Genetically engineered pre-microRNA-34a prodrug suppresses orthotopic osteosarcoma xenograft tumor growth via the induction of apoptosis and cell cycle arrest.

Osteosarcoma (OS) is the most common primary malignant bone tumor in children, and microRNA-34a (miR-34a) replacement therapy represents a new treatment strategy. This study was to define the effectiveness and safety profiles of a novel bioengineered miR-34a prodrug in orthotopic OS xenograft tumor mouse model. Highly purified pre-miR-34a prodrug significantly inhibited the proliferation of human 143B and MG-63 cells in a dose dependent manner and to much greater degrees than controls, which was attributed to induction of apoptosis and G2 cell cycle arrest. Inhibition of OS cell growth and invasion were associated with release of high levels of mature miR-34a from pre-miR-34a prodrug and consequently reduction of protein levels of many miR-34a target genes including SIRT1, BCL2, c-MET, and CDK6. Furthermore, intravenous administration of in vivo-jetPEI formulated miR-34a prodrug significantly reduced OS tumor growth in orthotopic xenograft mouse models. In addition, mouse blood chemistry profiles indicated that therapeutic doses of bioengineered miR-34a prodrug were well tolerated in these animals. The results demonstrated that bioengineered miR-34a prodrug was effective to control OS tumor growth which involved the induction of apoptosis and cell cycle arrest, supporting the development of bioengineered RNAs as a novel class of large molecule therapeutic agents

A general approach to high-yield biosynthesis of chimeric RNAs bearing various types of functional small RNAs for broad applications.

RNA research and therapy relies primarily on synthetic RNAs. We employed recombinant RNA technology toward large-scale production of pre-miRNA agents in bacteria, but found the majority of target RNAs were not or negligibly expressed. We thus developed a novel strategy to achieve consistent high-yield biosynthesis of chimeric RNAs carrying various small RNAs (e.g. miRNAs, siRNAs and RNA aptamers), which was based upon an optimal noncoding RNA scaffold (OnRS) derived from tRNA fusion pre-miR-34a (tRNA/mir-34a). Multi-milligrams of chimeric RNAs (e.g. OnRS/miR-124, OnRS/GFP-siRNA, OnRS/Neg (scrambled RNA) and OnRS/MGA (malachite green aptamer)) were readily obtained from 1 l bacterial culture. Deep sequencing analyses revealed that mature miR-124 and target GFP-siRNA were selectively released from chimeric RNAs in human cells. Consequently, OnRS/miR-124 was active in suppressing miR-124 target gene expression and controlling cellular processes, and OnRS/GFP-siRNA was effective in knocking down GFP mRNA levels and fluorescent intensity in ES-2/GFP cells and GFP-transgenic mice. Furthermore, the OnRS/MGA sensor offered a specific strong fluorescence upon binding MG, which was utilized as label-free substrate to accurately determine serum RNase activities in pancreatic cancer patients. These results demonstrate that OnRS-based bioengineering is a common, robust and versatile strategy to assemble various types of small RNAs for broad applications

Novel Wavelet Threshold Denoising Method in Axle Press-Fit Zone Ultrasonic Detection

Axles are important part of railway locomotives and vehicles. Periodic ultrasonic inspection of axles can effectively detect and monitor axle fatigue cracks. However, in the axle press-fit zone, the complex interface contact condition reduces the signal-noise ratio (SNR). Therefore, the probability of false positives and false negatives increases. In this work, a novel wavelet threshold function is created to remove noise and suppress press-fit interface echoes in axle ultrasonic defect detection. The exponential threshold function proposed by Andria [1] can\u27t get a gradual curve for later optimum searching process; and the novel wavelet threshold function with two variables is designed to ensure the precision of optimum searching process. Based on the positive correlation between the correlation coefficient and SNR [2] and with the experiment phenomenon that the defect and the press-fit interface echo have different axle-circumferential correlation characteristics, a discrete optimum searching process for two undetermined variables in novel wavelet threshold function is conducted. The performance of the proposed method is assessed by comparing it with traditional threshold methods using real data. The statistic results of the amplitude and the peak SNR of defect echoes show that the proposed wavelet threshold denoising method not only maintains the amplitude of defect echoes but also has a higher peak SNR

Spin-flip reflection at the normal metal-spin superconductor interface

We study spin transport through a normal metal-spin superconductor junction. A spin-flip reflection is demonstrated at the interface, where a spin-up electron incident from the normal metal can be reflected as a spin-down electron and the spin $2\times \hbar/2$ will be injected into the spin superconductor. When the (spin) voltage is smaller than the gap of the spin superconductor, the spin-flip reflection determines the transport properties of the junction. We consider both graphene-based (linear-dispersion-relation) and quadratic-dispersion-relation normal metal-spin superconductor junctions in detail. For the two-dimensional graphene-based junction, the spin-flip reflected electron can be along the specular direction (retro-direction) when the incident and reflected electron locates in the same band (different bands). A perfect spin-flip reflection can occur when the incident electron is normal to the interface, and the reflection coefficient is slightly suppressed for the oblique incident case. As a comparison, for the one-dimensional quadratic-dispersion-relation junction, the spin-flip reflection coefficient can reach 1 at certain incident energies. In addition, both the charge current and the spin current under a charge (spin) voltage are studied. The spin conductance is proportional to the spin-flip reflection coefficient when the spin voltage is less than the gap of the spin superconductor. These results will help us get a better understanding of spin transport through the normal metal-spin superconductor junction.Comment: 11 pages, 9 figure

Ginzburg-Landau-type theory of non-polarized spin superconductivity

Since the concept of spin superconductor was proposed, all the related studies concentrate on spin-polarized case. Here, we generalize the study to spin-non-polarized case. The free energy of non-polarized spin superconductor is obtained, and the Ginzburg-Landau-type equations are derived by using the variational method. These Ginzburg-Landau-type equations can be reduced to the spin-polarized case when the spin direction is fixed. Moreover, the expressions of super linear and angular spin currents inside the superconductor are derived. We demonstrate that the electric field induced by super spin current is equal to the one induced by equivalent charge obtained from the second Ginzburg-Landau-type equation, which shows self-consistency of our theory. By applying these Ginzburg-Landau-type equations, the effect of electric field on the superconductor is also studied. These results will help us get a better understanding of the spin superconductor and the related topics such as Bose-Einstein condensate of magnons and spin superfluidity.Comment: 9 pages, 5 figure