Search

Fluorite of various occurrences could portray the hydrothermal metasomatism occurred in the giant Bayan Obo REE-Nb-Fe ore deposit. Two Mesoproterozoic and Paleozoic hydrothermal events with distinguished fluid origin and geochemical properties have been studied. In Mesoproterozoic, discrete fluorite from the dolomite-dominating REE-Nb ores and banded fluorite aggregates from the banded REE-Nb-Fe ores are extremely enriched in LREE and depleted in HFSE compared with the primitive mantle. In Paleozoic, fluorite from veined-breccia REE-Nb ores varies significantly in trace element components, ranging from LREE-enriched HFSE-depleted fluorite to fluorite with “flat” REE pattern and extremely depletion of Zr. The veined fluorites have variable and higher radiogenic Sr isotopic components (initial 87 Sr/ 86 Sr ratios: 0.703464–0.708208) than the discrete and banded fluorite (0.703183–0.705047), indicating crustal contamination in the Paleozoic hydrothermal fluids from Precambrian basement rocks and Bayan Obo Group. Fluorites of different occurrences and associated bastnäsite and monazite have similar Nd isotopic components and Nd evolution history, which is mostly consistent with whole rock of the ore-hosting dolomite. The Sm-Nd system of some fluorite and bastnäsite were reset during the Paleozoic alteration triggered by the closure of Paleo-Asian Ocean. In such geological setting, according to the δ 34 S of the dominating sulfur-bearing mineral, Paleozoic veined sulfides (∼0 ± 3‰), the prime sulfur source was oceanic crust/MORB. Relatively high δ 34 S of barite (∼13–14‰) was caused by fractionation of sulfur isotopes at an equilibrium temperature of 400–430 °C, rather than contribution from ancient seawater. The trace element, Sr-Nd isotope of fluorite and sulfur isotope characters of sulfides indicate carbonatitic origin of the Mesoproterozoic hydrothermal fluids, while the Paleozoic fluids, derived from subducted Paleo-Asian oceanic crust, carried sulfur components from MORB, scavenged high radiogenic Sr components from Precambrian basement rocks or Bayan Obo group, may leached a deep-seated carbonatite stock and finally altered the Mesoproterozoic mineralized ore-hosting dolomite. Both the Mesoproterozoic and Paleozoic hydrothermal fluids had initial temperature of ∼400–500 °C, and gangue minerals (fluorite, sulfide and sulfate) precipitated at the temperature of ∼320–440 °C. Preliminary thermodynamic calculations of the REE-F-C-Ca system constrained that the pressure of both fluids would not exceed 2 kbar. The drop of temperature and increase of pH are two critical factors to REE mineralization. Paragenesis of Fe-bearing minerals indicates an increase of fO 2 in the Mesoproterozoic hydrothermal fluids and a drop of fS 2 in the Paleozoic fluids in the Fe-O-S system. Furthermore, in the Ca-F-C-O system, the Mesoproterozoic hydrothermal fluids evolved with increasing aCa 2+ and decreasing aF − , while the Paleozoic fluids present characteristic of mixing origin again with significantly variable aCa 2+ and aF − . [ABSTRACT FROM AUTHOR]

[Display omitted] RNA-binding proteins (RBPs) dysfunction has been implicated in a number of diseases, and RBPs have traditionally been considered to be undruggable targets. Here, targeted degradation of RBPs is achieved based on the aptamer-based RNA-PROTAC, which consists of a genetically encoded RNA scaffold and a synthetic heterobifunctional molecule. The target RBPs can bind to their RNA consensus binding element (RCBE) on the RNA scaffold, while the small molecule can recruit E3 ubiquitin ligase to the RNA scaffold in a non-covalent manner, thereby inducing proximity-dependent ubiquitination and subsequent proteasome-mediated degradation of the target protein. Different RBPs targets, including LIN28A and RBFOX1, have been successfully degraded by simply replacing the RCBE module on the RNA scaffold. In addition, the simultaneous degradation of multiple target proteins has been realized by inserting more functional RNA oligonucleotides into the RNA scaffold. [ABSTRACT FROM AUTHOR]

Herein we developed a useful method for the preparation of the desired sulfilimines with readily available sulfonamides as nitrogen sources and iodobenzene as the catalyst. The reaction proceeds via the in-situ produced hypervalent iodine from catalytic simple iodobenzene under electrooxidation conditions. This oxidative coupling strategy can be employed for a wide range of aromatic sulfide and sulfonamide. The obtained sulfilimines could be easily transformed to biologically important N H free sulfoximines in good yields. [Display omitted] Sulfilimines, the aza-analogs of sulfoxides, are valuable building blocks in organic synthesis and serve as important functional groups in medicinal chemistry. Herein we reported an efficient and environmentally friendly method of preparing sulfilimines from readily available thioether and sulfonamide as substrate. The reaction proceeds via the in-situ produced hypervalent iodine from catalytic simple iodobenzene under electrooxidation conditions. A series of sulfilimines were obtained in moderate to good yields. [ABSTRACT FROM AUTHOR]

BRD4-targeted proteolysis targeting chimera (PROTAC) have exhibited promising in vitro and in vivo anticancer activity in a number of cancer models. However, the clinical development of current reported BRD4-PROTACs have stagnated, largely due to the safety risks caused by their poor degradation selectivity. In this study, we designed and synthesized a series of PROTACs based on our recently reported dual BET/PLK1 inhibitor WNY0824 , which led to the discovery of an isoform-selective and potent BRD4-PROTAC 12a (WWL0245). WWL0245 exhibited excellent selective cytotoxicity in the BETi sensitive cancer cell lines, including AR-positive prostate cancer cell lines. It could also efficiently induce ubiquitin-proteasomal degradation of BRD4 in AR-positive prostate cancer cell lines, with sub-nanomolar half-maximal degrading concentration (DC 50) and maximum degradation (D max) > 99%. Moreover, WWL0245 induced cell cycle arrest at the G0/G1 phase and apoptosis in AR-positive prostate cancer by downregulation of the protein levels of AR, PSA and c-Myc as well as transcriptionally suppressed AR-regulated genes. WWL0245 was thus expected to be developed as a promising drug candidate for AR-positive prostate cancer and a valuable tool compound to study the biological function of BRD4. [Display omitted] • A series of PROTACs were designed and synthesized based on the dual BET/PLK1 inhibitor WNY0824. • 12a (WWL0245) is a potent and highly selective BRD4-PROTAC. • 12a exhibited better antiproliferative activity in AR-positive prostate cancer cells than WNY0824. [ABSTRACT FROM AUTHOR]

Abstract: Cells of the human embryonic kidney cell line (HEK 293) were grown as suspended aggregates in stirred vessels and infected with a recombinant adenovirus vector (Ad-TH-GFP). Regular spherical aggregates with the mean diameter less than 300 μm and a viable cell density greater than 5×106 cells·ml−1 were readily achieved after 9 day culture in spinner flasks. The HEK 293 cells growing as suspended aggregates could be efficiently infected by Ad-TH-GFP at an MOI of 10 with a prolonging infection time up to 144 hour post-infection (hpi). The time profile of Ad-TH-GFP production was strongly corresponding to the infection process with a virus concentration peak occurred consistently at 144 h after infection. And the infected aggregates essentially maintained spherical in shape, the portion of dissociated cells from the infected aggregates was less than 5% at 144 hpi. Perfusion culture of HEK 293 cells grown as suspended aggregates in a 7.5 L stirred tank bioreactor and infected with Ad-TH-GFP at a density higher than 1×107 cells·ml−1 resulted in a similar Ad-TH-GFP production kinetics, but a much higher virus yield approximately at 5.7×1011 GTU ml−1 at 144 hpi to that of the infected spinner flask cultures. These results demonstrate the feasibility for using suspended cell aggregates as an immobilization system to facilitate perfusion in stirred tank bioreactors, and improve volumetric productivities by eliminating the cell density effect. [Copyright &y& Elsevier]