Downregulation of 26S proteasome catalytic activity promotes epithelial-mesenchymal transition.

The epithelial-mesenchymal transition (EMT) endows carcinoma cells with phenotypic plasticity that can facilitate the formation of cancer stem cells (CSCs) and contribute to the metastatic cascade. While there is substantial support for the role of EMT in driving cancer cell dissemination, less is known about the intracellular molecular mechanisms that govern formation of CSCs via EMT. Here we show that β2 and β5 proteasome subunit activity is downregulated during EMT in immortalized human mammary epithelial cells. Moreover, selective proteasome inhibition enabled mammary epithelial cells to acquire certain morphologic and functional characteristics reminiscent of cancer stem cells, including CD44 expression, self-renewal, and tumor formation. Transcriptomic analyses suggested that proteasome-inhibited cells share gene expression signatures with cells that have undergone EMT, in part, through modulation of the TGF-β signaling pathway. These findings suggest that selective downregulation of proteasome activity in mammary epithelial cells can initiate the EMT program and acquisition of a cancer stem cell-like phenotype. As proteasome inhibitors become increasingly used in cancer treatment, our findings highlight a potential risk of these therapeutic strategies and suggest a possible mechanism by which carcinoma cells may escape from proteasome inhibitor-based therapy

Reductions of docosahexaenoic acid-containing phosphatidylcholine levels in the anterior horn of an ALS mouse model

AbstractIn this study, we analyzed the spatiotemporal alterations of phospholipid composition in the spinal cord of an amyotrophic lateral sclerosis (ALS) mouse model (G93A-mutated human superoxide dismutase 1 transgenic mice [SOD1G93A mice]) using imaging mass spectrometry (IMS), a powerful method to visualize spatial distributions of various types of molecules in situ. Using this technique, we deciphered the phospholipid distribution in the pre-symptomatic stage, early stage after disease onset, and terminal stages of disease in female SOD1G93A mouse spinal cords. These experiments revealed a significant decrease in levels of docosahexaenoic acid (DHA)-containing phosphatidylcholines (PCs), such as PC (diacyl-16:0/22:6), PC (diacyl-18:0/22:6), and PC (diacyl-18:1/22:6) in the L5 anterior horns of terminal stage (22-week-old) SOD1G93A mice. The reduction in PC (diacyl-16:0/22:6) level could be reflecting the loss of motor neurons themselves in the anterior horn of the spinal cord in ALS model mice. In contrast, other PCs, such as PC (diacyl-16:0/16:0), were observed specifically in the L5 dorsal horn gray matter, and their levels did not vary between ALS model mice and controls. Thus, our study showed a significant decrease in DHA-containing PCs, but not other PCs, in the terminal stage of ALS in model mice, which is likely to be a reflection of neuronal loss in the anterior horns of the spinal cords. Given its enrichment in dorsal sensory regions, the preservation of PC (diacyl-16:0/16:0) may be the result of spinal sensory neurons being unaffected in ALS. Taken together, these findings suggest that ALS spinal cords show significant alterations in PC metabolism only at the terminal stage of the disease, and that these changes are confined to specific anatomical regions and cell types

Properties of Nb3Al Wires Processed by Double Rapid Heating and Quenching

AbstractWe have been developing Nb3Al wires processed by rapid heating and quenching for a number of years as promising candidates for use in future high-field accelerator magnets. These wires have better strain and stress tolerances than Nb3Sn wires do, but to meet the demands of future accelerator magnet designs, it is necessary to further improve their performance. In particular,it is necessary to increase their non-copper critical current density in 12-20T fields. To pursue this goal, we introduced double rapid heating and quenching (DRHQ) treatment into the fabrication process for Nb3Al wires, and studied the mechanical and superconducting properties of the resulting DRHQ-processed wires

Residual Strain Dependence on Matrix Structure in RHQ-Nb3Al Wires by Neutron Diffraction Measurement

We prepared three types of non-Cu RHQ-Nb3Al wire samples with different matrix structures: an all-Ta matrix,a composite matrix of Nb and Ta with a Ta inter filament, and an all-Nb matrix. Neutron diffraction patterns of the wire samples were measured at room temperature in J-PARC "TAKUMI". To obtain residual strains of materials, we estimated lattice constant a by multi-peak analysis in the wire. Powder sample of each wire was measured, where the powder was considered to be strain-free. The grain size of all the powder samples was below 0.02 mm. For wire sample with the all-Nb matrix, we also obtained lattice spacing d by a single-peak analysis. Residual strains of Nb3Al filament were estimated from the two analysis results and were compared. Result, residual strains obtained from the multi-peak analysis showed a good accuracy with small standard deviation. The multi-peak analysis results for the residual strains of Nb3Al filament in the three samples were all tensile residual strain in the axial direction, they are 0.12%, 0.12%, and 0.05% for the all-Ta matrix, the composite matrix, and the all-Nb matrix, respectively. Difference in the residual strain of Nb3Al filament between the composite and all-Nb matrix samples indicates that type of inter-filament materials show a great effect on the residual strain. In this paper, we report the method of measurement, method of analysis, and results for residual strain in the tree types of non-Cu RHO-Nb3Al wires.Comment: 7 pages, 8 figure

Health effects of omega-3,6,9 fatty acids: Perilla frutescens is a good example of plant oils

Perilla frutescens seeds are a good source of polyunsaturated fatty acids (PUFAs). The seeds of perilla are small end globular weight about 4 g/1000, contained approximately 35–45% oil. However the leaves are a very poor source of oil, since they contain only 0.2%. In addition, only the seed oil contains the omega 3 fatty acid alpha-linolenic acid (ALA). In comparing to other plant oils, perilla seed oil consistently contains the one of the highest proportion of omega-3 (ALA) fatty acids, at 54–64%. The omega-6 (linoleic acid) component is usually around 14% and omega-9 (Oleic acid) is also present in perilla oil. These polyunsaturated fatty acids are most beneficial to human health and in prevention of different diseases like cardiovascular disorders, cancer, inflammatory, rheumatoid arthritis etc

Long-lived neutral-kaon flux measurement for the KOTO experiment

The KOTO ($K^0$ at Tokai) experiment aims to observe the CP-violating rare decay $K_L \rightarrow \pi^0 \nu \bar{\nu}$ by using a long-lived neutral-kaon beam produced by the 30 GeV proton beam at the Japan Proton Accelerator Research Complex. The $K_L$ flux is an essential parameter for the measurement of the branching fraction. Three $K_L$ neutral decay modes, $K_L \rightarrow 3\pi^0$, $K_L \rightarrow 2\pi^0$, and $K_L \rightarrow 2\gamma$ were used to measure the $K_L$ flux in the beam line in the 2013 KOTO engineering run. A Monte Carlo simulation was used to estimate the detector acceptance for these decays. Agreement was found between the simulation model and the experimental data, and the remaining systematic uncertainty was estimated at the 1.4\% level. The $K_L$ flux was measured as $(4.183 \pm 0.017_{\mathrm{stat.}} \pm 0.059_{\mathrm{sys.}}) \times 10^7$ $K_L$ per $2\times 10^{14}$ protons on a 66-mm-long Au target.Comment: 27 pages, 16 figures. To be appeared in Progress of Theoretical and Experimental Physic