Enterovirus 71 (EV71) poses serious threats to human health, particularly in Southeast Asia, and no drugs or vaccines are available. Previous work identified the stem loop II structure of the EV71 internal ribosomal entry site as vital to viral translation and a potential target. After screening an RNA-biased library using a peptide-displacement assay, we identify DMA-135 as a dose-dependent inhibitor of viral translation and replication with no significant toxicity in cell-based studies. Structural, biophysical, and biochemical characterization support an allosteric mechanism in which DMA-135 induces a conformational change in the RNA structure that stabilizes a ternary complex with the AUF1 protein, thus repressing translation. This mechanism is supported by pull-down experiments in cell culture. These detailed studies establish enterovirus RNA structures as promising drug targets while revealing an approach and mechanism of action that should be broadly applicable to functional RNA targeting.

Binding of B(C6F5)3 to a sulfonate oxygen of (ortho-phosphino-arenesulfonate)PdR catalysts results in a 3–4 fold increase in the rate of chain growth and a larger increase in the rate of chain transfer. The reaction of (PO-Et)PdMe(py) (1a, [PO-Et]− = ortho-{(2-Et-Ph)2P}-para-toluenesulfonate) with 1 equiv of B(C6F5)3 yields the base-free dimer {(PO-Et)PdMe}2 (2a), in which the (PO-Et)PdMe units are linked through an eight-membered [PdSO2]2 ring. The reaction of {(PO-3,5- t Bu2)PdMe}2(TMEDA) (4b; [PO-3,5- t Bu2]− = ortho-{(3,5- t Bu2-Ph)2P}-para-toluenesulfonate, TMEDA = N,N,N′,N′-tetramethylethylenediamine) with BF3·Et2O yields the soluble base-free dimer {(PO-3,5- t Bu2)PdMe}2 (2b), in which the (PO-3,5- t Bu2)PdMe units are linked through a four-membered Pd2O2 ring. 2b reacts with 2 equiv of B(C6F5)3 to yield {[PO·B(C6F5)3-3,5- t Bu2]PdMe}2 (5b, [PO·B(C6F5)3-3,5- t Bu2]− = [2-{(3,5- t Bu2-Ph)2P}-4-Me-C6H3SO2OB(C6F5)3]−), which crystallizes from Et2O as the monomeric complex [PO·B(C6F5)3-3,5- t Bu2]PdMe(Et2O) (6b). In both 5b and 6b, the B(C6F5)3 binds to a sulfonate oxygen. In toluene solution at 60 °C, 2b polymerizes ethylene (80 psi) to linear polyethylene with M n = 3,000, while the B(C6F5)3 adducts 5b and 6b yield ethylene oligomers (M n = 160–170). 5b and 6b are 3–4 times more active than 2b. Similarly, 1a polymerizes ethylene to linear polyethylene with M n = 29,300 (toluene, 80 °C, 435 psi), while 1a-4 B(C6F5)3 yields polymer with M n = 2,520 with a 4 fold increase in activity. 2b reacts with ethylene at 7 °C to form the ethylene adduct (PO-3,5- t Bu2)PdMe(CH2CH2) (7b) followed by multiple insertions to generate (PO-3,5- t Bu2)Pd(CH2CH2) n CH3 species. In contrast, 5b reacts with ethylene to form [PO·B(C6F5)3-3,5- t Bu2]PdMe(CH2CH2) (8b) followed by insertion and β-H transfer to yield propene with subsequent catalytic formation of 1-butene and higher olefins. The rate of ethylene insertion of 8b is 3 times greater than that of 7b, consistent with the batch polymerization results. The polymer yield and molecular weight data show that binding of B(C6F5)3 to 2b and 1a increases the chain transfer rates by a factor of 80 and 42, respectively.

The musculoskeletal system is sensitive to its loading environment; this is of particular concern under conditions such as disuse, paralysis, and extended-duration space flight. Although structural and mechanical changes to tendon and bone following paralysis and disuse are well understood, there is a pressing need to understand how this unloading affects the bone-tendon interface (enthesis); the location most prone to tears and injury. We therefore elucidated these effects of unloading in the entheses of adult mice shoulders that were paralyzed for 21 days by treatment with botulinum toxin A. Unloading significantly increased the extent of mechanical failure and was associated with structural changes across hierarchical scales. At the millimeter scale, unloading caused bone loss. At the micrometer scale, unloading decreased bioapatite crystal size and crystallographic alignment in the enthesis. At the nanometer scale, unloading induced compositional changes that stiffened the bioapatite/collagen composite tissue. Mathematical modeling and mechanical testing indicated that these factors combined to increase local elevations of stress while decreasing the ability of the tissue to absorb energy prior to failure, thereby increasing injury risk. These first observations of the multiscale effects of unloading on the adult enthesis provide new insight into the hierarchical features of structure and composition that endow the enthesis with increased resistance to failure.

Copolymerizations of ethylene with polar monomers such as 5-hexene-1-yl acetate and allyl acetate are explored using nickel complexes bearing a class of anilinonaphthoquinone ligands. High tolerability of this complex toward polar comonomer is achieved by the installation of sterically bulky substituent on the aniline ligand. Moreover, the heterogenization of the nickel complexes using silica-supported modified methylaluminoxane enhances the copolymerization performances. The catalyst is highly active and thermally stabile to give semicrystalline ester-functionalized high molecular weight polyethylenes.

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The practical synthesis of polar-functionalized polyolefins using transition-metal-catalyzed copolymerization of olefins with polar monomers is a challenge; the use of heterogeneous catalysts is little explored. Herein, we report the synthesis of heterogeneous naphthoquinone-based nickel (Ni/ SiO 2 ) and palladium (Pd/SiO 2 ) catalysts through hydrogen bonding interactions of the ligands with the silica surface. Ni/ SiO 2 exhibits high activities (up to 2.65 10 6 g mol À1 h À1 ) during the copolymerization of ethylene with 5-hexene-1-ylacetate, affording high-molecular-weight (M n up to 630 000) polar-functionalized semicrystalline polyethylene (comonomer incorporation up to 2.8 mol %), along with great morphology control. The resulting copolymers possess improved surface properties and great mechanical properties. Pd/SiO 2 can mediate ethylene copolymerization with polar monomers with moderate activity to produce high-molecular-weight copolymers with tunable comonomer incorporation.Scheme 1. Plausible heterogenization approaches for olefin polymerization catalysts.

A series of N-(5,6,7-trihydroquinolinylidene)-2-benzhydrylbenzenamine ligands was synthesized and characterized by (1)H/(13)C NMR and IR spectroscopy, and by elemental analysis. These ligands reacted with NiCl(2) or NiBr(2)(DME) to form the title halide complexes, which were also characterized by IR spectroscopy and elemental analysis. Single crystal X-ray diffraction revealed that the representative nickel complexes crystallized as centro-symmetric dimers with chloro-bridges linking distorted octahedral nickel centers. On activation with either methylaluminoxane (MAO) or diethylaluminium chloride (Et(2)AlCl), all nickel pre-catalysts showed high activities for ethylene polymerization, producing polyethylene with narrow molecular weight distribution, consistent with single-site catalysis. The nature of the ligands and reaction parameters were investigated and discussed in terms of their influence on the catalytic behavior of these nickel pre-catalysts.

A series of phosphine-sulfonate nickel and palladium complexes [(o-R 2 -PC 6 H 4 SO 3 )M(allyl)] (1a, R = Ph, M = Ni; 1b, R = o-MeO-C 6 H 4 , M = Ni; 1c, R = Cy, M = Ni, 2, R = Cy, M = Pd) were synthesized and characterized.