They have low 18 O values (–5.1 to –2.7 ), suggesting the involvement of meteoric fluids. Fluorine-rich fluids played an important role in remobilizing and transporting some high field strength elements (HFSE), including Zr, from the host granites into the skarn system. Reaction between HFSE-bearing fluids and carbonate rocks at the prograde stage decomposed F complexes to deposit HFSE-rich skarn minerals and baddeleyite. At the retrograde stage, alteration of the HFSE-rich skarn minerals released HFSE, including Zr and Sn, consequently producing a mineral assemblage of zircon, cassiterite, and retrograde skarn minerals. Dating results of zircons from the Tengtie skarn system by SIMS indicates roughly less than several million years duration for skarnization. Our study indicates that Zr was not only mobile locally under favorable conditions, but was also readily transported and deposited in different stages of skarnization.

Description: Scattered T DM2 (3.8–3.2 Ga) for 3.28–2.99 Ga zircons from the Proterozoic Delhi Supergroup in northwestern India provide evidence for generation of juvenile crust and reworking of older crust. Depleted mantle-like Hf( t ) values (+7.2 to +5.6) for 2.86–2.71 Ga zircons indicate that generation of juvenile crust occurred during this period and ceased at 2.71 Ga. Extensive magmatism at 2.66–2.34, 2.11–2.01 and 1.60–1.37 Ga was dominated by reworking of pre-existing crust with variable ages, and the last two periods were accompanied by formation of juvenile crust. An Eoarchaean age of 3671 ± 15 Ma represents the oldest age found in NW India. Zircons formed during supercontinent assembly have positive to negative Hf( t ) values, suggesting involvement of juvenile and ancient crust, whereas largely positive Hf( t ) values for zircons crystallized subsequent to supercontinent amalgamation suggest involvement of predominantly juvenile crust. Correlation of detrital age patterns and tectonomagmatic events indicates a conjugate position for northern Indian and the Cathaysia Block of South China during the assembly of Nuna. The South China Block remained juxtaposed to India until its separation from Pangaea in the late Palaeozoic. Supplementary material: Supplementary data, including detailed metadata related to laboratory and sample preparation methods, U-Pb and Lu-Hf isotopic compositions of the analyzed samples and standards are available at https://doi.org/10.6084/m9.figshare.c.3711847

Description: Scattered T DM2 (3.8–3.2 Ga) for 3.28–2.99 Ga zircons from the Proterozoic Delhi Supergroup in northwestern India provide evidence for generation of juvenile crust and reworking of older crust. Depleted mantle-like Hf( t ) values (+7.2 to +5.6) for 2.86–2.71 Ga zircons indicate that generation of juvenile crust occurred during this period and ceased at 2.71 Ga. Extensive magmatism at 2.66–2.34, 2.11–2.01 and 1.60–1.37 Ga was dominated by reworking of pre-existing crust with variable ages, and the last two periods were accompanied by formation of juvenile crust. An Eoarchaean age of 3671 ± 15 Ma represents the oldest age found in NW India. Zircons formed during supercontinent assembly have positive to negative Hf( t ) values, suggesting involvement of juvenile and ancient crust, whereas largely positive Hf( t ) values for zircons crystallized subsequent to supercontinent amalgamation suggest involvement of predominantly juvenile crust. Correlation of detrital age patterns and tectonomagmatic events indicates a conjugate position for northern Indian and the Cathaysia Block of South China during the assembly of Nuna. The South China Block remained juxtaposed to India until its separation from Pangaea in the late Palaeozoic. Supplementary material: Supplementary data, including detailed metadata related to laboratory and sample preparation methods, U-Pb and Lu-Hf isotopic compositions of the analyzed samples and standards are available at https://doi.org/10.6084/m9.figshare.c.3711847