Therapeutic Vaccines and Antibodies for Treatment of Orthopoxvirus Infections

Despite the eradication of smallpox several decades ago, variola and monkeypox viruses still have the potential to become significant threats to public health. The current licensed live vaccinia virus-based smallpox vaccine is extremely effective as a prophylactic vaccine to prevent orthopoxvirus infections, but because of safety issues, it is no longer given as a routine vaccine to the general population. In the event of serious human orthopoxvirus infections, it is important to have treatments available for individual patients as well as their close contacts. The smallpox vaccine and vaccinia immune globulin (VIG) were used in the past as therapeutics for patients exposed to smallpox. VIG was also used in patients who were at high risk of developing complications from smallpox vaccination. Thus post-exposure vaccination and VIG treatments may again become important therapeutic modalities. This paper summarizes some of the historic use of the smallpox vaccine and immunoglobulins in the post-exposure setting in humans and reviews in detail the newer animal studies that address the use of therapeutic vaccines and immunoglobulins in orthopoxvirus infections as well as the development of new therapeutic monoclonal antibodies

Re-examining Phonological and Lexical Correlates of Second Language Comprehensibility:The Role of Rater Experience

Few researchers and teachers would disagree that some linguistic aspects of second language (L2) speech are more crucial than others for successful communication. Underlying this idea is the assumption that communicative success can be broadly defined in terms of speakers’ ability to convey the intended meaning to the interlocutor, which is frequently captured through a listener-based rating of comprehensibility or ease of understanding (e.g. Derwing & Munro, 2009; Levis, 2005). Previous research has shown that communicative success – for example, as defined through comprehensible L2 speech – depends on several linguistic dimensions of L2 output, including its segmental and suprasegmental pronunciation, fluency-based characteristics, lexical and grammatical content, as well as discourse structure (e.g. Field, 2005; Hahn, 2004; Kang et al., 2010; Trofimovich & Isaacs, 2012). Our chief objective in the current study was to explore the L2 comprehensibility construct from a language assessment perspective (e.g. Isaacs & Thomson, 2013), by targeting rater experience as a possible source of variance influencing the degree to which raters use various characteristics of speech in judging L2 comprehensibility. In keeping with this objective, we asked the following question: What is the extent to which linguistic aspects of L2 speech contributing to comprehensibility ratings depend on raters’ experience

Vaccinia Virus Serpin-1 Deletion Mutant Exhibits a Host Range Defect Characterized by Low Levels of Intermediate and Late mRNAs

AbstractOrthopoxviruses encode three serpin homologs—SPI-1, SPI-2 and SPI-3—of which SPI-2 has been well characterized as an inhibitor of ICE-like proteases. A rabbitpox virus SPI-1 deletion mutant exhibited a host range restriction in human lung A549 and pig kidney 15 cell lines that was attributed to apoptosis. Here we report that replication of a vaccinia virus SPI-1 deletion mutant (ΔSPI-1) was restricted in primary human keratinocytes as well as A549 cells. Although chromatin condensation was detected in some A549 cells, other morphological or biochemical signs of apoptosis including DNA fragmentation, cleavage of poly(ADP-ribose)polymerase or nuclear mitotic apparatus protein, or caspase 3 activation were not found. Moreover, ΔSPI-1 protected A549 cells from apoptosis induced by tumor necrosis factor, whereas the corresponding ΔSPI-2 mutant did not. Further studies indicated undiminished amounts of vaccinia virus early mRNA and replicated DNA in the absence of the SPI-1 product. However, there were reduced amounts of viral intermediate and late mRNAs, viral late proteins, cleaved core proteins, and virus particles. These data suggested that apoptosis is not the determining factor in the host range restriction of ΔSPI-1 and that the SPI-1 gene product is needed to allow efficient expression of intermediate and late genes in A549 cells

Functional Analysis of Vaccinia Virus B5R Protein: Role of the Cytoplasmic Tail

AbstractVaccinia extracellular enveloped virus (EEV) is important for cell-to-cell and long-range virus spread bothin vitroandin vivo. Six genes have been identified that encode protein constituents of the EEV outer membrane, and some of these proteins are critical for EEV formation. The B5R gene encodes an EEV-specific type I membrane protein, and deletion of this gene markedly decreases EEV formation and results in a small plaque phenotype. Data suggest that the transmembrane domain, cytoplasmic tail, or both contain the EEV localization signals that are required for targeting of the B5R protein to EEV and for EEV formation. Here, we report the construction of mutant vaccinia viruses in which the wild-type B5R gene was replaced with a mutated one that encodes a protein with the putative cytoplasmic tail deleted. The mutated protein showed normal intracellular distribution and was properly incorporated into EEV. Vaccinia viruses expressing the B5R protein lacking the cytoplasmic tail formed plaques that were similar in type and size to those formed by wild-type viruses and produced equivalent amounts of infectious EEV. These results indicate that the B5R cytoplasmic tail is not necessary for EEV formation and points to the transmembrane domain as the major determinant for targeting the B5R protein to the outer membrane of EEV and for supporting EEV formation

Contemporary political theorists in context

Charting the progression from the preoccupation with the boundaries of the modern state, through to the current debates on rights, identity and justice; the three sections of the book enable the ideas of significant political thinkers to unfold through a telling of the key political events that gave a social context for their thought: Section I: The Inter-War Debate: Weber, Gramsci and Schmitt Section II: Post-War Debates: Arendt, Oakeshott, De Beauvoir and Adorno Section III: Contemporary Debates: Rawls, Nozick, Kymlicka and Foucault Written in an accessible and concise format, features include: 'rewind' and 'fast-forward' indicators to easily guide students around the text discussion points, revision notes and further reading in each chapter informative text boxes to highlight key concepts, people and events. By exploring an often ignored relationship in political thought, the influence of thought upon historical change and the influence of historical change upon theory, this text delivers new and exciting angles from which to approach politics today. Contemporary Political Theorists in Context is essential reading for all students of social and political theory

Culturally Disruptive Research: A Critical (Re)Engagement with Research Processes and Teaching Practices

Purpose As scholars, educators and policymakers recognize the impact of partnership-based research, there is a growing need for more in-depth understanding of how to conduct this work, especially with and in diverse project teams. The purpose of this paper is to provide a critical examination of adopting a culturally disruptive approach in a research–practice partnership (RPP) that includes Indigenous and non-Indigenous researchers, designers and educators who worked together to collaboratively design culturally situated experiences for sixth graders. Design/methodology/approach Following a design-based implementation research methodology, data from design and implementation are presented as two case studies to illustrate key findings. Findings Leveraging the frame of culturally disruptive pedagogy, key tensions, disruptions, self-discoveries and resulting pedagogical innovations are outlined. While the authors experienced multiple forms of disruptions as researchers, designers and educators, they focused on tracing two powerful cases of how culturally disruptive research directly and immediately resulted in pedagogical innovations. Together the cases illustrate a broader shift toward interdependence that the team experienced over the course of the school year. Research limitations/implications A new frame for conducting culturally disruptive research is presented. Both the theoretical application and practical implementation of this frame demonstrate its usefulness in conceptualizing culturally situated research through cultivating an uncomfortable yet generative interdependence. Practical implications Findings include examples and strategies for how to practically conduct multi-sector, interdisciplinary research and teaching. Scholars and educators share their stories which illustrate the practical impact of this work. Originality/value Critical insights presented in this paper build on and contribute to the growing body of work around RPPs, community-based research and other critical partnership methods