2\u27-O-Methyl at 20-mer Guide Strand 3\u27 Termini May Negatively Affect Target Silencing Activity of Fully Chemically Modified siRNA

Small interfering RNAs (siRNAs) have the potential to treat a broad range of diseases. siRNAs need to be extensively chemically modified to improve their bioavailability, safety, and stability in vivo. However, chemical modifications variably impact target silencing for different siRNA sequences, making the activity of chemically modified siRNA difficult to predict. Here, we systematically evaluated the impact of 3\u27 terminal modifications (2\u27-O-methyl versus 2\u27-fluoro) on guide strands of different length and showed that 3\u27 terminal 2\u27-O-methyl modification negatively impacts activity for \u3e60% of siRNA sequences tested but only in the context of 20- and not 19- or 21-nt-long guide strands. These results indicate that sequence, modification pattern, and structure may cooperatively affect target silencing. Interestingly, the introduction of an extra 2\u27-fluoro modification in the seed region at guide strand position 5, but not 7, may partially compensate for the negative impact of 3\u27 terminal 2\u27-O-methyl modification. Molecular modeling analysis suggests that 2\u27-O-methyl modification may impair guide strand interactions within the PAZ domain of argonaute-2, which may affect target recognition and cleavage, specifically when guide strands are 20-nt long. Our findings emphasize the complex nature of modified RNA-protein interactions and contribute to design principles for chemically modified siRNAs

Effect of physical activity, nutritional education, and consumption of extra virgin olive oil on lipid, physiological and anthropometric profiles in a pediatric population

BACKGROUND. The aim of this study was to determine the effects of nutritional education and vigorous physical activity on health-related parameters. METHODS. The sample group consisted of 134 children from 5 rurally located schools. Participants were divided between 5 different experimental groups: control group (CG), physical activity group (PA), nutritional education group (NE), combined intervention group (PA+NE), and a combined intervention group with additional substitution of normally used oil for extra virgin olive oil (EVOO; PA+NE+EVOO). The intervention consisted of 60 minute sessions of physical activity held twice a week as well as nutritional education sessions held over 6 months. RESULTS. Students in the groups receiving physical activity reduced their fat percentage and increased their muscle mass post intervention. At post-test the lipid profile improved in all intervention groups. The proportion of macronutrients and dietary cholesterol improved in the groups receiving nutritional education. The post-test comparison showed significantly lower fat percentage, sum of skinfolds and waist circumference in NE relative to CG and PA relative to CG. Diastolic blood pressure and glycaemia were significantly lower in PA+NE+EVOO relative to CG. CONCLUSION. A school-based program consisting of nutritional education or nutritional education plus a physical activity program showed a positive effect on health-related parameters in children

Evidence for Secretion of a Netrin-1-like Protein by Tetrahymena thermophila

Netrin-1 is a pleiotropic signaling molecule with targets in many mammalian cell types. Though first characterized as a chemotactic signal involved in neuronal guidance during development, netrin-1 has since been found to have a regulatory role in angiogenesis, and is also used as a biomarker in certain cancers. Tetrahymena thermophila are free-living protists that rely on chemotactic signals to find food, as well as to escape predators. Chemoattractants cause the cells to swim faster in the forward direction, while chemorepellents cause ciliary reversal, resulting in movement of the cell away from the noxious stimulus. We have previously found that netrin-1 is a chemorepellent in T. thermophila. More recently, we have detected netrin-1 by ELISA in both whole cell extract and secreted protein samples obtained from T. thermophila. In addition, we have immunolocalized netrin-1 staining to the cytosol of T. thermophila using an anti-netrin-1 antibody. We are currently running Western blots to determine the molecular weight of this protein and compare it to its vertebrate counterparts. Further experimentation is needed to determine the physiological role of this protein in T. thermophila

More data, more problems: Strategically addressing data ethics and policy issues in LIS curricula and courses

Library and information science (LIS) schools are revising undergraduate and graduate curricula and individual courses to prepare students for data-centric careers, as well as to participate in a data-driven society. To meet these new challenges, programs are developing courses on, among other things, data curation, analytics, visualization, algorithm design, and artificial intelligence. While such changes reflect new workforce and society needs, it remains to be seen whether or not such efforts adequately address the very real and serious ethics and policy issues associated with related data practices (e.g., privacy, bias, fairness, and justice). The Information Ethics SIG and the Information Policy SIG have merged to present a panel on data ethics and policy issues in LIS education. In this session, two recent books on information ethics and information policy will be discussed to bring context to the panel, three papers will be presented, and the audience will have an opportunity to participate in a structured discussion. The papers will address three topics that explore the implications and concerns of living in a data-driven society: collaborative strategies for contributing to the data ethics education landscape, young adult information privacy concerns when using mobile devices, and artificial intelligence and social responsibility. The structured discussion will invite participation on issues raised by the papers, as well as implications for practice in LIS education

Short chain fatty acids: microbial metabolites for gut-brain axis signalling

The role of the intestinal microbiota as a regulator of gut-brain axis signalling has risen to prominence in recent years. Understanding the relationship between the gut microbiota, the metabolites it produces, and the brain will be critical for the subsequent development of new therapeutic approaches, including the identification of novel psychobiotics. A key focus in this regard have been the short-chain fatty acids (SCFAs) produced by bacterial fermentation of dietary fibre, which include butyrate, acetate, and propionate. Ongoing research is focused on the entry of SCFAs into systemic circulation from the gut lumen, their migration to cerebral circulation and across the blood brain barrier, and their potential to exert acute and chronic effects on brain structure and function. This review aims to discuss our current mechanistic understanding of the direct and indirect influence that SCFAs have on brain function, behaviour and physiology, which will inform future microbiota-targeted interventions for brain disorders

Comparative route of administration studies using therapeutic siRNAs show widespread gene modulation in Dorset sheep

siRNAs comprise a class of drugs that can be programmed to silence any target gene. Chemical engineering efforts resulted in development of divalent siRNAs (di-siRNAs), which support robust and long-term efficacy in rodent and nonhuman primate brains upon direct cerebrospinal fluid (CSF) administration. Oligonucleotide distribution in the CNS is nonuniform, limiting clinical applications. The contribution of CSF infusion placement and dosing regimen on relative accumulation, specifically in the context of large animals, is not well characterized. To our knowledge, we report the first systemic, comparative study investigating the effects of 3 routes of administration - intrastriatal (i.s.), i.c.v., and intrathecal catheter to the cisterna magna (ITC) - and 2 dosing regimens - single and repetitive via an implanted reservoir device - on di-siRNA distribution and accumulation in the CNS of Dorset sheep. CSF injections (i.c.v. and ITC) resulted in similar distribution and accumulation across brain regions. Repeated dosing increased homogeneity, with greater relative deep brain accumulation. Conversely, i.s. administration supported region-specific delivery. These results suggest that dosing regimen, not CSF infusion placement, may equalize siRNA accumulation and efficacy throughout the brain. These findings inform the planning and execution of preclinical and clinical studies using siRNA therapeutics in the CNS

LSST Science Book, Version 2.0

A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo