Interferon γ expressed by a recombinant respiratory syncytial virus attenuates virus replication in mice without compromising immunogenicity

Interferon γ (IFN-γ) has pleiotropic biological effects, including intrinsic antiviral activity as well as stimulation and regulation of immune responses. An infectious recombinant human respiratory syncytial virus (rRSV/mIFN-γ) was constructed that encodes murine (m) IFN-γ as a separate gene inserted into the G-F intergenic region. Cultured cells infected with rRSV/mIFN-γ secreted 22 μg mIFN-γ per 106 cells. The replication of rRSV/mIFN-γ, but not that of a control chimeric rRSV containing the chloramphenicol acetyl transferase (CAT) gene as an additional gene, was 63- and 20-fold lower than that of wild-type (wt) RSV in the upper and lower respiratory tract, respectively, of mice. Thus, the attenuation of rRSV/mIFN-γ in vivo could be attributed to the activity of mIFN-γ and not to the presence of the additional gene per se. The mice were completely resistant to subsequent challenge with wt RSV. Despite its growth restriction, infection of mice with rRSV/mIFN-γ induced a level of RSV-specific antibodies that, on day 56, was comparable to or greater than that induced by infection with wt RSV. Mice infected with rRSV/mIFN-γ developed a high level of IFN-γ mRNA and an increased amount of interleukin 12 p40 mRNA in their lungs, whereas other cytokine mRNAs tested were unchanged compared with those induced by wt RSV. Because attenuation of RSV typically is accompanied by a reduction in immunogenicity, expression of IFN-γ by an rRSV represents a method of attenuation in which immunogenicity can be maintained rather than be reduced.

Active site mutant transgene confers tolerance to human β-glucuronidase without affecting the phenotype of MPS VII mice

Mucopolysaccharidosis type VII (MPS VII; Sly syndrome) is an autosomal recessive lysosomal storage disorder due to an inherited deficiency of β-glucuronidase. A naturally occurring mouse model for this disease was discovered at The Jackson Laboratory and shown to be due to homozygosity for a 1-bp deletion in exon 10 of the gus gene. The murine model MPS VII (gusmps/mps) has been very well characterized and used extensively to evaluate experimental strategies for lysosomal storage diseases, including bone marrow transplantation, enzyme replacement therapy, and gene therapy. To enhance the value of this model for enzyme and gene therapy, we produced a transgenic mouse expressing the human β-glucuronidase cDNA with an amino acid substitution at the active site nucleophile (E540A) and bred it onto the MPS VII (gusmps/mps) background. We demonstrate here that the mutant mice bearing the active site mutant human transgene retain the clinical, morphological, biochemical, and histopathological characteristics of the original MPS VII (gusmps/mps) mouse. However, they are now tolerant to immune challenge with human β-glucuronidase. This “tolerant MPS VII mouse model” should be useful for preclinical trials evaluating the effectiveness of enzyme and/or gene therapy with the human gene products likely to be administered to human patients with MPS VII.

Introducing more equity in the CAP: a difficult challenge. Egmont Paper #55, June 2012

[From the Introduction]. The main question addressed by this paper is how to reach a more equitable distribution of CAP’s payments pragmatically, politically and economically? Pragmatically, the CAP is a multi-functional policy, which has to combine different goals, i.e. to be more equitable, green and market-oriented. However, these objectives are not always compatible and require trade-offs. Politically, regarding the CAP’s significant share (40%) of the EU budget and the current public debt crisis, Member States are most likely to keep their attention on the juste retour calculations rather than the promotion of the European public interest in the EU negotiations. Economically, reaching a more equitable distribution of payments should be achieved without significant disruptive changes that could have serious consequences on the costs and benefits of the agricultural sector in the EU. Considering these elements, it is already clear that reaching a more equitable distribution of CAP’s payments represents a difficult challenge.

How far do the borders of the west extend? Russian/Polish strategic conflicts in the period 1990-2010. OSW Report, 2010-03-18

From a historical perspective, the last two decades can almost be regarded as a 'golden age' of Polish-Russian relations. This is the first time in several centuries that a sovereign Poland and Russia have been able to develop mutual relations without resorting to force; moreover, they have established a bilateral legal basis and put into practice its provisions on "the inviolability of borders, territorial integrity, non-interference with internal affairs and the nations' right to self-determination. This does not change the fact that since 1990 the atmosphere between the two countries has much more often been chilly and tense. Contrary to the widely-held belief, Polish-Russian conflicts do not stem from genetic Russophobia on the part of Poland, or irrational prejudice on the part of Russia. Their substance is real and concerns strategic issues. At the deepest level, though, this is a dispute about how far the borders of the Western world extend, and about the Russian Federation's sphere of influence. However, it is not a clash between two states; moreover, Poland is certainly not the most important actor in this regard, although due to the historical context and its geographic location, it is one of the countries that lies closest to the 'line of contact', and is therefore particularly entangled in the disagreement.

The growth challenge for Europe and the EMU. CHALLENGE EUROPE Issue 22- Challenges and new beginnings: Priorities for the EU's new leadership, September 2014.

The European economy is slowly and painfully striving to reemerge from the last six years of crisis. It was a crisis of enormous intensity and contagiousness, given the unprecedented depth of global financial integration combined with the systemic flaws in the EMU architecture. And it is not over, as the high levels of unemployment and the growing divergence between Member States testify. The threat of fragmentation is imminent as ever: fragmentation between euro-ins and euro-outs; fragmentation between North and South; fragmentation within societies, with increasing income inequality and a growing number of, what used to be, the middle class population slipping through the social safety net and below poverty lines. Policies of front-loaded fiscal consolidation have left welfare states in economically weaker countries severely underfunded. According to OECD data, the number of people living in households without any income from work has doubled in Greece, Ireland and Spain, and has risen by 20% or more in Estonia, Italy, Latvia, Portugal, and Slovenia. Fertility rates have dropped further since the crisis, deepening the demographic and fiscal challenges of ageing. There are long-term implications from these deteriorating trends, regarding people's long-term health, education and upward mobility from low-income families. It is also highly likely that many of the people unemployed for a long period of time will never again be able to gain proper access to the job market and build a normal career track. The enduring effects of the crisis risk creating vicious cycles of low growth, high debt levels, austerity, declining productivity, and stagnation. These developments carry heavy implications for the future growth prospects of the European economies, for future prosperity, and for the sustainability of pension systems and welfare states. They must be urgently reversed.

What is happening to the Schengen borders? CEPS Liberty and Security in Europe No. 86, December 2015

What is happening to the Schengen borders? Is Schengen in ‘crisis’? This paper examines the state of play in the Schengen system in light of the developments during 2015. It critically examines the assertion that Schengen is ‘in crisis’ and seeks to set the record straight on what has been happening to the intra-Schengen border-free and common external borders system. The paper argues that Schengen is here to stay and that reports about the reintroduction of internal border checks are exaggerated as they are in full compliance with the EU rule of law model laid down in the Schengen Borders Code and subject to scrutiny by the European Commission. It also examines the legal challenges inherent to police checks within the internal border areas as having an equivalent effect to border checks as well as the newly adopted proposal for a European Border and Coast Guard system. The analysis shows that the most far-reaching challenge to the current and future configurations of EU border policies relates to ensuring that they are in full compliance with fundamental human rights obligations to refugees, effective accountability and independent monitoring of the implementation of EU legal standards. This should be accompanied by a transparent and informed discussion on which ‘Schengen’ and which 'common European Border and Coast Guard Agency' we exactly want within current democratic rule of law and fundamental rights remits.

Achieving a high level of smoothness in concrete pavements without sacrificing long-term performance /

"HRDI-11/10-05(2M)E"--P. [4] of cover.

A set of alphabets : of all the various hands of modern use, with examples in each style : also, the mechanical & analytical construction of letters, figures & titles, with designs for titles, ciphers, monograms, borders, compasses, flourishes, etc. ... /

"Entered according to Act of Congress in the year 1870, by Geo. E. Woodward, in the office of the Librarian of Congress."

Transactions of the American Institute of Mining and Metallurgical Engineers.

Consists of transactions of various Branches and Divisions of the Institute.

Minutes of proceedings of the Institution of Civil Engineers.

Vol. for 1844 issued without title.

Challenge for the future : professional schools of engineering /

Includes bibliographical references.

Journal of proceedings of the National Marine Engineers' Beneficial Association of the United States of America : record of the convention.

Some proceedings issued without series title.

Functional memory CD8+ T cells can be generated in vivo without evident T help

Synthetic cytotoxic T cell (CTL) epitope peptides provide an effective and safe means of vaccination against cancers and viruses, as these peptides can induce specific CD8+ effector T cells in vivo. However, the effector CD8+ T cells induced by the minimal CTL epitope peptides do not last past about 3 weeks after the induction and no functional memory CD8+ T cells are generated. It is held that simultaneous induction of CD4+ T cells by incorporating peptides containing T-helper epitopes in the vaccine at the time of primary vaccination are necessary for the induction of long-lived functional memory CD8+ T cells. We now report that, surprisingly, incorporation of medium length (>20 AA) peptides devoid of detectable T-helper epitopes in a minimal CTL epitope-based vaccine can also induce long-lasting! functional rumour antigen specific memory CD8+ T cells that are capable of promoting protection against tumour challenge. This observation may have implications for the formulation of therapeutic anti-cancer and anti-virus peptide vaccines where a strong induction of CD4 T help would be undesirable. (C) 2004 Elsevier Ltd. All rights reserved.

Effect of inspiratory flow on methacholine challenge in children

Regulation of inspiratory flow alters the outcomes of the methacholine (MHC) challenge in adults and cough receptor sensitivity in children. The effect of inspiratory flow on the reproducibility of the MHC challenge in children is unknown. The aim of this study was to evaluate the effect of inspiratory flow alteration on the repeatabilty of the MHC challenge in children with and without asthma. Twenty-five children undertook the MHC challenge on three different days by using a dosimeter connected to a setup that allowed regulation of inspiratory flow and pattern. Children were randomized to commence the challenges at 20 or 60 L/min, and the last challenge was performed at 20 L/min. The within-subject standard deviation, 95% range for change, and doubling dose for the differing inspiratory flow (20 vs. 60 L/min) was more than twice that of when inspiratory flow was maintained at 20 L/min for both occasions. The range of the limits of agreement of the Bland and Altman plot was smaller when inspiratory flow was constant. For short-term comparative individual studies in children, inspiratory flow should be regulated. Laboratories and research measuring change in airway hyperrepsonsiveness to MHC should determine and report reproducibility indices of the challenge so airway hyperresponsiveness changes can be interpreted meaningfully.

Editorial

This special issue of the Journal of the Operational Research Society is dedicated to papers on the related subjects of knowledge management and intellectual capital. These subjects continue to generate considerable interest amongst both practitioners and academics. This issue demonstrates that operational researchers have many contributions to offer to the area, especially by bringing multi-disciplinary, integrated and holistic perspectives. The papers included are both theoretical as well as practical, and include a number of case studies showing how knowledge management has been implemented in practice that may assist other organisations in their search for a better means of managing what is now recognised as a core organisational activity. It has been accepted by a growing number of organisations that the precise handling of information and knowledge is a significant factor in facilitating their success but that there is a challenge in how to implement a strategy and processes for this handling. It is here, in the particular area of knowledge process handling that we can see the contributions of operational researchers most clearly as is illustrated in the papers included in this journal edition. The issue comprises nine papers, contributed by authors based in eight different countries on five continents. Lind and Seigerroth describe an approach that they call team-based reconstruction, intended to help articulate knowledge in a particular organisational. context. They illustrate the use of this approach with three case studies, two in manufacturing and one in public sector health care. Different ways of carrying out reconstruction are analysed, and the benefits of team-based reconstruction are established. Edwards and Kidd, and Connell, Powell and Klein both concentrate on knowledge transfer. Edwards and Kidd discuss the issues involved in transferring knowledge across frontières (borders) of various kinds, from those borders within organisations to those between countries. They present two examples, one in distribution and the other in manufacturing. They conclude that trust and culture both play an important part in facilitating such transfers, that IT should be kept in a supporting role in knowledge management projects, and that a staged approach to this IT support may be the most effective. Connell, Powell and Klein consider the oft-quoted distinction between explicit and tacit knowledge, and argue that such a distinction is sometimes unhelpful. They suggest that knowledge should rather be regarded as a holistic systemic property. The consequences of this for knowledge transfer are examined, with a particular emphasis on what this might mean for the practice of OR Their view of OR in the context of knowledge management very much echoes Lind and Seigerroth's focus on knowledge for human action. This is an interesting convergence of views given that, broadly speaking, one set of authors comes from within the OR community, and the other from outside it. Hafeez and Abdelmeguid present the nearest to a 'hard' OR contribution of the papers in this special issue. In their paper they construct and use system dynamics models to investigate alternative ways in which an organisation might close a knowledge gap or skills gap. The methods they use have the potential to be generalised to any other quantifiable aspects of intellectual capital. The contribution by Revilla, Sarkis and Modrego is also at the 'hard' end of the spectrum. They evaluate the performance of public–private research collaborations in Spain, using an approach based on data envelopment analysis. They found that larger organisations tended to perform relatively better than smaller ones, even though the approach used takes into account scale effects. Perhaps more interesting was that many factors that might have been thought relevant, such as the organisation's existing knowledge base or how widely applicable the results of the project would be, had no significant effect on the performance. It may be that how well the partnership between the collaborators works (not a factor it was possible to take into account in this study) is more important than most other factors. Mak and Ramaprasad introduce the concept of a knowledge supply network. This builds on existing ideas of supply chain management, but also integrates the design chain and the marketing chain, to address all the intellectual property connected with the network as a whole. The authors regard the knowledge supply network as the natural focus for considering knowledge management issues. They propose seven criteria for evaluating knowledge supply network architecture, and illustrate their argument with an example from the electronics industry—integrated circuit design and fabrication. In the paper by Hasan and Crawford, their interest lies in the holistic approach to knowledge management. They demonstrate their argument—that there is no simple IT solution for organisational knowledge management efforts—through two case study investigations. These case studies, in Australian universities, are investigated through cultural historical activity theory, which focuses the study on the activities that are carried out by people in support of their interpretations of their role, the opportunities available and the organisation's purpose. Human activities, it is argued, are mediated by the available tools, including IT and IS and in this particular context, KMS. It is this argument that places the available technology into the knowledge activity process and permits the future design of KMS to be improved through the lessons learnt by studying these knowledge activity systems in practice. Wijnhoven concentrates on knowledge management at the operational level of the organisation. He is concerned with studying the transformation of certain inputs to outputs—the operations function—and the consequent realisation of organisational goals via the management of these operations. He argues that the inputs and outputs of this process in the context of knowledge management are different types of knowledge and names the operation method the knowledge logistics. The method of transformation he calls learning. This theoretical paper discusses the operational management of four types of knowledge objects—explicit understanding; information; skills; and norms and values; and shows how through the proposed framework learning can transfer these objects to clients in a logistical process without a major transformation in content. Millie Kwan continues this theme with a paper about process-oriented knowledge management. In her case study she discusses an implementation of knowledge management where the knowledge is centred around an organisational process and the mission, rationale and objectives of the process define the scope of the project. In her case they are concerned with the effective use of real estate (property and buildings) within a Fortune 100 company. In order to manage the knowledge about this property and the process by which the best 'deal' for internal customers and the overall company was reached, a KMS was devised. She argues that process knowledge is a source of core competence and thus needs to be strategically managed. Finally, you may also wish to read a related paper originally submitted for this Special Issue, 'Customer knowledge management' by Garcia-Murillo and Annabi, which was published in the August 2002 issue of the Journal of the Operational Research Society, 53(8), 875–884.