An unprecedented Pd-catalyzed regioselective activation of gem-difluorinated cyclopropanes induced by C-C bond cleavage is reported. It provides a general and efficient access to a variety of 2-fluoroallylic amines, ethers, esters, and alkylation products in high Z-selectivity, which are important skeletons in many biologically active molecules. In addition, the transformation represents the first general application of gem-difluorinated cyclopropanes as reaction partners in transition-metal-catalyzed cross-coupling reaction.

Itami et al. recently reported the C-O electrophile-controlled chemoselectivity of Ni-catalyzed coupling reactions between azoles and esters: the decarbonylative C-H coupling product was generated with the aryl ester substrates, while C-H/C-O coupling product was generated with the phenol derivative substrates (such as phenyl pivalate). With the aid of DFT calculations (M06L/6-311+G(2d,p)-SDD//B3LYP/6-31G(d)-LANL2DZ), the present study systematically investigated the mechanism of the aforementioned chemoselective reactions. The decarbonylative C-H coupling mechanism involves oxidative addition of C(acyl)-O bond, base-promoted C-H activation of azole, CO migration, and reductive elimination steps (C-H/Decar mechanism). This mechanism is partially different from Itami's previous proposal (Decar/C-H mechanism) because the C-H activation step is unlikely to occur after the CO migration step. Meanwhile, C-H/C-O coupling reaction proceeds through oxidative addition of C(phenyl)-O bond, base-promoted C-H activation, and reductive elimination steps. It was found that the C-O electrophile significantly influences the overall energy demand of the decarbonylative C-H coupling mechanism, because the rate-determining step (i.e., CO migration) is sensitive to the steric effect of the acyl substituent. In contrast, in the C-H/C-O coupling mechanism, the release of the carboxylates occurs before the rate-determining step (i.e., base-promoted C-H activation), and thus the overall energy demand is almost independent of the acyl substituent. Accordingly, the decarbonylative C-H coupling product is favored for less-bulky group substituted C-O electrophiles (such as aryl ester), while C-H/C-O coupling product is predominant for bulky group substituted C-O electrophiles (such as phenyl pivalate).

Background Myopia is a good model for understanding the interaction between genetics and environmental stimuli. Here we dissect the biological processes affecting myopia progression. Methods Human Genetic Analyses: (1) gene set analysis (GSA) of new genome wide association study (GWAS) data for 593 individuals with high myopia (refraction ≤ -6 diopters [D]); (2) over-representation analysis (ORA) of 196 genes with de novo mutations, identified by whole genome sequencing of 45 high-myopia trio families, and (3) ORA of 284 previously reported myopia risk genes. Contributions of the enriched signaling pathways in mediating the genetic and environmental interactions during myopia development were investigated in vivo and in vitro . Results All three genetic analyses showed significant enrichment of four KEGG signaling pathways, including amphetamine addiction, extracellular matrix (ECM) receptor interaction, neuroactive ligand-receptor interaction, and regulation of actin cytoskeleton pathways. In individuals with extremely high myopia (refraction ≤ -10 D), the GSA of GWAS data revealed significant enrichment of the HIF-1α signaling pathway. Using human scleral fibroblasts, silencing the key nodal genes within protein-protein interaction networks for the enriched pathways antagonized the hypoxia-induced increase in myofibroblast transdifferentiation. In mice, scleral HIF-1α downregulation led to hyperopia, whereas upregulation resulted in myopia. In human subjects, near work, a risk factor for myopia, significantly decreased choroidal blood perfusion, which might cause scleral hypoxia. Interpretation Our study implicated the HIF-1α signaling pathway in promoting human myopia through mediating interactions between genetic and environmental factors. Funding National Natural Science Foundation of China grants; Natural Science Foundation of Zhejiang Province.

Long noncoding RNAs (lncRNAs) have been reported to play vital roles in various human cancers. The aim of this study was to explore the critical role of lncRNA HOXA11-AS in uveal melanoma (UM) progression. Briefly, we found that HOXA11-AS is overexpressed in UM tissues and cells; HOXA11-AS could regulate UM cell growth, invasion, and apoptosis. Mechanistically, RNA immunoprecipitation demonstrated that HOXA11-AS could simultaneously interact with enhancer of zeste homolog 2 (EZH2) to suppress its target p21 protein expression. In addition, we demonstrated that HOXA11-AS functioned as a molecular sponge for miR-124, and overexpression of miR-124 attenuated the proliferation and invasion-promoting effect of HOXA11-AS. Collectively, our findings reveal an oncogenic role for HOXA11-AS in UM tumorigenesis.