compounds were synthesized by solid-state reaction. The samples were characterized by x-ray diffraction measurements and found to have the ZrCuSiAs crystal structure. Electrical resistivity and magnetic susceptibility measurements were performed on all of the samples and specific heat measurements were made on those with Ln = La, Ce, and Yb. All of these compounds exhibit superconductivity in the range 1.9 K -5.4 K, which has not previously been reported for the compounds based on Ce, Pr, and Yb. The YbO 0.5 F 0.5 BiS 2 compounds was also found to exhibit magnetic order at ~2.7 K that apparently coexists with superconductivity below 5.4 K.
We report a strategy to induce superconductivity in the BiS2-based compound LaOBiS2. Instead of substituting F for O, we increase the charge-carrier density (electron dope) via substitution of tetravalent Th +4 , Hf +4 , Zr +4 , and Ti +4 for trivalent La +3 . It is found that both the LaOBiS2 and ThOBiS2 parent compounds are bad metals and that superconductivity is induced by electron doping with Tc values of up to 2.85 K. The superconducting and normal states were characterized by electrical resistivity, magnetic susceptibility, and heat capacity measurements. We also demonstrate that reducing the charge-carrier density (hole doping) via substitution of divalent Sr +2 for La +3 does not induce superconductivity.
A number of marine natural products are potent inhibitors of proteases, an important drug target class in human diseases. Hence, marine cyanobacterial extracts were assessed for inhibitory activity to human cathepsin L. Herein, we have shown that gallinamide A potently and selectively inhibits the human cysteine protease, cathepsin L. With 30 min of preincubation, gallinamide A displayed an IC50 of 5.0 nM, and kinetic analysis demonstrated an inhibition constant of ki = 9000 ± 260 M−1 s−1. Preincubation-dilution and activity-probe experiments revealed an irreversible mode of inhibition, and comparative IC50 values display a 28- to 320- fold greater selectivity toward cathepsin L than closely related human cysteine cathepsins V or B. Molecular docking and molecular dynamics simulations were used to determine the pose of gallinamide in the active site of cathepsin L. These data resulted in the identification of a pose characterized by high stability, a consistent hydrogen bond network, and the reactive Michael acceptor enamide of gallinamide A positioned near the active site cysteine of the protease, leading to a proposed mechanism of covalent inhibition. These data reveal and characterize the novel activity of gallinamide A as a potent inhibitor of human cathepsin L.
We
compare established docking programs, AutoDock Vina and Schrödinger’s
Glide, to the recently published NNScore scoring functions. As expected,
the best protocol to use in a virtual-screening project is highly
dependent on the target receptor being studied. However, the mean
screening performance obtained when candidate ligands are docked with
Vina and rescored with NNScore 1.0 is not statistically different
than the mean performance obtained when docking and scoring with Glide.
We further demonstrate that the Vina and NNScore docking scores both
correlate with chemical properties like small-molecule size and polarizability.
Compensating for these potential biases leads to improvements in virtual
screen performance. Composite NNScore-based scoring functions suited
to a specific receptor further improve performance. We are hopeful
that the current study will prove useful for those interested in computer-aided
drug design.
Bioengineered skin substitutes can facilitate wound closure in severely burned patients, but deficiencies limit their outcomes compared with native skin autografts. To identify gene programs associated with their in vivo capabilities and limitations, we extended previous gene expression profile analyses to now compare engineered skin after in vivo grafting with both in vitro maturation and normal human skin. Cultured skin substitutes were grafted on full-thickness wounds in athymic mice, and biopsy samples for microarray analyses were collected at multiple in vitro and in vivo time points. Over 10,000 transcripts exhibited large-scale expression pattern differences during in vitro and in vivo maturation. Using hierarchical clustering, 11 different expression profile clusters were partitioned on the basis of differential sample type and temporal stage-specific activation or repression. Analyses show that the wound environment exerts a massive influence on gene expression in skin substitutes. For example, in vivo-healed skin substitutes gained the expression of many native skin-expressed genes, including those associated with epidermal barrier and multiple categories of cell-cell and cell-basement membrane adhesion. In contrast, immunological, trichogenic, and endothelial gene programs were largely lacking. These analyses suggest important areas for guiding further improvement of engineered skin for both increased homology with native skin and enhanced wound healing.
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