Sustained polymeric delivery of gene silencing antisense ODNs, siRNA, DNAzymes and ribozymes: in vitro and in vivo studies

Small interfering RNA (siRNA), antisense oligonucleotides (ODNs), ribozymes and DNAzymes have emerged as sequence-specific inhibitors of gene expression that may have therapeutic potential in the treatment of a wide range of diseases. Due to their rapid degradation in vivo, the efficacy of naked gene silencing nucleic acids is relatively short lived. The entrapment of these nucleic acids within biodegradable sustained-release delivery systems may improve their stability and reduce the doses required for efficacy. In this study, we have evaluated the potential in vitro and in vivo use of biodegradable poly (d,l-lactide-co-glycolide) copolymer (PLGA) microspheres as sustained delivery devices for ODNs, ribozyme, siRNA and DNA enzymes. In addition, we investigated the release of ODN conjugates bearing 5′-end lipophilic groups. The in vitro sustained release profiles of microsphere-entrapped nucleic acids were dependent on variables such as the type of nucleic acid used, the nature of the lipophilic group, and whether the nucleic acid used was single or double stranded. For in vivo studies, whole body autoradiography was used to monitor the bio-distribution of either free tritium-labelled ODN or that entrapped within PLGA microspheres following subcutaneous administration in Balb-c mice. The majority of the radioactivity associated with free ODN was eliminated within 24 h whereas polymer-released ODN persisted in organs and at the site of administration even after seven days post-administration. Polymer microsphere released ODN exhibited a similar tissue and cellular tropism to the free ODN. Micro-autoradiography analyses of the liver and kidneys showed similar bio-distribution for polymer-released and free ODNs with the majority of radioactivity being concentrated in the proximal convoluted tubules of the kidney and in the Kupffer cells of the liver. These findings suggest that biodegradable PLGA microspheres offer a method for improving the in vivo sustained delivery of gene silencing nucleic acids, and hence are worthy of further investigation as delivery systems for these macromolecules.

An introduction to television studies. 3rd edition.

This is a comprehensive textbook for students of Television Studies, now updated for its third edition. The book provides students with a framework for understanding the key concepts and main approaches to Television Studies, including audience research, television history and broadcasting policy, and the analytical study of individual programmes. The book includes a glossary of key terms used in the television industry and in the academic study of television, there are suggestions for further reading at the end of each chapter, and chapters include suggested activities for use in class or as assignments. The case studies in the book include analysis of advertisements, approaches to news reporting, television scheduling, and challenges to television in new contexts of viewing on computers and mobile devices. The topics of individual chapters are: studying television, television histories, television cultures, television texts and narratives, television genres and formats, television production, television quality and value, television realities and representation, television censorship and regulation, television audiences, and the likely future for television.

Projection of global wave climate change towards the end of the 21st century

Wind generated waves at the sea surface are of outstanding importance for both their practical relevance in many aspects, such as coastal erosion, protection, or safety of navigation, and for their scientific relevance in modifying fluxes at the air-sea interface. So far long-term changes in ocean wave climate have been studied mostly from a regional perspective with global dynamical studies emerging only recently. Here a global wave climate study is presented, in which a global wave model (WAM) is driven by atmospheric forcing from a global climate model (ECHAM5) for present day and potential future climate conditions represented by the IPCC (Intergovernmental Panel for Climate Change) A1B emission scenario. It is found that changes in mean and extreme wave climate towards the end of the twenty-first century are small to moderate, with the largest signals being a poleward shift in the annual mean and extreme significant wave heights in the mid-latitudes of both hemispheres, more pronounced in the Southern Hemisphere, and most likely associated with a corresponding shift in mid-latitude storm tracks. These changes are broadly consistent with results from the few studies available so far. The projected changes in the mean wave periods, associated with the changes in the wave climate in the mid to high latitudes, are also shown, revealing a moderate increase in the equatorial eastern side of the ocean basins. This study presents a step forward towards a larger ensemble of global wave climate projections required to better assess robustness and uncertainty of potential future wave climate change.

The end of the opportunism vs trust debate: bounded reliability as a new envelope concept in research on MNE governance

Modern transaction cost economics (TCE) thinking has developed into a key intellectual foundation of international business (IB) research, but the Williamsonian version has faced substantial criticism for adopting the behavioral assumption of opportunism. In this paper we assess both the opportunism concept and existing alternatives such as trust within the context of IB research, especially work on multinational enterprise (MNE) governance. Case analyses of nine global MNEs illustrate an alternative to the opportunism assumption that captures more fully the mechanisms underlying failed commitments inside the MNE. As a substitute for the often-criticized assumption of opportunism, we propose the envelope concept of bounded reliability (BRel), an assumption that represents more accurately and more completely the reasons for failed commitments, without invalidating the other critical assumption in conventional TCE (and internalization theory) thinking, namely the widely accepted envelope concept of bounded rationality (BRat). Bounded reliability as an envelope concept includes two main components, within the context of global MNE management: opportunism as intentional deceit, and benevolent preference reversal. The implications for IB research of adopting the bounded reliability concept are far reaching, as this concept may increase the legitimacy of comparative institutional analysis in the social sciences.

Secondary cyclogenesis along an occluded front leading to damaging wind gusts: windstorm Kyrill, January 2007

Windstorm Kyrill affected large parts of Europe in January 2007 and caused widespread havoc and loss of life. In this study the formation of a secondary cyclone, Kyill II, along the occluded front of the mature cyclone Kyrill and the occurrence of severe wind gusts as Kyrill II passed over Germany are investigated with the help of high-resolution regional climate model simulations. Kyrill underwent an explosive cyclogenesis south of Greenland as the storm crossed polewards of an intense upper-level jet stream. Later in its life cycle secondary cyclogenesis occurred just west of the British Isles. The formation of Kyrill II along the occluded front was associated (a) with frontolytic strain and (b) with strong diabatic heating in combination with a developing upper-level shortwave trough. Sensitivity studies with reduced latent heat release feature a similar development but a weaker secondary cyclone, revealing the importance of diabatic processes during the formation of Kyrill II. Kyrill II moved further towards Europe and its development was favored by a split jet structure aloft, which maintained the cyclone’s exceptionally deep core pressure (below 965 hPa) for at least 36 hours. The occurrence of hurricane force winds related to the strong cold front over North and Central Germany is analyzed using convection-permitting simulations. The lower troposphere exhibits conditional instability, a turbulent flow and evaporative cooling. Simulation at high spatio-temporal resolution suggests that the downward mixing of high momentum (the wind speed at 875 hPa widely exceeded 45 m s-1) accounts for widespread severe surface wind gusts, which is in agreement with observed widespread losses.

Estimating age of mature adults from the degeneration of the sternal end of the clavicle

The sternal end of the clavicle has been illustrated to be useful in aging young adults, however, no studies have investigated what age-related changes occur to the sternal end post epiphyseal fusion. In this study, three morphological features (i.e., surface topography, porosity, and osteophyte formation) were examined and scored using 564 clavicles of individuals of European ancestry (n = 318 males; n = 246 females), with known ages of 40+ years, from four documented skeletal collections: Hamann-Todd, Pretoria, St. Bride's, and Coimbra. An ordinal scoring method was developed for each of the three traits. Surface topography showed the strongest correlation with age, and composite scores (formed by summing the three separate trait scores) indicated progressive degeneration of the surface with increasing chronological age. Linear regression analyses were performed on the trait scores to produce pooled-sample age estimation equations. Blind tests of the composite score method and regression formulae on 56 individuals, aged 40+ years, from Christ Church Spitalfields, suggest accuracies of 96.4% for both methods. These preliminary results display the first evidence of the utility of the sternal end of the clavicle in aging older adult individuals. However, in the current format, these criteria should only be applied to individuals already identified as over 40 years in order to refine the age ranges used for advanced age. These findings do suggest the sternal end of the clavicle has potential to aid age estimates beyond the traditional "mature adult" age category (i.e., 46+ years), and provides several suggestions for future research.

Advances in Discourse Studies

Methods of approaching the study of discourse have developed rapidly in the last ten years, influenced by a growing interdisciplinary spirit among linguistics and anthropology, sociology, cognitive and cultural psychology and cultural studies, as well as among established sub-fields within linguistics itself. Among the more recent developments are an increasing ‘critical’ turn in discourse analysis, a growing interest in historical, ethnographic and corpus-based approaches to discourse, more concern with the social contexts in which discourse occurs, the social actions that it is used to take and the identities that are constructed through it, as well as a revaluation of what counts as ‘discourse’ to include multi-modal texts and interaction. Advances in Discourse Studies brings together contributions from leading scholars in the field, investigating the historical and theoretical relationships between new advances in discourse studies and pointing towards new directions for the future of the discipline. Featuring discussion questions, classroom projects and recommended readings at the end of each section, as well as case studies illustrating each approach discussed, this is an invaluable resource for students of interdisciplinary discourse analysis.