Evaluating p97 Inhibitor Analogues for Potency against p97–p37 and p97–Npl4–Ufd1 Complexes

We previously found that the p97 cofactor, p47, significantly decreased the potency of some ATP‐competitive p97 inhibitors such as ML240 [2‐(2‐amino‐1H‐benzo[d]imidazol‐1‐yl)‐N‐benzyl‐8‐methoxyquinazolin‐4‐amine] and ML241 [2‐(2H‐benzo[b][1,4]oxazin‐4(3H)‐yl)‐N‐benzyl‐5,6,7,8 tetrahydroquinazolin‐4‐amine]. In this study, we aimed to evaluate inhibitor potencies against two additional p97 cofactor complexes, p97–p37 and p97–Npl4–Ufd1. We focused on these two cofactor complexes, because the protein sequence of p37 is 50 % identical to that of p47, and the Npl4–Ufd1 heterodimer (NU) is the most‐studied p97 cofactor complex. We screened 200 p97 inhibitor analogues for their ability to inhibit the ATPase activity of p97 alone and of p97–p37 and p97–NU complexes. In contrast to the effect of p47, p37 and NU did not significantly change the potencies of most of the compounds. These results highlight differences among p97 cofactors in influencing p97 conformation and effects of inhibitors on p97 complexes, as compared to p97 alone. Continued efforts are needed to advance the development of complex‐specific p97 inhibitors.     

Optimization strategy for encapsulation efficiency and size of drug loaded silica xerogel/polymer core‐shell composite nanoparticles prepared by gelation‐emulsion method

It has been commonly discovered that reducing particle size always accompanies with undesirable deterioration of drug encapsulation efficiency in double emulsion based techniques. However, a clear optimization strategy for process variables to minimize this negative impact has been rarely reported. To fill this gap, we have successfully developed an optimization strategy for silica xerogel/polymer composite nanoparticles prepared by our recently developed gelation‐emulsion method. To develop this strategy, interactive effects of multiple process variables were investigated through a four‐factor three‐level experimental design by considering all screened dominant process variables influencing particle size and encapsulation efficiency, including sonication time of second emulsion (t₂), sonication power of the second emulsion (P₂), total volume of the second emulsion (V₂) and volume ratio of aqueous phase and primary emulsion (r). The optimization strategy for fabricating the target particle size with optimal encapsulation efficiency was designed by adjusting the process variables in the order of r, V₂, t₂, and P₂ With this strategy, conspicuous enhancement of the encapsulation efficiency (e.g., from 27 to 63% for a particle size of 211 nm) and significant increment of the feasible size range through our novel fabrication method from 192–569 nm to 90–914 nm have been achieved in this study. POLYM. ENG. SCI., 2017. © 2017 Society of Plastics Engineers     

Manifestation of external size reduction effects on the yield point of nanocrystalline rhodium using nanopillars approach

In this study, pure rhodium was fabricated and mechanically investigated at the nanoscale for the first time. The nanopillars approach was employed to study the effects of size on the yield point. Nanopillars with different diameters were fabricated using electroplating followed by uniaxial compression tests. Scanning electron microscopy (SEM) was used as a quality control technique by imaging the pillars before and after compression to ensure the absence of cracks, buckling, barrelling or any other problems. Transmission electron microscopy and SEM were used as microstructural characterization techniques. Due to substrate-induced effects, only the plastic region of the stress–strain curves were investigated, and it was revealed that the yield point increases with size reduction up to certain limit, then decreases with further reduction of the nanopillar size (diameter). The later weakening effect is consistent with the literature, which demonstrates the reversed size effect (the failure of the plasticity theory) in nanocrystalline metals, i.e. smaller is weaker. In this study, however, the effect of size reduction is not only weakening, but is strengthening-then-weakening, which the authors believe is the true behavior of nanocrystalline materials.     

A Finite-Volume-Based Approach for Dynamic Fluid-Structure Interaction

It is common to adopt finite-element methods to solve solid mechanics problems and finite-volume methods for fluid dynamics computations. The use of different methods causes complication of the solution procedure for problems involving both fluids and solids. In this study, a partitioned approach based on the finite-volume method for dynamic fluid–structure interaction is presented. The method is formulated in a way suitable for an unstructured mesh with arbitrary grid geometry. The variables for the fluid are stored at the centroids of grid cells, whereas those for the solid at the grid nodes. The latter arrangement makes it more suitable for large structure deformation. After spatial discretization for the solid using the finite-volume approach, the resulting system of ordinary differential equations is solved implicitly using the dual-time-stepping scheme. As for the fluid calculation, a pressure-based algorithm is employed and the time step is advanced in a prediction-correction manner. The finite-volume method for the solid is assessed by calculating the deformation and dynamics of a cantilever under various loads. Good agreement with analytical solutions is obtained. Then, the solution procedure is applied to two cases with coupled fluid flow and structure dynamics. One is the flow over a vertical plate with one end fixed on the floor in a channel. The other is the flow over a cylinder with a plate attached to it on the lee side.     

Acute toxicity of mercury to Daphnia magna under different conditions

We investigated the variations of acute toxicity of mercury (Hg) in Daphnia magna under different temperatures, population origins, body sizes, and Hg pre-exposures. We measured Hg concentrations in the water and in the surviving daphnids, and used the subcellular fractionation approach to determine Hg in the metal-sensitive fraction (MSF) to predict Hg toxicity. The 24-h median lethal concentrations and 24-h lethal body burden were 12-55 microg L(-1) and 10-26 mg kg(-1) wet wt, respectively. High Hg tolerance accompanied by reduced Hg uptake occurred in the daphnids under extreme conditions (low temperature and high pre-exposure to Hg). Correlating Hg levels in different compartments and daphnid survival resulted in the following order of sequence: aqueous Hg > whole body Hg > Hg in the MSF. However, the threshold lethal concentration of Hg (concentration causing 1% mortality) based on the concentration of Hg in the MSF was the best indicator of Hg toxicity. Therefore, the subcellular fractionation approach is less useful in explaining acute toxicity than is sub-lethal Hg toxicity. The number of Hg binding sites in the animals varied under different conditions but the affinity of the transporter to Hg generally decreased as the animals' tolerance increased. Mercury tolerance under different conditions could be enhanced by reducing the Hg uptake, enhancing the intrinsic tolerance, and/or increasing the detoxification activity.     

Effect of antioxidant in endothelial cells exposed to oxidized low-density lipoproteins

Antioxidants such as probucol and alpha-tocopherol have been shown to attenuate the oxidation of low-density lipoproteins (LDL) and atherosclerotic lesions in animal models of atherosclerosis. The purpose of this study is to determine the protection effect of antioxidants on endothelial cells when exposed to oxidized and native LDL. In a cell-free system, we found that probucol, alpha-tocopherol, and ascorbic acid inhibited copper-induced LDL oxidation by a dose-dependent fashion (from 1 microM to 10 mM). In porcine aortic endothelial cells, antioxidants alone did not change basal endothelin-1 (ET-1) secretion. When porcine aortic endothelial cells were exposed to LDL and oxidized-LDL, both of them stimulated ET-1 secretion dose-dependently, whereas oxidized-LDL elicited higher ET-1 secretion. However, probucol, alpha-tocopherol, and ascorbic acid did not prevent LDL or oxidized-LDL induced ET-1 secretion. Furthermore, nimodipine inhibited both of native and oxidized LDL induced ET-1 secretion. Since Ca2+ channel blocker reduced the elevation of induced ET-1 secretion, the [Ca2+]i is possibly involved for the regulation of ET-1 secretion. Our results suggest that antioxidants can only prevent the oxidation of LDL rather than oxidized and native LDL-induced ET-1 secretion in vascular endothelial cells. The increase in the [Ca2+]i of endothelial cells through the opening of voltage-dependent Ca2+ channels may be involved in the LDL-induced ET-1 release.     

Benign solitary fibrous tumour of the pre-sacral space: MRI findings

Benign solitary fibrous tumour, a rare mesenchymal tumour of adults, usually arises from the pleura. Only a few cases have been reported in the retroperitoneum and, to our knowledge, there has been no report of its imaging features. We describe the MRI features of benign solitary fibrous tumour arising from the pre-sacral space.