Design, synthesis, conformational analysis and nucleic acid hybridisation properties of thymidyl pyrrolidine-amide oligonucleotide mimics (POM)

Pyrrolidine-amide oligonucleotide mimics (POM) 1 were designed to be stereochemically and conformationally similar to natural nucleic acids, but with an oppositely charged, cationic backbone. Molecular modelling reveals that the lowest energy conformation of a thymidyl-POM monomer is similar to the conformation adopted by ribonucleosides. An e cient solution phase synthesis of the thymidyl POM oligomers has been developed, using both N-alkylation and acylation coupling strategies. 1H NMR spectroscopy con rmed that the highly water soluble thymidyl-dimer, T2-POM, preferentially adopts both a con guration about the pyrrolidine N-atom and an overall conformation in D2O that are very similar to a typical C3 -endo nucleotide in RNA. In addition the nucleic acid hybridisation properties of a thymidyl-pentamer, T5-POM, with an N-terminal phthalimide group were evaluated using both UV spectroscopy and surface plasmon resonance (SPR). It was found that T5-POM exhibits very high a nity for complementary ssDNA and RNA, similar to that of a T5-PNA oligomer. SPR experiments also showed that T5-POM binds with high sequence delity to ssDNA under near physiological conditions. In addition, it was found possible to attenuate the binding a nity of T5-POM to ssDNA and RNA by varying both the ionic strength and pH. However, the most striking feature exhibited by T5-POM is an unprecedented kinetic binding selectivity for ssRNA over DNA

Cyclic-RGD Peptides Increase the Adenoviral Transduction of Human Mesenchymal Stem Cells

Human mesenchymal stem cells (hMSCs) have been extensively explored for drug delivery applications due to their safety, immunomodulatory properties, and ability to differentiate into new tissues. The experiments presented in this study were designed to determine peptide-based mechanisms to increase the adenoviral transduction of hMSCs for the purpose of improving their capacity as drug delivery vehicles. Specifically, we demonstrated that cyclic- RGD peptides increased the internalization of adenoviruses into MSCs. MSCs treated with cyclic-RGD peptides had a transduction efficiency of 76.6%±4%, which was significantly greater than the 23.5%±12.2% transduction efficiency of untreated stem cells (P<0.05). Blocking endocytosis with inhibitors of dynamin or actin polymerization decreased the cyclic-RGD-mediated increase in transduction efficiency. MSCs treated with cyclic-RGD and adenoviruses carrying the gene for bone morphogenetic protein-2 produced significantly greater concentrations of this growth factor compared to stem cells treated with only adenoviruses or adenoviruses cocultured with cyclic-RAD peptides. Furthermore, this stem cell-produced bone morphogenetic protein induced alkaline phosphatase expression in C2C12 cells indicating growth factor bioactivity. Taken together, these studies suggest that cyclic-RGD peptides could be used to increase the adenoviral transduction of hMSCs and increase their therapeutic potential.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140200/1/scd.2012.0379.pd

THE SUPERMARKET INDUSTRY AT THE START OF THE 21st CENTURY: KEY FINDINGS FROM THE 2000 SUPERMARKET PANEL

The 2000 Supermarket Panel gathered data on store characteristics, management practices, and operating performance from a representative, nation-wide sample of supermarkets. The Panel is unique because the unit of analysis is the individual store, and the same stores will be surveyed over time. Linking information on management practices and store and market characteristics with measures for key performance measures provides useful information for both strategic and tactical decisions. Descriptive findings are presented for stores groups by ownership group size and format. Results from a multivariate analysis of relationships between store performance and key performance drivers also are presented.Agribusiness,

External Shear in Quadruply Imaged Lens Systems

We use publicly available N-body simulations and semi-analytic models of galaxy formation to estimate the levels of external shear due to structure near the lens in gravitational lens systems. We also describe two selection effects, specific to four-image systems, that enhance the probability of observing systems to have higher external shear. Ignoring additional contributions from "cosmic shear" and assuming that lens galaxies are not significantly flattened, we find that the mean shear at the position of a quadruple lens galaxy is 0.11, the rms shear is roughly 0.15, and there is roughly a 45% likelihood of external shear greater than 0.1. This is much larger than previous estimates and in good agreement with typical measured external shear. The higher shear primarily stems from the tendency of early-type galaxies, which are the majority of lenses, to reside in overdense regions.Comment: 5 pages, 2 figures, ApJ in press, minor revision

What is on Tap? The Role of Spin in Compact Objects and Relativistic Jets

We examine the role of spin in launching jets from compact objects across the mass scale. Our work includes a total of 37 Seyferts, 11 stellar-mass black holes, and 13 neutron stars. We find that when the Seyfert reflection lines are modeled with Gaussian line features (a crude proxy for inner disk radius and therefore spin), only a slight inverse correlation is found between the Doppler-corrected radio luminosity at 5 GHz (a proxy for jet power) and line width. When the Seyfert reflection features are fit with relativistically-blurred disk reflection models that measure spin, there is a tentative positive correlation between the Doppler-corrected radio luminosity and the spin measurement. Further, when we include stellar-mass black holes in the sample, to examine the effects across the mass scale, we find a slightly stronger correlation with radio luminosity per unit mass and spin, at a marginal significance (2.3 sigma confidence level). Finally, when we include neutron stars, in order to probe lower spin values, we find a positive correlation (3.3 sigma confidence level) between radio luminosity per unit mass and spin. Although tentative, these results suggest that spin may have a role in determining the jet luminosity. In addition, we find a slightly more significant correlation (4.4 sigma confidence level) between radio luminosity per Bolometric luminosity and spin, using our entire sample of black holes and neutrons stars. Again, although tentative, these relations point to the possibility that the mass accretion rate, i.e. Bolometric luminosity, is also important in determining the jet luminosity, in addition to spin. Our analysis suggests that mass accretion rate and disk or coronal magnetic field strength may be the "throttle" in these compact systems, to which the Eddington limit and spin may set the maximum jet luminosity that can be achieved.Comment: 14 pages, 13 Figures, ApJ Accepte

An Evolutionary Framework for Association Testing in Resequencing Studies

Sequencing technologies are becoming cheap enough to apply to large numbers of study participants and promise to provide new insights into human phenotypes by bringing to light rare and previously unknown genetic variants. We develop a new framework for the analysis of sequence data that incorporates all of the major features of previously proposed approaches, including those focused on allele counts and allele burden, but is both more general and more powerful. We harness population genetic theory to provide prior information on effect sizes and to create a pooling strategy for information from rare variants. Our method, EMMPAT (Evolutionary Mixed Model for Pooled Association Testing), generates a single test per gene (substantially reducing multiple testing concerns), facilitates graphical summaries, and improves the interpretation of results by allowing calculation of attributable variance. Simulations show that, relative to previously used approaches, our method increases the power to detect genes that affect phenotype when natural selection has kept alleles with large effect sizes rare. We demonstrate our approach on a population-based re-sequencing study of association between serum triglycerides and variation in ANGPTL4.</p

Life-Cycle Management of Ammunition: Safety, Security, and Sustainability

Ammunition is an essential resource for the implementation of a national defense and security policy. National ammunition stockpiles—regardless of their functional classification—can pose risks to national security and public safety. Poor accounting and inadequate physical security of storage facilities can lead to the diversion of ammunition from the national stockpile to terrorists, criminals, and other armed groups, increasing insecurity and instability. Furthermore, the deterioration of munition components can contribute to unplanned explosions at munitions sites (UEMS), which can have significant negative socioeconomic and political consequences for the public and national governments. Comprehensive ammunition management ensures that the right types and quantities of ammunition are available, at the right time, to support national strategic and operational needs. It is also seen as the only long-term strategy for preventing the excessive accumulation of surplus and for mitigating the safety and security risks inherent to all ammunition stockpiles. Such an approach takes into account the technical aspects of ammunition management that are often covered by stockpile management efforts, as well as the related structural and political dynamics. This results in planning challenges and has significant budgetary implications for governments. A systems-based approach to the life-cycle management of ammunition (LCMA), and a long-term strategy to execute it, can help a state to address these challenges by minimizing the probability of excessive surplus accumulation and mitigating diversion and UEMS risks while meeting national strategic and operational needs