Owing to the prevalence of nitrogen-containing compounds in functional materials, natural products and important pharmaceutical agents, chemists have actively searched for the development of ...efficient and selective methodologies allowing for the facile construction of carbon-nitrogen bonds. While metal-catalyzed C-N cross-coupling reactions have been established as one of the most general protocols for C-N bond formation, these methods require starting materials equipped with functional groups such as (hetero)aryl halides or their equivalents, thus generating stoichiometric amounts of halide salts as byproducts. To address this aspect, a transition-metal-catalyzed direct C-H amination approach has emerged as a step- and atom-economical alternative to the conventional C-N cross-coupling reactions. However, despite the significant recent advances in metal-mediated direct C-H amination reactions, most available procedures need harsh conditions requiring stoichiometric external oxidants. In this context, we were curious to see whether a transition-metal-catalyzed mild C-H amination protocol could be achieved using organic azides as the amino source. We envisaged that a dual role of organic azides as an environmentally benign amino source and also as an internal oxidant via N-N2 bond cleavage would be key to develop efficient C-H amination reactions employing azides. An additional advantage of this approach was anticipated: that a sole byproduct is molecular nitrogen (N2) under the perspective catalytic conditions. This Account mainly describes our research efforts on the development of rhodium- and iridium-catalyzed direct C-H amination reactions with organic azides. Under our initially optimized Rh(III)-catalyzed amination conditions, not only sulfonyl azides but also aryl- and alkyl azides could be utilized as facile amino sources in reaction with various types of C(sp(2))-H bonds bearing such directing groups as pyridine, amide, or ketoxime. More recently, a new catalyst system using Ir(III) species was developed for the direct C-H amidation of arenes and alkenes with acyl azides under exceptionally mild conditions. As a natural extension, amidation of primary C(sp(3))-H bonds could also be realized on the basis of the superior activity of the Cp*Ir(III) catalyst. Mechanistic investigations revealed that a catalytic cycle is operated mainly in three stages: (i) chelation-assisted metallacycle formation via C-H bond cleavage; (ii) C-N bond formation through the in situ generation of a metal-nitrenoid intermediate followed by the insertion of an imido moiety to the metal carbon bond; (iii) product release via protodemetalation with the concomitant catalyst regeneration. In addition, this Account also summarizes the recent advances in the ruthenium- and cobalt-catalyzed amination reactions using organic azides, developed by our own and other groups. Comparative studies on the relative performance of those catalytic systems are briefly described.
Externally stimuli‐triggered spatially and temporally controlled gene delivery can play a pivotal role in achieving targeted gene delivery with maximized therapeutic efficacy. In this study, a ...photothermally controlled gene delivery carrier is developed by conjugating low molecular‐weight branched polyethylenimine (BPEI) and reduced graphene oxide (rGO) via a hydrophilic polyethylene glycol (PEG) spacer. This PEG–BPEI–rGO nanocomposite forms a stable nano‐sized complex with plasmid DNA (pDNA), as confirmed by physicochemical studies. For the in vitro gene transfection study, PEG–BPEI–rGO shows a higher gene transfection efficiency without observable cytotoxicity compared to unmodified controls in PC‐3 and NIH/3T3 cells. Moreover, the PEG–BPEI–rGO nanocomposite demonstrates an enhanced gene transfection efficiency upon NIR irradiation, which is attributed to accelerated endosomal escape of polyplexes augmented by locally induced heat. The endosomal escaping effect of the nanocomposite is investigated using Bafilomycin A1, a proton sponge effect inhibitor. The developed photothermally controlled gene carrier has the potential for spatial and temporal site‐specific gene delivery.
Phototriggered gene transfection is enabled by a novel nano‐sized PEG–BPEI–rGO nanocomposite, developed by conjugating polymers with reduced graphene oxide (rGO) for photothermal gene transfection. This new concept of an NIR‐responsive nanocomposite could provide significant insight to design the gene carriers endowed with controlled and advanced target‐specific gene delivery.
Graphene oxide has unique physiochemical properties, showing great potential in biomedical applications. In the present work, functionalized reduced graphene oxide (PEG-BPEI-rGO) has been developed ...as a nanotemplate for photothermally triggered cytosolic drug delivery by inducing endosomal disruption and subsequent drug release. PEG-BPEI-rGO has the ability to load a greater amount of doxorubicin (DOX) than unreduced PEG-BPEI-GO via π-π and hydrophobic interactions, showing high water stability. Loaded DOX could be efficiently released by glutathione (GSH) and the photothermal effect of irradiated near IR (NIR) in test tubes as well as in cells. Importantly, PEG-BPEI-rGO/DOX complex was found to escape from endosomes after cellular uptake by photothermally induced endosomal disruption and the proton sponge effect, followed by GSH-induced DOX release into the cytosol. Finally, it was concluded that a greater cancer cell death efficacy was observed in PEG-BPEI-rGO/DOX complex-treated cells with NIR irradiation than those with no irradiation. This study demonstrated the development of the potential of a PEG-BPEI-rGO nanocarrier by photothermally triggered cytosolic drug delivery via endosomal disruption.
The halo effect is raters’ undesirable tendency to assign more similar ratings across rating criteria than they should. The impacts of the halo effect on ratings have been studied in rater-mediated ...L2 writing assessment. Little is known, however, about the extent to which rating criteria order in analytic rating scales is associated with the magnitude of the group- and individual-level halo effects. Thus, this study attempts to examine the extent to which the magnitude of the halo effect is associated with rating criteria order in analytic rating scales. To select essays untainted by the effects of rating criteria order, a balanced Latin square design was implemented along with the employment of four expert raters. Next, 11 trained novice Korean raters rated the 30 screened essays with respect to the four rating criteria in three different rating orders: standard-, reverse-, and random-order. A three-facet rating scale model (L2 writer ability, rater severity, criterion difficulty) was fitted to estimate the group- and individual-level halo effects. The overall results of this study showed that the similar magnitude of the group-level halo effect was detected in the standard- and reverse-order rating rubrics while the random presentation of rating criteria decreased the group-level halo effect. A theoretical implication of the study is the necessity of considering rating criteria order as a source of construct-irrelevant easiness or difficulty when developing analytic rating scales.
Abstract
The endoplasmic reticulum (ER)-mitochondria contact site (ERMCS) is crucial for exchanging biological molecules such as phospholipids and Ca
2+
ions between these organelles. Mitoguardin-2 ...(MIGA2), a mitochondrial outer membrane protein, forms the ERMCS in higher eukaryotic cells. Here, we report the crystal structures of the MIGA2 Lipid Droplet (LD) targeting domain and the ER membrane protein VAPB bound to the phosphorylated FFAT motif of MIGA2. These structures reveal that the MIGA2 LD targeting domain has a large internal hydrophobic pocket that accommodates phospholipids and that two phosphorylations of the FFAT motif are required for tight interaction of MIGA2 with VAPB, which enhances the rate of lipid transport. Further biochemical studies show that MIGA2 transports phospholipids between membranes with a strong preference for binding and trafficking phosphatidylserine (PS). These results provide a structural and molecular basis for understanding how MIGA2 mediates the formation of ERMCS and facilitates lipid trafficking at the ERMCS.
Polycarbonate composites reinforced with graphite and functionalized graphene sheets (FGS) were produced using melt compounding. Composite samples with different degrees of graphite orientation were ...processed via injection, compression molding and long-term annealing. Electron microscopy and X-ray scattering revealed that FGS was nearly exfoliated. However, graphite remained multi-layer even after melt processing. Flow induced orientation of graphite was observed from both injection and compression molded samples. Graphite particles in samples after long-term annealing exhibited more random orientation. Composites with the exfoliated FGS required a smaller amount of reinforcement for rigidity and connectivity percolation, as determined by melt rheology and electrical conductivity measurements. FGS also showed better performance in suppressing gas permeability of polycarbonate. However, improvements by FGS dispersion in tensile modulus and dimensional stability were not as significant. This may be due to defects in the sheet structure formed during oxidation and pyrolysis used to exfoliate.
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Accurate identification of active sites is critical for elucidating catalytic reaction mechanisms and developing highly efficient and selective electrocatalysts. Herein, we report the atomic‐level ...identification of active sites using atomically well‐defined gold nanoclusters (Au NCs) Au25, Au38, and Au144 as model catalysts in the electrochemical CO2 reduction reaction (CO2RR). The studied Au NCs exhibited remarkably high CO2RR activity, which increased with increasing NC size. Electrochemical and X‐ray photoelectron spectroscopy analyses revealed that the Au NCs were activated by removing one thiolate group from each staple motif at the beginning of CO2RR. In addition, density functional theory calculations revealed higher charge densities and upshifts of d‐states for dethiolated Au sites. The structure–activity properties of the studied Au NCs confirmed that dethiolated Au sites were the active sites and that CO2RR activity was determined by the number of active sites on the cluster surface.
Active sites for the electroreduction of CO2 to CO were experimentally identified for the first time using atomically well‐defined Au nanoclusters. The partially dethiolated Au site bridging S and Au atoms in the staple motif exhibits higher charge density and upshift of d‐states, which promote the catalytic process by stabilizing the reaction intermediate.
Activation of epithelial-mesenchymal transition (EMT) is thought to be an essential step for cancer metastasis. Tumor cells undergo EMT in response to a diverse range of extra- and intracellular ...stimulants. Recently, it was reported that metabolic shifts control EMT progression and induce tumor aggressiveness. In this review, we summarize the involvement of altered glucose, lipid, and amino acid metabolic enzyme expression and the underlying molecular mechanisms in EMT induction in tumor cells. Moreover, we propose that metabolic regulation through gene-specific or pharmacological inhibition may suppress EMT and this treatment strategy may be applied to prevent tumor progression and improve anti-tumor therapeutic efficacy. This review presents evidence for the importance of metabolic changes in tumor progression and emphasizes the need for further studies to better understand tumor metabolism.
Abstract We present a cationic polymer architecture composed of phenylboronic acid (PBA), sugar-installed polyethylenimine (PEI), and polyethylene glycol (PEG). The chemical bonding of PBA with the ...diol in the sugar enabled the crosslinking of low-molecular-weight (MW) PEI to form high-MW PEI, resulting in strong interaction with anionic DNA for gene delivery. Inside the cell, the binding of PBA and sugar was disrupted by either acidic endosomal pH or intracellular ATP, so gene payloads were released effectively. This dual stimuli-responsive gene release drove the polymer to deliver DNA for high transfection efficiency with low cytotoxicity. In addition, PBA moiety with PEGylation facilitated the binding of polymer/DNA polyplexes to sialylated glycoprotein which is overexpressed on the tumor cell membrane, and thus provided high tumor targeting ability. Therapeutic application of our polymer was demonstrated as an anti-angiogenic gene delivery agent for tumor growth inhibition. Our judicious designed polymer structure based on PBA provides enormous potential as a gene delivery agent for effective gene therapy by stimuli-responsiveness and tumor targeting.
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