RNA Interference by Single- and Double-stranded siRNA With a DNA Extension Containing a 3′ Nuclease-resistant Mini-hairpin Structure

Selective gene silencing by RNA interference (RNAi) involves double-stranded small interfering RNA (ds siRNA) composed of single-stranded (ss) guide and passenger RNAs. siRNA is recognized and processed by Ago2 and C3PO, endonucleases of the RNA-induced silencing complex (RISC). RISC cleaves passenger RNA, exposing the guide RNA for base-pairing with its homologous mRNA target. Remarkably, the 3' end of passenger RNA can accommodate a DNA extension of 19-nucleotides without loss of RNAi function. This construct is termed passenger-3'-DNA/ds siRNA and includes a 3'-nuclease-resistant mini-hairpin structure. To test this novel modification further, we have now compared the following constructs: (I) guide-3'-DNA/ds siRNA, (II) passenger-3'-DNA/ds siRNA, (III) guide-3'-DNA/ss siRNA, and (IV) passenger-3'-DNA/ss siRNA. The RNAi target was SIRT1, a cancer-specific survival factor. Constructs I-III each induced selective knock-down of SIRT1 mRNA and protein in both noncancer and cancer cells, accompanied by apoptotic cell death in the cancer cells. Construct IV, which lacks the SIRT1 guide strand, had no effect. Importantly, the 3'-DNA mini-hairpin conferred nuclease resistance to constructs I and II. Resistance required the double-stranded RNA structure since single-stranded guide-3'-DNA/ss siRNA (construct III) was susceptible to serum nucleases with associated loss of RNAi activity. The potential applications of 3'-DNA/siRNA constructs are discussed. Molecular Therapy-Nucleic Acids (2014) 2, e141; doi:10.1038/mtna.2013.68; published online 7 January 2014

Real-life effectiveness of once-daily calcipotriol and betamethasone dipropionate gel vs. ointment formulations in psoriasis vulgaris: final analysis of the 52-week PRO-long study

Background: Topical therapies are the mainstay of treatment for psoriasis vulgaris. The fixed combination of calcipotriol (Cal) 50 mu g/g plus betamethasone 0.5 mg/g (as dipropionate; BD) is a first-line topical treatment and available as a gel or ointment. The use of these fixed combination products was compared in PRO-long, a long-term noninterventional study, for which interim results (4 and 12 weeks) have previously been reported. Objective: To describe and compare patients' perspectives on the fixed combination gel and ointment formulations; to include efficacy, adherence behaviour, treatment satisfaction and health-related quality of life (HRQoL) aspects during long-term real-life psoriasis management. Methods: PRO-long was a multicentre, prospective, observational, 52-week study of patients prescribed fixed combination Cal/BD gel or ointment in clinical practice. For final analysis the following were assessed at weeks 24, 36 and 52: differences in the proportion of patients with 'mild'/'very mild' disease according to patient's global assessment of disease severity, adherence behaviour, treatment satisfaction (nine-item treatment satisfaction questionnaire for medication) and HRQoL (Skindex-29). Results: Patients (n = 328) were prescribed once-daily Cal/BD gel (n = 152) or ointment (n = 176). At week 52, a higher proportion of patients reported that the severity of their psoriasis was 'mild'/'very mild' vs. baseline (gel: 60.2 vs. 47.1%; ointment: 58.8 vs. 42.4%), with greater treatment satisfaction reported in patients using gel vs. those using ointment. A higher proportion of patients found the gel 'easy' to use compared with the ointment (66.7 vs. 45.2%). Daily application of treatment took <= 5 min for 86.1% of patients using gel and 71.0% of patients using ointment. Conclusion: This real-life study has demonstrated similar effectiveness between the Cal/BD formulations. However, over a 52-week treatment period, patients reported greater treatment satisfaction with the gel, which was considered easier to use, faster to apply and overall a more convenient product

Toward a theory of music information retrieval queries: System design implications

This paper analyzes a set of 161 music-related information requests posted to the rec.music.country.old-time newsgroup. These postings are categorized by the types of detail used to characterize the poster's information need, the type of music information requested, the intended use for the information, and additional social and contextual elements present in the postings. The results of this analysis suggest that similar studies of 'native' music information requests can be used to inform the design of effective, usable music information retrieval interfaces

MFL homework in Year 9 French: rising to the challenge

The objectives of this article are, first, to describe a collaborative project between teacher educators and a foreign languages (FL) department in a specialist language college and, second, to evaluate its success. The project focuses on Year 9 pupils across the ability range (in four groups) and involves staff in both institutions working together to plan and produce stimulating homework tasks in French, integrated into the spring term scheme of work. Pupils' work and progress were evaluated and their views sought as well as those of participating staff. A classroom-based action research approach was adopted for the project. The article concludes with outcomes, which include recommendations and ideas to increase the effectiveness of FL homework

Measuring the Hidden Aspects of Solar Magnetism

2008 marks the 100th anniversary of the discovery of astrophysical magnetic fields, when George Ellery Hale recorded the Zeeman splitting of spectral lines in sunspots. With the introduction of Babcock's photoelectric magnetograph it soon became clear that the Sun's magnetic field outside sunspots is extremely structured. The field strengths that were measured were found to get larger when the spatial resolution was improved. It was therefore necessary to come up with methods to go beyond the spatial resolution limit and diagnose the intrinsic magnetic-field properties without dependence on the quality of the telescope used. The line-ratio technique that was developed in the early 1970s revealed a picture where most flux that we see in magnetograms originates in highly bundled, kG fields with a tiny volume filling factor. This led to interpretations in terms of discrete, strong-field magnetic flux tubes embedded in a rather field-free medium, and a whole industry of flux tube models at increasing levels of sophistication. This magnetic-field paradigm has now been shattered with the advent of high-precision imaging polarimeters that allow us to apply the so-called "Second Solar Spectrum" to diagnose aspects of solar magnetism that have been hidden to Zeeman diagnostics. It is found that the bulk of the photospheric volume is seething with intermediately strong, tangled fields. In the new paradigm the field behaves like a fractal with a high degree of self-similarity, spanning about 8 orders of magnitude in scale size, down to scales of order 10 m.Comment: To appear in "Magnetic Coupling between the Interior and the Atmosphere of the Sun", eds. S.S. Hasan and R.J. Rutten, Astrophysics and Space Science Proceedings, Springer-Verlag, Heidelberg, Berlin, 200

The impact of MIREX on scholarly research (2005-2010)

This paper explores the impact of the MIREX (Music Information Retrieval Evaluation eXchange) evaluation initiative on scholarly research. Impact is assessed through a bibliometric evaluation of both the MIREX extended abstracts and the papers citing the MIREX results, the trial framework and methodology, or MIREX datasets. Impact is examined through number of publications and citation analysis. We further explore the primary publication venues for MIREX results, the geographic distribution of both MIREX contributors and researchers citing MIREX results, and the spread of MIREX-based research beyond the MIREX contributor teams. This analysis indicates that research in this area is highly collaborative, has achieved an international dissemination, and has grown to have a significant profile in the research literature

Relevance of Abelian Symmetry and Stochasticity in Directed Sandpiles

We provide a comprehensive view on the role of Abelian symmetry and stochasticity in the universality class of directed sandpile models, in context of the underlying spatial correlations of metastable patterns and scars. It is argued that the relevance of Abelian symmetry may depend on whether the dynamic rule is stochastic or deterministic, by means of the interaction of metastable patterns and avalanche flow. Based on the new scaling relations, we conjecture critical exponents for avalanche, which is confirmed reasonably well in large-scale numerical simulations.Comment: 4 pages, 3 figures; published versio

Greenstone as a music digital library toolkit

Greenstone is an open source digital library system that has developed and matured since its inception in 1995. Today it is used in over 60 countries, with a strong emphasis on humanitarian aid. The software is also used as a framework for research in other fields such has human computer interaction, text-mining, and ethnography. This article provides a summary of Greenstone's uses to date with music documents. First we discuss incorporating musical formats into the Greenstone system; then we describe provision for searching and browsing in a music collection

Visual collaging of music in a digital library

This article explores the role visual browsing can play within a digital music library. The context to the work is provided through a review of related techniques drawn from the fields of digital libraries and human computer interaction. Implemented within the open source digital library toolkit Greenstone, a prototype system is described that combines images located through textual metadata with a visualisation technique known as collaging to provide a leisurely, undirected interaction with a music collection. Emphasis in the article is given to the augmentations of the basic technique to work in the musical domain