Small RNA zippers lock miRNA molecules and block miRNA function in mammalian cells.

MicroRNAs (miRNAs) loss-of-function phenotypes are mainly induced by chemically modified antisense oligonucleotides. Here we develop an alternative inhibitor for miRNAs, termed \u27small RNA zipper\u27. It is designed to connect miRNA molecules end to end, forming a DNA-RNA duplex through a complementary interaction with high affinity, high specificity and high stability. Two miRNAs, miR-221 and miR-17, are tested in human breast cancer cell lines, demonstrating the 70∼90% knockdown of miRNA levels by 30-50 nM small RNA zippers. The miR-221 zipper shows capability in rescuing the expression of target genes of miR-221 and reversing the oncogenic function of miR-221 in breast cancer cells. In addition, we demonstrate that the miR-221 zipper attenuates doxorubicin resistance with higher efficiency than anti-miR-221 in human breast cancer cells. Taken together, small RNA zippers are a miRNA inhibitor, which can be used to induce miRNA loss-of-function phenotypes and validate miRNA target genes

Generating Functionals and Lagrangian PDEs

We introduce the concept of Type-I/II generating functionals defined on the space of boundary data of a Lagrangian field theory. On the Lagrangian side, we define an analogue of Jacobi's solution to the Hamilton-Jacobi equation for field theories, and we show that by taking variational derivatives of this functional, we obtain an isotropic submanifold of the space of Cauchy data, described by the so-called multisymplectic form formula. We also define a Hamiltonian analogue of Jacobi's solution, and we show that this functional is a Type-II generating functional. We finish the paper by defining a similar framework of generating functions for discrete field theories, and we show that for the linear wave equation, we recover the multisymplectic conservation law of Bridges.Comment: 31 pages; 1 figure -- v2: minor change

Ticagrelor, but not clopidogrel, reduces arterial thrombosis via endothelial tissue factor suppression

The P2Y12 antagonist ticagrelor reduces mortality in patients with acute coronary syndrome (ACS), compared with clopidogrel, and the mechanisms underlying this effect are not clearly understood. Arterial thrombosis is the key event in ACS; however, direct vascular effects of either ticagrelor or clopidogrel with focus on arterial thrombosis and its key trigger tissue factor have not been previously investigated.Methods and results: Human aortic endothelial cells were treated with ticagrelor or clopidogrel active metabolite (CAM) and stimulated with tumour necrosis factor-alpha (TNF-α); effects on procoagulant tissue factor (TF) expression and activity, its counter-player TF pathway inhibitor (TFPI) and the underlying mechanisms were determined. Further, arterial thrombosis by photochemical injury of the common carotid artery, and TF expression in the murine endothelium were examined in C57BL/6 mice treated with ticagrelor or clopidogrel. Ticagrelor, but not CAM, reduced TNF-α-induced TF expression via proteasomal degradation and TF activity, independently of the P2Y12 receptor and the equilibrative nucleoside transporter 1 (ENT1), an additional target of ticagrelor. In C57BL/6 mice, ticagrelor prolonged time to arterial occlusion, compared with clopidogrel, despite comparable antiplatelet effects. In line with our in vitro results, ticagrelor, but not clopidogrel, reduced TF expression in the endothelium of murine arteries.Conclusion: Ticagrelor, unlike clopidogrel, exhibits endothelial-specific antithrombotic properties and blunts arterial thrombus formation. The additional antithrombotic properties displayed by ticagrelor may explain its greater efficacy in reducing thrombotic events in clinical trials. These findings may provide the basis for new indications for ticagrelor

A review on catalytic oxidation of chloroaromatics from flue gas

Commercial catalysts for the catalytic oxidation of chloroaromatics are mainly based on either noble metals or transition metal oxides supported on a suitable carrier. This paper reviews studies relative to these two generic groups of catalysts and their performances for chloroaromatic decomposition, i.e. conversion efficiency, stability and selectivity towards harmless products (e.g., CO2), and in particular, avoiding the formation of polychlorinated by-products. The various approaches towards improved catalysts, including tuning the support, adding dopants or promoters, improving the preparation methods, or auxiliary means such as the introduction of ozone (O3) or hydrogen peroxide (H2O2) in the gas to be treated, and combination with non-thermal plasma treatment are systematically reviewed. This review also appraises various modes of deactivation (i.e., originating from fouling, coking, poisoning, sintering of the catalyst, and from volatilization of its active phases) as well as possible methods for regeneration

Managing biological invasions in urban environments with the acceptance sampling approach.

Detections of invasive species outbreaks are often followed by the removal of susceptible host organisms in order to slow the spread of the invading pest population. We propose the acceptance sampling approach for detection and optional removal of susceptible host trees to manage an outbreak of the emerald ash borer (EAB), a highly destructive forest pest, in Winnipeg, Canada. We compare the strategy with two common delimiting survey techniques that do not consider follow-up management actions such as host removal. Our results show that the management objective influences the survey strategy. The survey-only strategies maximized the capacity to detect new infestations and prioritized sites with high likelihood of being invaded. Comparatively, the surveys with subsequent host removal actions allocated most of the budget to sites where complete host removal would minimize the pest's ability to spread to uninvaded locations. Uncertainty about the pest's spread causes the host removal measures to cover a larger area in a uniform spatial pattern and extend to farther distances from already infested sites. If a decision maker is ambiguity-averse and strives to avoid the worst-case damages from the invasion, the optimal strategy is to survey more sites with high host densities and remove trees from sites at farther distances, where EAB arrivals may be uncertain, but could cause significant damage if not detected quickly. Accounting for the uncertainty about spread helps develop a more robust pest management strategy. The approach is generalizable and can support management programs for new pest incursions

Mice deficient in the Vici syndrome gene <i>Epg5</i> exhibit features of retinitis pigmentosa

<p>Autophagy helps to maintain cellular homeostasis by removing misfolded proteins and damaged organelles, and generally acts as a cytoprotective mechanism for neuronal survival. Here we showed that mice deficient in the Vici syndrome gene <i>Epg5</i>, which is required for autophagosome maturation, show accumulation of ubiquitin-positive inclusions and SQSTM1 aggregates in various retinal cell types. In <i>epg5</i>^−/− retinas, photoreceptor function is greatly impaired, and degenerative features including progressively reduced numbers of photoreceptor cells and increased numbers of apoptotic cells in the outer nuclear layer are observed, while the morphology of other parts of the retina is not severely affected. Downstream targets of the unfolded protein response (UPR), including the death inducer DDIT3/CHOP, and also levels of cleaved CASP3 (caspase 3), are elevated in <i>epg5</i>^−/− retinas. Thus, apoptotic photoreceptor cell death in <i>epg5</i>^−/− retinas may result from the elevated UPR. Our results reveal that <i>Epg5-</i>deficient mice recapitulate key characteristics of retinitis pigmentosa and thus may provide a valuable model for investigating the molecular mechanism of photoreceptor degeneration.</p